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short half-life of 64CU. In both patients the initial excretoryrate of labelled copper approaches that of control 1 but is verymuch less than that of control 2. Thereafter the label rapidlydisappears from the bile and hardly any is detectable at 48 h.This suggests that the mechanism of excretion of copper intothe bile in Wilson’s disease is passive with the metal bound tolow-molecular-weight diffusible compounds and that no energymediated mechanism is involved. It is improbable that thesefindings are due to dilution of copper in the enlarged body poolof the metal because patient 2. (therapeutically a poor com-plier) had a very much higher concentration of copper in hisliver than did patient 1. However, both showed remarkablysimilar patterns of excretion and total amounts of 6’Cu recov-ered during the study. Moreover sufficient of the labelled cop-per reached the site of excretion in the first 12 h to give con-centrations comparable with that of the first control subject.Thus if an efficient excretory mechanism had been intact thereshould have been some evidence of a secondary rise even if notof the same order of magnitude as shown by the controls.We conclude that the accumulation of copper in the tissues

of patients with Wilson’s disease results from the I absence orsevere deficiency of an energy mediated secretory mechanismfor the metal in the hepatocytes, presumably as a result of alysosomal defect. 10

.

Department of Medicine,University of Cambridge,Addenbrooke’s HospitalCambridge CB2 2QQ

K. GIBBSJ. M. WALSHE

GLUCOSE TOLERANCE AND ISCHÆMIC HEARTDISEASE

SiR,—Dr Fuller and his colleagues (June 28, p. 1373) pres-ent interesting data on impaired glucose tolerance (IGT) andcoronary heart disease (CHD) from the Whitehall Study.However, their data invite additional analyses.

Their data indicated a qualitative, threshold effect of blood-sugar on CHD risk above about 96 mg/dl. No quantitativeeffect on risk was present below or above this level, as indi-cated by the non-significance of the logitic coefficients forblood sugar in separate analyses of the normoglycaemic andIGT group. Left unexplained is whether or not the excessCHD risk in the IGT group may be explained by an excess ofother risk factors in the IGT group. Indeed, Fuller et al. foundan excess of ECG abnormalities in the IGT group. Prevalencesof other risk factors in the two groups are not presented.May I suggest that these workers repeat the logistic analysis

for the normoglycaemic and IGT group combined entering adichotomous independent variable "IGT yes/no" (i.e., blood-sugar greater or less than 96 mg/dl) in place of blood-sugar.This will help to show if IGT is independently predictive ofCHD mortality. If such an analysis indicated that "IGT

yes/no" was not independently predictive of CHD, this wouldnot necessarily exonerate IGT as a causal factor in CHD sinceIGT might be somehow biologically promoting a more defini-tive risk factor such as ECG abnormalities (hence the excess)or blood pressure.’ The problem of using multivariate analysiswhen cardiovascular disease risk factors are potentially causallylinked will be discussed elsewhere.2 There is no easy solu-tion to this problem other than careful consideration of thepossible biologic links between risk factors. Finally, the finding

10. Sternlieb I, van den Hamer CJA, Morell AG, Alpert S, Gregoriadis G,Scheinberg IH. Lysosomal defect of hepatic copper excretion in Wilson’sdisease. Gastroenterology 1973; 64: 99-105.

1. Jarrett RJ, Keen H, McCartney M, Fuller JH, Hamilton PJS, Reid DD,Rose G. Glucose tolerance and blood pressure in two population samples:Their relation to diabetes mellitus and hypertension. Int J Epidemiol1978; 7: 15-24.

2. Criqui MH, Barrett-Connor E, Holdbrook MJ, Austin M, Turner JD. Clus-tering of cardiovascular disease risk factors. Prev Med (in press).

of not only an increased prevalence of ECG abnormalities inthe IGT group but a worse prognosis for each abnormality isinteresting, but multivariate analysis is necessary here to deter-mine if the poorer prognoses in the IGT group are due to each

abnormality separately or to a tendency of abnormalities tocluster in the IGT group.

Department of Community Medicine,San Diego School of Medicine,University of California,La Jolla, California 92093, U.S.A. MICHAEL H. CRIQUI

I.C.I. VIEW OF CLOFIBRATE TRIAL

SiR,-May I use your correspondence columns to correct astatement in the lay Press attributed to I.C.I. concerning thepaper W.H.O. Cooperative Trial on Primary Prevention ofIschaemic Heart Disease using Clofibrate to Lower Serum Cho-lesterol : Mortality Follow-Up, published in The’Lancet of Aug.

_

23. Following publication of the paper a journalist of the PressAssociation had a long discussion with an official of LC.I. headoffice, the outcome of which was the appearance in severalnewspapers of the following comment: "We are very certainfrom examination of the results that the explanation for theexcess death rate is not one that is drug-related. It is chancethat is happening." I.C.I.’s comment, as reported, added that"it would be irresponsible to withdraw the drug". Thesequotations do not represent the view of.I.C.I. in respect of thistrial.The interpretation of the results of this trial presents many

difficulties. The authors draw attention to several inconsisten-cies within the data and to the lack of biological support forthe statistical differences indicating an adverse effect both inthe trial and after treatment had stopped. LC.I. accepts thata toxic effect of clofibrate is one of the three possible explana-tions for the findings in this trial. None of the other trials,although admittedly containing smaller numbers of subjectsand of a shorter duration, has shown such an effect. Takinginto consideration all the evidence from a large number ofclinical trials we believe there is a continuing place for the useof this drug in accordance with the indications in our currentdata sheet.

I.C.l.’s view coincides with that of the Committee on Safetyof Medicines who have issued a Press statement including thefollowing paragraph: "The Committee does not believe that thehazards are such that supply of the products containing clofi-brate should be banned. Doctors will therefore be able to con-tinue to prescribe clofibrate where they consider it appropriate.The Committee has emphasised, however, that its use shouldbe restricted to specified conditions indicated in the currentdata sheet." ,

I.C.I. Ltd,Pharmaceuticals Division,Alderley Park, Macclesfield, Cheshire C. C. DOWNIE

RAPID DIAGNOSIS OF RESPIRATORY SYNCYTIALVIRUS INFECTIONS IN CHILDREN

SIR,-On July 5 (p. 32) you published a collaborative studyof respiratory syncytial virus (RSV) infections seen in six Euro-pean virus laboratories (Copenhagen, Newcastle, Oslo, Stock-holm, Turku, Vienna) between November, 1978, and May,1979. We have done a survey in Normandy, France, from Nov-ember, 1979, to June, 1980, in which nasal secretions fromchildren admitted to hospital in Caen, Flers, or Lisieux withacute respiratory disease were tested by the indirect fluorescentantibody technique.’ RSV immune and control sera and anti-globulin conjugates were supplied by Wellcome Laboratories.

1. Gardner PS, McQuillin J. Rapid virus diagnosis. London: Butterworths,1974.

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RSV was identified in 56 of the 170 specimens (32.9%). Thepeak was in January and February, 1980, when 37 out of 56specimens were positive (66%). 3 RSV infections were detectedin May and June. 72% of the infected children were two to sixmonths old.The rapid immunofluorescence technique can be recom-

mended for the diagnosis of RSV infections. Specimens can betransported easily, for 2-3 h, without special treatment, and aresult is available in 2-3 h. The quality of the reagentsnow commercially available is satisfactory. Moreover, in ourhands this technique is more sensitive than either isolation incell culture or serological tests.

Virology Laboratory,Centre Hospitalier Universitaire,14040 Caen, France F. FREYMUTH

HÆMOPHILUS EQUIGENITALIS IN SEXUALLYTRANSMITTED DISEASE

SiR,—Dr Mardh and colleagues’ failure (Aug. 9, p. 310) todemonstrate agglutinins to Haemophilus equigenitalis in 40Swedish males with non-gonococcal urethritis is similar to ourexperience.

145 single and 33 paired sera from 178 men with non-gono-coccal urethritis were all negative for H. equigenitalis agglu-tinins. The sera were examined by titration against an antigenprepared according to the method of Taylor and Rosenthalusing a positive control raised in the rabbit and supplied bythese workers.’ This control serum continued to give reproduc-ible results as each batch of sera was examined and it did not

produce autoagglutination.Two negative control specimens yielded a reaction to the

test. One was obtained from a specimen submitted to thislaboratory for other antibody studies and the other from theCambridge laboratory. Both were contaminated with Pseudo-monas species and demonstrated a mixed precipitation/agglu-tination reaction. With our own specimen the same reactionoccurred in the absence of antigen and the Cambridge serumspecimen was insufficient to test.

However, contamination has been ruled out as causing anyof the positive results in Cambridge, including those subse-quently found to demonstrate autoagglutination. We had con-sidered contamination to be an unlikely explanation in anycase, because of the confirmatory evidence of the Whitechapelimmunofluorescence studies.2

Like other workers we cannot explain these findings but feelthat the negative studies cast doubt on any special significancefor these antibodies in sexually transmitted disease.

Departments of Venereologyand Microbiology,

General Hospital,Birmingham B4 6NH

J. C. CLAYD. W. BURDON

ANTABUSE EFFECT WITH CEPHALOSPORINS

SIR,-Like Neu and Prince3 and Portier et a1.4 we haveobserved alcohol intolerance associated with administration ofa cephalosporin. Last year we did a human volunteer study ofthe pharmacokinetics of cefoperazone (T1S51), giving singledoses of 1 or 2 g by various parenteral routes over a period of

1. Taylor CED, Rosenthal RO. Agglutinins to the causative organism of conta-gious equine metritis 1977 in human serum. Lancet 1978; i: 1038.

2. Wilkinson AE, Rodin P. Organism of contagious equine metritis 1977 andhuman venereal disease. Lancet 1978; ii: 1093.

3. Neu HC, Prince AS. Interaction between moxalactam and alcohol. Lancet1980; i: 422.

4. Portier H, Chalopin JM, Freysz M, Tanter Y. Interaction between cephalo-sporins and alcohol. Lancet 1980; ii: 263.

8 weeks. The subjects were forbidden alcohol for 24 h arounddoses, but four took alcoholic beverages 36 h after a dose. Inthree ’Antabuse’ type effects developed, on three separate occa-sions in one subject, which led to spontaneous complaints tothe controlling investigator. Symptoms included tachycardiawith a bounding pulse, flushing over the face and shoulders,and a feeling of intoxication well beyond that anticipated withdrinking, up to 48 h after a dose of cefoperazone.The reason why alcohol intolerance should be associated

with the newer cephalosporins is not immediately apparent. Itcould be a consequence of high biliary excretion, which mightalso explain the marked incidence of lower gastrointestinalside-effects from cefoperazone complained of by the volunteersin our study. Symptoms, which sometimes included diarrhoea,usually commenced 24 h after a dose and typically lasted 2-4days, although they sometimes persisted longer. Our volun-teers are, in the main, experienced in antibiotic volunteer stu-dies and had not previously had such severe side-effects, soboth the alcohol intolerance and bowel symptoms are likely tobe real. There are only a few instances of diarrhoea in patientstreated so far with cefoperazone (data on Pfizer companyfiles).

Department of Medical Microbiology,Southmead Hospital,Bristol BS10 5NB

D. S. REEVESA. J. DAVIES

FATIGUE AS AN UNWANTED EFFECT OF DRUGS

SIR,-Fatigue is a common non-specific symptom, and

many drugs have been blamed for causing it besides the

beta-adrenoceptor antagonists discussed in your editorial (June14).

Studies of drugs as diverse as acebutolol,’ lithium,2 and anti-histamines3 have shown that patients complain of more symp-toms ("fatigue", "weakness", "lack of energy") with theseactive medications than when taking a placebo.

However, there is little agreement on how fatigue should bedefined. Terms such as "tiredness" and "weakness" are oftenused interchangeably and scored arbitrarily. If investigatorsused a standard system for measuring fatigue (such as the per-ceived exertion scale of Borg you mention, or the checklist ofPearson and Byars’), it would help to eliminate such ambi-guity, with eventual clinical benefits: a physician attempting toprescribe from the ever-growing selection of, for instance,beta-blockers might be able to identify the drug with the leastfatigue-causing potential.The placebo effect alone accounts for a surprisingly large

amount of fatigue. Marini and Sheard2 studied the effects oflithium and placebo in adolescents, and found that 24% ofthem complained of weakness after taking placebo alone for-one month.No drug should be blamed for causing fatigue until it has

been evaluated prospectively in a randomised, placebo-controlled trial in which fatigue has been measured by somereproducible and specific system of scoring.

Department of Medicine,Georgetown University Hospital,Washington, D.C. 20007, U.S.A. MICHAEL PHILLIPS

1. Rod JL, Admon D, Kimchi A, Gotsman MS, Lewis BS. Evaluation of thebeta-blocking drug acebutolol in angina pectoris. Am Heart J 1979, 98:604-12.

2. Marini JL, Sheard MH. Sustained release lithium carbonate in a double-blind study: Serum lithium levels, side effects and placebo response. J ClinPharmacol 1976; 16: 276-83.

3. Higgins EA, Chiles WD, McKenzie JM, Jennings AE, Funkhouser GE,Mullens SR. Effects of altitude and two decongestant-antihistamine prep-arations on physiological functions and performance. Aviat Space EnvironMed 1979; 50: 154-58.

4. Pearson RG, Byars GE Jr. The development and validation of a checklist formeasuring subjective fatigue. USAF School of Aviation Medicine reportno TR-56-115, 1956.