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REYE'S SYNDROME
607
SIR,—The association of acute brain swelling with fatty liver in encephalitis-like illnesses of children was first noted by Brain and Hunter in 1929,1-3 and acute encephalopathy and fatty degeneration of viscera (Reye’s syndrome) was first described as a disease entity of obscure cause by Reye et al. in 1963.4 I have read an article entitled " Fatal Hypoglycsemia in Early Non-icteric Infective Hepatitis " by Tomlinson6 which was published in 1955 and described a patient who presented with all the typical features of Reye’s syndrome. This 6-year-old girl had a mild prodromal illness lasting 5 days which terminated abruptly in coma, generalised convulsions, and death within 12 hours. Blood-sugar was 15 mg. per 100 ml., blood-urea 64 mg. per 100 ml., and cerebrospinal fluid was clear and under normal pressure with 6 lymphocytes per c.mm. Necropsy revealed extremely pronounced fine fatty infiltration of the liver cells and fairly well defined fine fatty infiltration of the proximal convoluted tubules of the kidneys. Several days to weeks after this child’s death her two sisters and mother experienced a mild illness of short duration with jaundice. I believe that the case described by Tomlinson is one of the earliest reports of Reye’s syndrome. Department of Pædiatrics, National Taiwan University Hospital, Taipei, Republic of China.
D. C. LIANG.
SIR The increase in the consumption of diazepam in a variety of pyschosomatic conditions and a supposed limiting effect of this drug on sexual behaviour of middle-aged men induced us to study the plasma-testosterone concentration in men, aged 35-55 years, with minor complaints of nervousness or mental tension. Surprisingly, we found that plasma-testosterone levels were significantly increased when these subjects were taking 10-20 mg/d of diazepam (‘ Valium ’) orally for two weeks (see accompanying table). PLASMA TESTOSTERONE AND 11-HYDROXYCORTICOID LEVELS IN MEN TREATED WITH DIAZEPAM
A small but not significant reduction was observed in plasma-11-hydoxycorticoid concentration; the individual and mean values showed that the subjects were not under stress.
We shall continue these studies and
at
present
can
only speculate on the possible mechanism-e.g., liver enzyme induction, alteration in the clearance of blood testosterone, increased synthesis. Whatever the reasons, it is clear that these results provide grounds for suspecting more general endocrine changes associated with the intake of
diazepam.
It has been reported that in the U.K. alone the consumption of valium has increased from 497 kg to 1896 kg 1. 2. 3. 4. 5.
reflects the world trend. Therefore, results from steroid measurements made for clinical purposes should be viewed with the possibility in mind of the effect of this drug. Clinical Pharmacology and Stress Unit,
Hospital Aeronautico, D.I.G.I.D. (Ministry of Defence) and University of Buenos Aires Medical School, Buenos Aires, Argentine.
A. E. ARGÜELLES J. ROSNER.
CARDIOVASCULAR MALDEVELOPMENT ASSOCIATED WITH MATERNAL EXPOSURE TO AMANTADINE
SIR,-We have recently observed an infant with a complex cardiovascular lesion (single ventricle with pulmonary atresia) whose mother was exposed during the first 3 months of pregnancy (which encompasses the vulnerable period of cardiogenesis) to 100 mg/d of amantadine hydrochloride, a relatively new drug which is used as an antiviral agent and control Parkinson’s disease. In the case of this 29-yearold mother, the drug was taken for a movement disorder very much like parkinsonism. The movement disorder was significantly relieved by the drug. The drug’s mechanism of action is not clear, but it has been shown to cause an increase in dopamine release. Congestive heart-failure has developed in patients taking it. Amantadine has proved to be embryotoxic and teratogenic in rats receiving 50 mg-1 kg-l d-1 (12 times the recommended human dose).2 We have consulted with the manufacturer of the drug and find they have received no previous reports of teratogenic effects in man. Although it is unlikely that many women with parkinsonism will be of reproductive age, the use of amantadine as an antiviral agent could produce situations of risk.
to
DIAZEPAM AND PLASMA-TESTOSTERONE LEVELS _
In this time the consumption of chlordiazepoxide (‘ Librium ’) has increased from 3459 kg There is every reason to believe that this to 4199 kg.l
between 1966 and 1970.
REYE’S SYNDROME
Bradford, W. D., Lathan, W. C. Am.J. Dis. Child. 1967, 114, 152. Bradford, W. D., Parker, J. C. Clin. Pediat. 1971, 10, 148. Brain, W. R., Hunter, D., Turnbull, H. M. Lancet, 1929, i, 221. Reye, R. D. K., Morgen, G., Baral, J. ibid. 1963, i, 749. Tomlinson, B. E. ibid. 1955, i, 1300.
Department of Pediatrics, University of Colorado Medical Center, Denver, Colorado 80220, U.S.A.
JAMES J. NORA AUDREY H. NORA GARY L. WAY.
CYSTIC FIBROSIS: DETECTION OF HETEROZYGOTES have SIR,-We developed a new technique for detecting cystic fibrosis (c.F.) and the heterozygote for c.F. The assay can be done by any laboratory having an aggregometer for measuring platelet aggregation. It involves measuring the inhibition of A.D.P.-induced platelet aggregation by prostaglandin El (p.G.E1 was kindly provided by Dr J. Pike, Upjohn Company, Kalamazoo, Michigan). The level of inhibition of aggregation by p.G.E1 is lower in C.F. patients and known heterozygotes than in healthy subjects. An outline of our procedure follows. Only plastic or siliconised glassware is used for the handling of blood. 9 ml of blood is drawn into 1 ml of 3-8% sodium citrate. The platelet-rich plasma (P.R.P.) is obtained by centrifuging at 175 g for 10 min at 20-22 °C. To 0.9 ml P.R.P. in a siliconised cuvette we add 0-1 ml of 4 µg/ml A.D.P. or 0-1 ml of 10 µg/ml p.G.E1 followed in 10 sec by 0-1 ml A.D.P. Platelet aggregation is studied in an aggregometer at 37 °C with constant stirring (1100 rpm) and continous recording of transmittance at 609 mµ. Quantitation of the results is obtained by comparing the transmittance recorded when only A.D.P. is added to Monopolies Commission Report on Chlordiazepoxide and Diazepam. H.M. Stationery Office, London, 1973. 2. Lamar, J. K., et al. Toxicol. appl. Pharmac. 1970, 17, 272. 1.
SIR,—The association of acute brain swelling with fatty liver in encephalitis-like illnesses of children was first noted by Brain and Hunter in 1929,1-3 and acute encephalopathy and fatty degeneration of viscera (Reye’s syndrome) was first described as a disease entity of obscure cause by Reye et al. in 1963.4 I have read an article entitled " Fatal Hypoglycsemia in Early Non-icteric Infective Hepatitis " by Tomlinson6 which was published in 1955 and described a patient who presented with all the typical features of Reye’s syndrome. This 6-year-old girl had a mild prodromal illness lasting 5 days which terminated abruptly in coma, generalised convulsions, and death within 12 hours. Blood-sugar was 15 mg. per 100 ml., blood-urea 64 mg. per 100 ml., and cerebrospinal fluid was clear and under normal pressure with 6 lymphocytes per c.mm. Necropsy revealed extremely pronounced fine fatty infiltration of the liver cells and fairly well defined fine fatty infiltration of the proximal convoluted tubules of the kidneys. Several days to weeks after this child’s death her two sisters and mother experienced a mild illness of short duration with jaundice. I believe that the case described by Tomlinson is one of the earliest reports of Reye’s syndrome. Department of Pædiatrics, National Taiwan University Hospital, Taipei, Republic of China.
D. C. LIANG.
SIR The increase in the consumption of diazepam in a variety of pyschosomatic conditions and a supposed limiting effect of this drug on sexual behaviour of middle-aged men induced us to study the plasma-testosterone concentration in men, aged 35-55 years, with minor complaints of nervousness or mental tension. Surprisingly, we found that plasma-testosterone levels were significantly increased when these subjects were taking 10-20 mg/d of diazepam (‘ Valium ’) orally for two weeks (see accompanying table). PLASMA TESTOSTERONE AND 11-HYDROXYCORTICOID LEVELS IN MEN TREATED WITH DIAZEPAM
A small but not significant reduction was observed in plasma-11-hydoxycorticoid concentration; the individual and mean values showed that the subjects were not under stress.
We shall continue these studies and
at
present
can
only speculate on the possible mechanism-e.g., liver enzyme induction, alteration in the clearance of blood testosterone, increased synthesis. Whatever the reasons, it is clear that these results provide grounds for suspecting more general endocrine changes associated with the intake of
diazepam.
It has been reported that in the U.K. alone the consumption of valium has increased from 497 kg to 1896 kg 1. 2. 3. 4. 5.
reflects the world trend. Therefore, results from steroid measurements made for clinical purposes should be viewed with the possibility in mind of the effect of this drug. Clinical Pharmacology and Stress Unit,
Hospital Aeronautico, D.I.G.I.D. (Ministry of Defence) and University of Buenos Aires Medical School, Buenos Aires, Argentine.
A. E. ARGÜELLES J. ROSNER.
CARDIOVASCULAR MALDEVELOPMENT ASSOCIATED WITH MATERNAL EXPOSURE TO AMANTADINE
SIR,-We have recently observed an infant with a complex cardiovascular lesion (single ventricle with pulmonary atresia) whose mother was exposed during the first 3 months of pregnancy (which encompasses the vulnerable period of cardiogenesis) to 100 mg/d of amantadine hydrochloride, a relatively new drug which is used as an antiviral agent and control Parkinson’s disease. In the case of this 29-yearold mother, the drug was taken for a movement disorder very much like parkinsonism. The movement disorder was significantly relieved by the drug. The drug’s mechanism of action is not clear, but it has been shown to cause an increase in dopamine release. Congestive heart-failure has developed in patients taking it. Amantadine has proved to be embryotoxic and teratogenic in rats receiving 50 mg-1 kg-l d-1 (12 times the recommended human dose).2 We have consulted with the manufacturer of the drug and find they have received no previous reports of teratogenic effects in man. Although it is unlikely that many women with parkinsonism will be of reproductive age, the use of amantadine as an antiviral agent could produce situations of risk.
to
DIAZEPAM AND PLASMA-TESTOSTERONE LEVELS _
In this time the consumption of chlordiazepoxide (‘ Librium ’) has increased from 3459 kg There is every reason to believe that this to 4199 kg.l
between 1966 and 1970.
REYE’S SYNDROME
Bradford, W. D., Lathan, W. C. Am.J. Dis. Child. 1967, 114, 152. Bradford, W. D., Parker, J. C. Clin. Pediat. 1971, 10, 148. Brain, W. R., Hunter, D., Turnbull, H. M. Lancet, 1929, i, 221. Reye, R. D. K., Morgen, G., Baral, J. ibid. 1963, i, 749. Tomlinson, B. E. ibid. 1955, i, 1300.
Department of Pediatrics, University of Colorado Medical Center, Denver, Colorado 80220, U.S.A.
JAMES J. NORA AUDREY H. NORA GARY L. WAY.
CYSTIC FIBROSIS: DETECTION OF HETEROZYGOTES have SIR,-We developed a new technique for detecting cystic fibrosis (c.F.) and the heterozygote for c.F. The assay can be done by any laboratory having an aggregometer for measuring platelet aggregation. It involves measuring the inhibition of A.D.P.-induced platelet aggregation by prostaglandin El (p.G.E1 was kindly provided by Dr J. Pike, Upjohn Company, Kalamazoo, Michigan). The level of inhibition of aggregation by p.G.E1 is lower in C.F. patients and known heterozygotes than in healthy subjects. An outline of our procedure follows. Only plastic or siliconised glassware is used for the handling of blood. 9 ml of blood is drawn into 1 ml of 3-8% sodium citrate. The platelet-rich plasma (P.R.P.) is obtained by centrifuging at 175 g for 10 min at 20-22 °C. To 0.9 ml P.R.P. in a siliconised cuvette we add 0-1 ml of 4 µg/ml A.D.P. or 0-1 ml of 10 µg/ml p.G.E1 followed in 10 sec by 0-1 ml A.D.P. Platelet aggregation is studied in an aggregometer at 37 °C with constant stirring (1100 rpm) and continous recording of transmittance at 609 mµ. Quantitation of the results is obtained by comparing the transmittance recorded when only A.D.P. is added to Monopolies Commission Report on Chlordiazepoxide and Diazepam. H.M. Stationery Office, London, 1973. 2. Lamar, J. K., et al. Toxicol. appl. Pharmac. 1970, 17, 272. 1.