1344 METOCLOPRAMIDE AND DYSTONIC REACTIONS IN SARDINIANS
SIR,-Dr Lloveras (May 5, p. 581) and Dr Caralps (March 10, p. 544) discuss dystonic reactions in patients with severe chronic renal failure who were taking metoclopramide. Dystonic reactions are unusually frequent in Sardinians, as we have found.’I In less than 9 months, we have seen in the emergency unit of the department of neurology 94 patients (42 males, 52 females) with dystonic reactions to neuroleptics. The mean age was 17-5 (82 years), younger patients being more susceptible to these reactions. The dystonia varied from simple crisis to multiple muscle involvement. None of these crises proceeded to severe dyspnoea. All patients recovered completely, on average in 9 min, after apomorphine 5-10 mg intramuscularly.2 Metoclopramide was responsible for 38% of these reactions; other neuroleptics, such as perphenazine, haloperidol, and trifluoperidol, were implicated less often. Metoclopramide had been taken orally in doses of 20-30 mg a day for a mean of 2.5days. In Italy, a high frequency of extrapyramidal reactions is confined to the island of Sardinia, whose population is especially homogeneous and where certain inherited conditions are
unusually
common
areas when he used a condom. A rash appeared which was controlled by hydrocortisone butyrate ointment. The rashed flared the morning after each episode of intercourse, and it was more extensive and irritating if intercourse took place in the week after the menses. The rash and symptoms responded to topical ’Trimovate’ (clobetasone butyrate, nystatin and oxytetracycline) cream. He recorded symptoms in relation to timing of intercourse and his wife’s menstrual cycle. The cycle was 6/18-25, with heavy loss, no pain, and no intermenstrual bleeding. It became apparent that the reactions were worse in the early part of the cycle, and that in the premenstrual week they were much milder, when intercourse could be followed by neither rash nor need for treatment. Symptoms increased when the dose of penicillamine was increased, but control was possible with twice daily application of trimovate cream. Although it is not possible to prove the case, cross-reactions
adjoining not
between penicillamine and penicillin have been reported, and it is likely that this is the explanation. I have not previously seen a contact reaction due to a drug or its metabolite in the vaginal secretions. Worcester Royal Infirmary, Castle Street Branch, Worcester WR1 3AS
P. C. H. NEWBOLD
(e.g., glucose-6-phosphate dehydro-
genase deficiency). No similar incidence in other regions of Italy has been reported, and isolated cases described from time to time in other hospitals have been in people from Sardinia. It therefore seems that genetic factors are involved in the development of dystonic reactions to metoclopramide. These factors cannot be related to the pharmacokinetics of the drug because the predisposition relates to all neuroleptics, phenotiazines or butyrophenones. Metoclopramide has neuroleptic properties in animals,3 and dopamine-receptor blockade is the common feature shared by these drugs. Genetic differences in the sensitivity of dopamine receptors may be the predisposing condition for dystonic reactions. This does not exclude a role for abnormal plasma levels of metoclopramide, as in patients with renal failure, in the development of extrapyramidal sideeffects. This problem may have a more general relevance to the use of neuroleptic drugs in patients with chronic renal failure -sulpiride, for example, though less likely, in our experience, to produce dystonic reactions, must be used with caution in patients with renal impairment. G. U. CORSINI Institute of Pharmacology, F. MARROSU University of Cagliari, 09100 Caghari, Italy G. L. GESSA
CONTACT REACTION TO PENICILLAMINE IN VAGINAL SECRETIONS
SIR,- The following case apparently represents a contact to penicillamine or a metabolite in vaginal secretions.
reaction
In 1948 the patient, a man then aged 25, had a leg ulcer which was treated with penicillin ointment. After ten days he had itching around the eyes; next day his face swelled up and he had itching all over. Penicillin sensitivity was diagnosed and the ointment stopped. He had a flare in 1956 after drinking milk from a cow which had had treatment for mastitis. He had another flare in 1975: when coaxing a daughter to take her penicillin mixture he took a spoonful himself. In March, 1976, he had perianal itching which was treated with ’Nystaform-HC’ (nystatin clioquinol and hydrocortisone) by his own practitioner. His symptoms worsened and he was given a clioquinol and hydrocortisone topical preparation (’Vioform-HC’), after which exfoliation had to be controlled by systemic steroids as an inpatient. Subsequent patch tests confirmed sensitivity to clioquinol. His wife had rheumatoid arthritis and she was started on penicillamine in January, 1978. A week later, after intercourse, irritation developed over his penis; it was localised to the base of the penis and
Corsini, G. U., Marrosu, F., Del Zompo, M., Mangoni, A., Gessa, G. L. VI Wrld Congr. Psychiat. (Honolulu, 1977.); abstr. 917. 2. Gessa R., Tagliamonte A., Gessa G.L. Lancet, 1972, ii, 981. 3. Mangoni A., Corsini G.,U., Piccardi, M.P., Gessa, G.L. Neuropharmaco-
GYNÆCOMASTIA AND DIAZEPAM ABUSE
SiR,—Gynaecomastia is a well-known side-effect of psychopharmacological drugs, including reserpine, phenothiazines, meprobamate, hydroxyzine, and sulpiride. Diazepam and chlordiazepoxide are thought to be mammotropic when given in high doses to rats.l,2 Lactation due to chlordiazepoxide has been described,3 but we know of no reports of gyn2ecomastia during diazepam abuse. A 55-year-old previously healthy taxi-driver was recommended to take 10-30 mg diazepam daily for non-specific nervous symptoms in November, 1976. During the spring of 1977 the man began to abuse diazepam, with daily intakes of up to 100 mg. During hospital admission June, 1977, withdrawal symptoms developed, treated with barbiturates. After his discharge, diazepam abuse quickly recurred with daily doses of 80-140 mg. During this period bilateral gynaecomastia developed. At readmission September, 1977, the gland masses were tender and enlarged, but no secretion was noticed. The patient of athletic type, with normal hair distribution and without testicular atrophy. Over the next 4 months neither diazepam nor N-desmethyldiazepam could be detected in blood-samples, and during this period the gynscomastia steadily resolved; the clinical changes had gone by June, 1978. In September, 1977, there had been no abnormal changes in liver or thyroid function tests, and testosterone, luteinising hormone, and follicular hormone levels were normal. Urine 17-ketosteroids, chorionic gonadotrophins, and oestrogen concentrations were also normal. Chromosome analyses and X-ray of chest and sella turcica were normal. The human prolactin serum concentration was non-specifically increased. To elucidate the influence of diazepam on serum-prolactin, the patient was given diazepam again in November, 1978, with his informed consent. A single dose of 20 mg diazepam was given orally at 8 A.M. and blood-samples were taken every 4 h for 24 h. A week later blood-samples were drawn at the same times after placebo. There were no significant changes in the serum-prolactin between the two series of samples, both sets of values being normal. The relation in time betwen the peak in the diazepam abuse and the development of gynsecomastia, and the resolution of gynaecomastia and tenderness shortly after diazepam abuse stopped, strongly indicate that diazepam was the causal factor. was
1.
logy, 1975, 14, 333.
1. Khazan, N., Primo, C., Danon, A., Assael, M., Sulman, F. Z. Archs. int. Pharmacodyn. 1962, 141, 291. 2. Superstine, E., Sulman, F. G. ibid. 1966, 160, 133. 3. Lampe, W. T. Metabolism, 1967, 16, 257.
G., Winnik, H.
1345
Investigations revealed no other abnormalities in this patient. drugs had been given before the gynscomastia appeared. Alcohol consumption was steady during and after the gynxcomastia (1 or 2 bottles of beer a day). On one interpretation of the relation between diazepam and G.A.B.A.-ergic transmission,4 a high-dose diazepam mammotropic effect without changes in serum-prolactin could be explained by a release of G.A.B.A. (-aminobutyric acid) mediated prolactin-inhibitory factor from the adenohypoNo other
Twelve women, admitted for infertility surgery, were given 16 mg dexamethasone (’Decadron’) intramuscularly on the evening before the operation and 64 mg (4x 16 mg) during the operation day and the first postoperative day. From the second postoperative day onwards 3 mg dexamethasone was given orally for 6 days. Eleven infertile patients matched by age and weight, with the same extensiveness of abdominal operations, served as controls.
ohvsis5 Medical Department CT,
Bispebjerg Hospital, DK-2400 Copenhagen, Denmark
HENNING
J. MOERCK
Psychopharmacological Research Laboratory, St. Hans Mental Hospital,
GERHARD MAGELUND
Roskilde
CADMIUM TOXICITY
SIR,-As representative of one of the sponsoring industrial organisations referred to by Linda McDougall (May 19, p. 1091), producer of the T.V. Eye programme on cadmium, I a
take exception to her characterisation of the Second International Cadmium Conference as being of value only to the industry. The conference was attended not just by people from industry but by many representatives of government and by academics also. We, as organisers, designed the programme to present all sides of the many controversies relating to the health and environmental effects of cadmium. I presume this is why the Thames Television team asked for the opportunity to cover the conference. They had the chance to cover all opinions. However, they chose to present only one side of a complex issue. In doing so, they gave their audience a biased viewpoint of the degree of environmental and industrial hazard posed by cadmium. We have come to expect this from the news media in the U.S. Until the experience with Thames T.V., we had expected more objectivity from the news media in the U.K. must
International Lead Zinc Research 292 Madison Avenue, New York, N.Y. 10017, U.S.A.
Fig. I-Serum-cortisol values on the evening before surgery, the day of operation, and 1, 2, 3, and 5 days afterwards.
on
In the dexamethasone group, serum-cortisol values were about two times higher on the first postoperative day- and in the control group about three times higher compared with preoperative values. The increase in serum-cortisol due to the stress of the operation was prevented by administration of dexamethasone and from the second postoperative day serum-cortisol levels were strongly suppressed in the dexamethasone group (fig. 1). The controls had normal serum-cortisol values with morning and evening variations from the third postoperative day onwards.
Organization, Inc.,
JEROME F. COLE, Vice-president
HIGH-DOSE DEXAMETHASONE AND ADRENAL FUNCTION
SIR,-Dr Spiegel and colleagues (March 24, p. 630) report that adrenal function is suppressed more often after short-term high-dose corticosteroid therapy than is generally appreciated. We have noticed the same tendency with the use of high-dose dexamethasone in connection with infertility surgery on otherwise healthy women. Corticosteroids, especially dexamethasone, are often used after infertility surgery because they tend to inhibit the fibroblastic proliferation necessary for the formation of collagenous connective tissue and so prevent adhesion. Not much has been published on the safety of this approach. Horne et al.’ have reported that the daily administration of 280 mg of dexamethasone during the first two postoperative days resulted in adrenal suppression in the second and third days. Urinary steroid levels had returned to normal levels by the fifth post-
operative day in all patients. 4. Guidotti,
A, Toffano, G., Baraldi, M., Schwartz, I. P., Costa, E. in GABA Neurotransmitters (edited by P. Krogsgaard-Larsen, J. Scheel-Krüger, and H. Kofod); p. 406. New York, 1979. 5. Müller, E. E., Cocchi, D., Locatelli, V., Krogsgaard-Larsen, P., Bruno, F., Racagni, G. ibid.p. 518. 1. Horne, H. W., Clyman, M., Debrovner, C., Griggs, G., Kistner, R., Kosasa, T., Stevenson, C. S.,Taymor,M.Int. J.Fertil. 1973, 18, 109.
Fig. 2-Urinary 24 h cortisol excretion. 24 h urinary cortisol secretion increased on the first and second postoperative days in both groups, but the increase was greater in the controls (fig. 2). A strong suppression of cortisol secretion was found on the fifth and sixth days in patients on dexamethasone whereas cortisol secretion was normal in the controls from the third postoperative day onwards. Short-term high-dose corticosteroid treatment results in a strong adrenal suppression which can continue after the patient is discharged, and this suppression may expose, for example, infections and symptom-free intra-abdominal bleeding. Department of Obstetrics and Gynæcology, University Central Hospital, 90220 Oulu 22, Finland
LARS RÖNNBERG SEPPO KIVINEN
SIR,-Dr Lloveras (May 5, p. 581) and Dr Caralps (March 10, p. 544) discuss dystonic reactions in patients with severe chronic renal failure who were taking metoclopramide. Dystonic reactions are unusually frequent in Sardinians, as we have found.’I In less than 9 months, we have seen in the emergency unit of the department of neurology 94 patients (42 males, 52 females) with dystonic reactions to neuroleptics. The mean age was 17-5 (82 years), younger patients being more susceptible to these reactions. The dystonia varied from simple crisis to multiple muscle involvement. None of these crises proceeded to severe dyspnoea. All patients recovered completely, on average in 9 min, after apomorphine 5-10 mg intramuscularly.2 Metoclopramide was responsible for 38% of these reactions; other neuroleptics, such as perphenazine, haloperidol, and trifluoperidol, were implicated less often. Metoclopramide had been taken orally in doses of 20-30 mg a day for a mean of 2.5days. In Italy, a high frequency of extrapyramidal reactions is confined to the island of Sardinia, whose population is especially homogeneous and where certain inherited conditions are
unusually
common
areas when he used a condom. A rash appeared which was controlled by hydrocortisone butyrate ointment. The rashed flared the morning after each episode of intercourse, and it was more extensive and irritating if intercourse took place in the week after the menses. The rash and symptoms responded to topical ’Trimovate’ (clobetasone butyrate, nystatin and oxytetracycline) cream. He recorded symptoms in relation to timing of intercourse and his wife’s menstrual cycle. The cycle was 6/18-25, with heavy loss, no pain, and no intermenstrual bleeding. It became apparent that the reactions were worse in the early part of the cycle, and that in the premenstrual week they were much milder, when intercourse could be followed by neither rash nor need for treatment. Symptoms increased when the dose of penicillamine was increased, but control was possible with twice daily application of trimovate cream. Although it is not possible to prove the case, cross-reactions
adjoining not
between penicillamine and penicillin have been reported, and it is likely that this is the explanation. I have not previously seen a contact reaction due to a drug or its metabolite in the vaginal secretions. Worcester Royal Infirmary, Castle Street Branch, Worcester WR1 3AS
P. C. H. NEWBOLD
(e.g., glucose-6-phosphate dehydro-
genase deficiency). No similar incidence in other regions of Italy has been reported, and isolated cases described from time to time in other hospitals have been in people from Sardinia. It therefore seems that genetic factors are involved in the development of dystonic reactions to metoclopramide. These factors cannot be related to the pharmacokinetics of the drug because the predisposition relates to all neuroleptics, phenotiazines or butyrophenones. Metoclopramide has neuroleptic properties in animals,3 and dopamine-receptor blockade is the common feature shared by these drugs. Genetic differences in the sensitivity of dopamine receptors may be the predisposing condition for dystonic reactions. This does not exclude a role for abnormal plasma levels of metoclopramide, as in patients with renal failure, in the development of extrapyramidal sideeffects. This problem may have a more general relevance to the use of neuroleptic drugs in patients with chronic renal failure -sulpiride, for example, though less likely, in our experience, to produce dystonic reactions, must be used with caution in patients with renal impairment. G. U. CORSINI Institute of Pharmacology, F. MARROSU University of Cagliari, 09100 Caghari, Italy G. L. GESSA
CONTACT REACTION TO PENICILLAMINE IN VAGINAL SECRETIONS
SIR,- The following case apparently represents a contact to penicillamine or a metabolite in vaginal secretions.
reaction
In 1948 the patient, a man then aged 25, had a leg ulcer which was treated with penicillin ointment. After ten days he had itching around the eyes; next day his face swelled up and he had itching all over. Penicillin sensitivity was diagnosed and the ointment stopped. He had a flare in 1956 after drinking milk from a cow which had had treatment for mastitis. He had another flare in 1975: when coaxing a daughter to take her penicillin mixture he took a spoonful himself. In March, 1976, he had perianal itching which was treated with ’Nystaform-HC’ (nystatin clioquinol and hydrocortisone) by his own practitioner. His symptoms worsened and he was given a clioquinol and hydrocortisone topical preparation (’Vioform-HC’), after which exfoliation had to be controlled by systemic steroids as an inpatient. Subsequent patch tests confirmed sensitivity to clioquinol. His wife had rheumatoid arthritis and she was started on penicillamine in January, 1978. A week later, after intercourse, irritation developed over his penis; it was localised to the base of the penis and
Corsini, G. U., Marrosu, F., Del Zompo, M., Mangoni, A., Gessa, G. L. VI Wrld Congr. Psychiat. (Honolulu, 1977.); abstr. 917. 2. Gessa R., Tagliamonte A., Gessa G.L. Lancet, 1972, ii, 981. 3. Mangoni A., Corsini G.,U., Piccardi, M.P., Gessa, G.L. Neuropharmaco-
GYNÆCOMASTIA AND DIAZEPAM ABUSE
SiR,—Gynaecomastia is a well-known side-effect of psychopharmacological drugs, including reserpine, phenothiazines, meprobamate, hydroxyzine, and sulpiride. Diazepam and chlordiazepoxide are thought to be mammotropic when given in high doses to rats.l,2 Lactation due to chlordiazepoxide has been described,3 but we know of no reports of gyn2ecomastia during diazepam abuse. A 55-year-old previously healthy taxi-driver was recommended to take 10-30 mg diazepam daily for non-specific nervous symptoms in November, 1976. During the spring of 1977 the man began to abuse diazepam, with daily intakes of up to 100 mg. During hospital admission June, 1977, withdrawal symptoms developed, treated with barbiturates. After his discharge, diazepam abuse quickly recurred with daily doses of 80-140 mg. During this period bilateral gynaecomastia developed. At readmission September, 1977, the gland masses were tender and enlarged, but no secretion was noticed. The patient of athletic type, with normal hair distribution and without testicular atrophy. Over the next 4 months neither diazepam nor N-desmethyldiazepam could be detected in blood-samples, and during this period the gynscomastia steadily resolved; the clinical changes had gone by June, 1978. In September, 1977, there had been no abnormal changes in liver or thyroid function tests, and testosterone, luteinising hormone, and follicular hormone levels were normal. Urine 17-ketosteroids, chorionic gonadotrophins, and oestrogen concentrations were also normal. Chromosome analyses and X-ray of chest and sella turcica were normal. The human prolactin serum concentration was non-specifically increased. To elucidate the influence of diazepam on serum-prolactin, the patient was given diazepam again in November, 1978, with his informed consent. A single dose of 20 mg diazepam was given orally at 8 A.M. and blood-samples were taken every 4 h for 24 h. A week later blood-samples were drawn at the same times after placebo. There were no significant changes in the serum-prolactin between the two series of samples, both sets of values being normal. The relation in time betwen the peak in the diazepam abuse and the development of gynsecomastia, and the resolution of gynaecomastia and tenderness shortly after diazepam abuse stopped, strongly indicate that diazepam was the causal factor. was
1.
logy, 1975, 14, 333.
1. Khazan, N., Primo, C., Danon, A., Assael, M., Sulman, F. Z. Archs. int. Pharmacodyn. 1962, 141, 291. 2. Superstine, E., Sulman, F. G. ibid. 1966, 160, 133. 3. Lampe, W. T. Metabolism, 1967, 16, 257.
G., Winnik, H.
1345
Investigations revealed no other abnormalities in this patient. drugs had been given before the gynscomastia appeared. Alcohol consumption was steady during and after the gynxcomastia (1 or 2 bottles of beer a day). On one interpretation of the relation between diazepam and G.A.B.A.-ergic transmission,4 a high-dose diazepam mammotropic effect without changes in serum-prolactin could be explained by a release of G.A.B.A. (-aminobutyric acid) mediated prolactin-inhibitory factor from the adenohypoNo other
Twelve women, admitted for infertility surgery, were given 16 mg dexamethasone (’Decadron’) intramuscularly on the evening before the operation and 64 mg (4x 16 mg) during the operation day and the first postoperative day. From the second postoperative day onwards 3 mg dexamethasone was given orally for 6 days. Eleven infertile patients matched by age and weight, with the same extensiveness of abdominal operations, served as controls.
ohvsis5 Medical Department CT,
Bispebjerg Hospital, DK-2400 Copenhagen, Denmark
HENNING
J. MOERCK
Psychopharmacological Research Laboratory, St. Hans Mental Hospital,
GERHARD MAGELUND
Roskilde
CADMIUM TOXICITY
SIR,-As representative of one of the sponsoring industrial organisations referred to by Linda McDougall (May 19, p. 1091), producer of the T.V. Eye programme on cadmium, I a
take exception to her characterisation of the Second International Cadmium Conference as being of value only to the industry. The conference was attended not just by people from industry but by many representatives of government and by academics also. We, as organisers, designed the programme to present all sides of the many controversies relating to the health and environmental effects of cadmium. I presume this is why the Thames Television team asked for the opportunity to cover the conference. They had the chance to cover all opinions. However, they chose to present only one side of a complex issue. In doing so, they gave their audience a biased viewpoint of the degree of environmental and industrial hazard posed by cadmium. We have come to expect this from the news media in the U.S. Until the experience with Thames T.V., we had expected more objectivity from the news media in the U.K. must
International Lead Zinc Research 292 Madison Avenue, New York, N.Y. 10017, U.S.A.
Fig. I-Serum-cortisol values on the evening before surgery, the day of operation, and 1, 2, 3, and 5 days afterwards.
on
In the dexamethasone group, serum-cortisol values were about two times higher on the first postoperative day- and in the control group about three times higher compared with preoperative values. The increase in serum-cortisol due to the stress of the operation was prevented by administration of dexamethasone and from the second postoperative day serum-cortisol levels were strongly suppressed in the dexamethasone group (fig. 1). The controls had normal serum-cortisol values with morning and evening variations from the third postoperative day onwards.
Organization, Inc.,
JEROME F. COLE, Vice-president
HIGH-DOSE DEXAMETHASONE AND ADRENAL FUNCTION
SIR,-Dr Spiegel and colleagues (March 24, p. 630) report that adrenal function is suppressed more often after short-term high-dose corticosteroid therapy than is generally appreciated. We have noticed the same tendency with the use of high-dose dexamethasone in connection with infertility surgery on otherwise healthy women. Corticosteroids, especially dexamethasone, are often used after infertility surgery because they tend to inhibit the fibroblastic proliferation necessary for the formation of collagenous connective tissue and so prevent adhesion. Not much has been published on the safety of this approach. Horne et al.’ have reported that the daily administration of 280 mg of dexamethasone during the first two postoperative days resulted in adrenal suppression in the second and third days. Urinary steroid levels had returned to normal levels by the fifth post-
operative day in all patients. 4. Guidotti,
A, Toffano, G., Baraldi, M., Schwartz, I. P., Costa, E. in GABA Neurotransmitters (edited by P. Krogsgaard-Larsen, J. Scheel-Krüger, and H. Kofod); p. 406. New York, 1979. 5. Müller, E. E., Cocchi, D., Locatelli, V., Krogsgaard-Larsen, P., Bruno, F., Racagni, G. ibid.p. 518. 1. Horne, H. W., Clyman, M., Debrovner, C., Griggs, G., Kistner, R., Kosasa, T., Stevenson, C. S.,Taymor,M.Int. J.Fertil. 1973, 18, 109.
Fig. 2-Urinary 24 h cortisol excretion. 24 h urinary cortisol secretion increased on the first and second postoperative days in both groups, but the increase was greater in the controls (fig. 2). A strong suppression of cortisol secretion was found on the fifth and sixth days in patients on dexamethasone whereas cortisol secretion was normal in the controls from the third postoperative day onwards. Short-term high-dose corticosteroid treatment results in a strong adrenal suppression which can continue after the patient is discharged, and this suppression may expose, for example, infections and symptom-free intra-abdominal bleeding. Department of Obstetrics and Gynæcology, University Central Hospital, 90220 Oulu 22, Finland
LARS RÖNNBERG SEPPO KIVINEN
