607

REYE’S SYNDROME

SIR,—The association of acute brain swelling with fattyliver in encephalitis-like illnesses of children was firstnoted by Brain and Hunter in 1929,1-3 and acute encephalo-pathy and fatty degeneration of viscera (Reye’s syndrome)was first described as a disease entity of obscure cause byReye et al. in 1963.4 I have read an article entitled " FatalHypoglycsemia in Early Non-icteric Infective Hepatitis "by Tomlinson 6 which was published in 1955 and describeda patient who presented with all the typical features ofReye’s syndrome. This 6-year-old girl had a mild prodromalillness 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 undernormal pressure with 6 lymphocytes per c.mm. Necropsyrevealed extremely pronounced fine fatty infiltration of theliver cells and fairly well defined fine fatty infiltration of theproximal convoluted tubules of the kidneys. Several daysto weeks after this child’s death her two sisters and motherexperienced a mild illness of short duration with jaundice.I believe that the case described by Tomlinson is one of theearliest reports of Reye’s syndrome.

Department of Pædiatrics,National Taiwan University Hospital,

Taipei,Republic of China. D. C. LIANG.

DIAZEPAM AND PLASMA-TESTOSTERONELEVELS

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SIR The increase in the consumption of diazepam in avariety of pyschosomatic conditions and a supposed limit-ing effect of this drug on sexual behaviour of middle-agedmen induced us to study the plasma-testosterone concentra-tion in men, aged 35-55 years, with minor complaints ofnervousness or mental tension. Surprisingly, we foundthat plasma-testosterone levels were significantly increasedwhen 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 MENTREATED WITH DIAZEPAM

A small but not significant reduction was observed inplasma-11-hydoxycorticoid concentration; the individualand mean values showed that the subjects were not understress. We shall continue these studies and at present canonly speculate on the possible mechanism-e.g., liver

enzyme induction, alteration in the clearance of bloodtestosterone, increased synthesis. Whatever the reasons,it is clear that these results provide grounds for suspectingmore general endocrine changes associated with the intakeof diazepam.

It has been reported that in the U.K. alone the con-sumption of valium has increased from 497 kg to 1896 kg

1. Bradford, W. D., Lathan, W. C. Am.J. Dis. Child. 1967, 114, 152.2. Bradford, W. D., Parker, J. C. Clin. Pediat. 1971, 10, 148.3. Brain, W. R., Hunter, D., Turnbull, H. M. Lancet, 1929, i, 221.4. Reye, R. D. K., Morgen, G., Baral, J. ibid. 1963, i, 749.5. Tomlinson, B. E. ibid. 1955, i, 1300.

between 1966 and 1970. In this time the consumption ofchlordiazepoxide (‘ Librium ’) has increased from 3459 kgto 4199 kg.l There is every reason to believe that thisreflects the world trend. Therefore, results from steroidmeasurements made for clinical purposes should be viewedwith the possibility in mind of the effect of this drug.

Clinical Pharmacology andStress 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 MALDEVELOPMENTASSOCIATED WITH MATERNALEXPOSURE TO AMANTADINE

SIR,-We have recently observed an infant with a com-plex cardiovascular lesion (single ventricle with pulmonaryatresia) whose mother was exposed during the first 3 monthsof pregnancy (which encompasses the vulnerable period ofcardiogenesis) to 100 mg/d of amantadine hydrochloride, arelatively new drug which is used as an antiviral agent andto control Parkinson’s disease. In the case of this 29-year-old mother, the drug was taken for a movement disordervery much like parkinsonism. The movement disorder wassignificantly relieved by the drug. The drug’s mechanismof action is not clear, but it has been shown to cause anincrease in dopamine release. Congestive heart-failurehas developed in patients taking it. Amantadine has provedto be embryotoxic and teratogenic in rats receiving 50 mg-1kg-l d-1 (12 times the recommended human dose).2 Wehave consulted with the manufacturer of the drug and findthey have received no previous reports of teratogeniceffects in man. Although it is unlikely that many womenwith parkinsonism will be of reproductive age, the use ofamantadine as an antiviral agent could produce situations ofrisk.

Department of Pediatrics,University of Colorado Medical Center,

Denver, Colorado 80220, U.S.A.

JAMES J. NORAAUDREY H. NORAGARY L. WAY.

CYSTIC FIBROSIS: DETECTION OFHETEROZYGOTES

SIR,-We have developed a new technique for detectingcystic fibrosis (c.F.) and the heterozygote for c.F. Theassay can be done by any laboratory having an aggregometerfor measuring platelet aggregation. It involves measuringthe inhibition of A.D.P.-induced platelet aggregation byprostaglandin El (p.G.E1 was kindly provided by Dr J. Pike,Upjohn Company, Kalamazoo, Michigan). The level ofinhibition of aggregation by p.G.E1 is lower in C.F. patientsand 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 centrifugingat 175 g for 10 min at 20-22 °C. To 0.9 ml P.R.P. in a silicon-ised cuvette we add 0-1 ml of 4 µg/ml A.D.P. or 0-1 ml of10 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 withconstant stirring (1100 rpm) and continous recording oftransmittance at 609 mµ.

Quantitation of the results is obtained by comparingthe transmittance recorded when only A.D.P. is added to

1. 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.