Zopiclone

788

resuscitation in these conditions has received careful consideration, with advice on prophylaxis.l,2 There are doubts about whether HIV infections can be transmitted in this way.’ It is generally recommended that mouth-to-mouth resuscitation be done with care and that barrier devices should be used when possible.3,4 It may be advisable to extend the use of barrier devices to cases where salmonella infection is suspected. A strong case’ can be made for including these devices in first-aid kits and for including a description of the technique in the Resuscitation Council’s handbook.’ Bishop Auckland General Hospital, Co Durham DL14 6AD, UK

F. AHMAD D. C. A. SENADHIRA

South West Durham Health Authority, Bishop Auckland

J. CHARTERS S. ACQUILLA

1. Benson AS. Control of communicable disease in man. 4th ed. Washington: American Public Health Association, 1985. 2. Department of Health and Social Security, Joint Committee on Vaccination and Immunisation. Immunisation against infectious disease. London: HM Stationery Office, 1988. 3. Saliteer SM, White GC, Cohen MS. HTLV-III exposure during cardio-pulmonary resuscitation. N Engl J Med 1985; 313: 1606-07. 4. Nickalls RWD, Thompson CW. Mouth-to-mask respiration. Br Med J 1986; 292: 1350. 5. Resuscitation Council (UK). Resuscitation for the citizen. London: Resuscitation Council (UK), 1984.

Loperamide poisoning

in children

SiR,—Dr Bhutta and Dr Tahir (Feb 10, p 363) express concern about the use of loperamide in very young children: there have been previous reports of ileus after therapeutic use in children.1,2 Whilst loperamide has been shown to be safe when used as an adjunct to oral rehydration in well-nourished children, this may not be true for malnourished populations in developing countries. We have commented on respiratory depression in a 15-month-old child after a single dose of loperamide 4 Toxicity was reversed by naloxone. This sensitivity to the drug may have been related to low serum protein concentrations or impaired hepatic function-factors which would be pertinent in the children reported from Pakistan. We also highlight the discrepancy in recommended dosage: while the lower age limit in many developing countries is 1 year, loperamide is not indicated below the age of 2 years in the USA5 and 4 years in the UK.s,6 Since all the children affected in Pakistan were aged 2 years or under, and all those who died were under 61 months, the lower age limit may need to be revised, and some way should be found of giving clearer instructions concerning use. There should be more control over community use ofloperamide in developing countries, especially since the use of antidiarrhoeal medications may distract from the urgent priority of oral rehydration. Poisons Unit,

Guy’s Hospital, London SE1 9RT,UK

NEIL A. MINTON JOHN A. HENRY

BK,Tripp JH, Milla PJ, Harries JT. Loperamide in severe protracted diarrhoea. Arch Dis Child 1983; 58: 39-43. von Muhlendahl KE, Bunjes R, Krienke EG. Loperamide-induced ileus. Lancet 1980; i: 209. Diarrhoeal Diseases Study Group (UK). Loperamide in acute diarrhoea in childhood: results of a double blind, placebo controlled multicentre clinical trial. Br Med J 1984; 289: 1263-67. Minton NA, Smith PGD. Loperamide toxicity in a child after a single dose. Br Med J 1987; 294: 1383. Reynolds JEF, ed. Martindale: the extra pharmacopoeia, 29th ed. London: Pharmaceutical Press, 1989: 1094. ABPI data sheet compendium 1989-90. London: Datapharm Publications, 1989 683-84.

1. Sandhu 2.

3.

4.

5. 6.

Ginkgo biloba extracts SIR,-The letter from the Dr Willmar Schwabe company (Feb 24, 475) on your Dec 23/30 Round the World report seems misleading. The fact that pharmacological or clinical studies exist is not itself proof of efficacy: it is the scientific quality of the evidence p

that matters, and none of the published data has appeared in medical journals of high reputation or high standards of peer review. Expert opinions, via biometric analysis or meta-analysis, are sometimes

commissioned by a drug company, and the outcome may be determined by the choice of whom to invite and by those who accept the invitation. Such studies cannot always be regarded as

independent. Our evaluation of data on Ginkgo biloba extract! has been criticised only by the company and by scientists who have done studies sponsored by that company. The criticisms consisted more of personal disparagement than of scientific comment and were not accepted for publication. All studies regarded by the company as proof of efficacy were included in our evaluation of ’Tebonin’ and ‘rokan’.1 The company tried to suppress negative information2 on its product by suing the author and the association of health insurance doctors, seeking a retraction of the statement and the payment damages. The Hamburg court judgment of Feb 5,1988, rejected the claims, and stated that the author had presented sufficient scientific evidence for his criticism. Having failed in court the company is continuing its strategy of suppressing negative scientific information by attempting to exclude critics from

meetings. There is little evidence that prescribing habits are indicators of proof of efficacy. The company seems to misinterpret successful marketing as indicating drug quality. It is not by chance that in Germany such conflicts arise more often with "natural" drug products. Such drugs can be licensed in Germany without proof of efficacy and the manufacturers feel that this entitles them to demand the same weak standards from scientists when evaluating such drugs. The preference for legal action may reflect manufacturer’s lack of skill and experience in scientific argument. Klinge Pharma GmbH, producer of a horsechestnut extract (’Venostasin’) licensed for chronic venous insufficiency, is attempting to sue authors of books or articles who have published negative verdicts on the drug. The freedom of science will be seriously restricted in Germany if such attempts succeed in court, but German medical scientists have not yet recognised the threat. Institute of Clinical Pharmacology, ZKH St-Jurgen-Strasse, D-2800 Bremen, West Germany

PETER S. SCHÖNHOFER

PS, Schulte-Sasse H, Manhold C, Werner B. Sind Extrakte aus den bei des Ginkgobaumes peripheren Durch-blutungs-und Himleistungsstorungen im Alter wirksam? Beurteilung von Tebonin und Rokan Intern Praxis 1989; 29: 585-601. Kassenarztliche Vereinigung Hamburg. KV Journal 1987 (Nov): 24-25.

1. Schonhofer

Blattern

2.

Zopiclone SiR,—Your March 3 editorial (p 507) is timely since, apart from the clinical study in insomnia by our group,l little has been published in the UK about the new non-benzodiazepine (BDZ) drug zopiclone. That such compounds (as opposed to tranquilliser analogues) are required is emphasised by the fact that the prescription of BDZ hypnotics continues unabated, whilst that for BDZ tranquillisers is dwindling rapidly. The implication is that, despite reluctance on the part of the doctor to prescribe and the patient to take these compounds, the need for them outweighs the potential harmful effects of dependence and withdrawal. Indeed, persistent insomnia can adversely affect daytime functioning and health (eg, in junior hospital doctors2). You express surprise that zopiclone, though not a BDZ, binds to BDZ receptors. But so do barbiturates and other drugs, such as the hypnotic agent zolpidem.3 These receptors are not specific for one class of drug (BDZ) but may be specific for hypnotic and anxiolytic compounds. Langer et a14 have proposed a classification into three receptor subtypesmega-1(? hypnotic), omega-2 (? anxiolytic), and omega-3 (peripheral)--which seems more logical. Just as the BDZs themselves may be phased out of clinical practice, so too should the term "BDZ receptor". Whether or not these new non-BDZ hypnotics and their tranquilliser cousins suriclone and alpidem5 will be clinically useful must depend on their being shown to be free of the problems associated with the BDZ compounds that they may replace. As your editorial stresses, the evidence that this is so remains equivocal.

789

However, zopiclone and zolpidem do possess

one

important

property which distinguishes them from the BDZ-namely, their effects on sleep patterns as revealed by electroencephalography (EEG). BDZ hypnotics radically alter sleep patterns, with a decrease in slow-wave and rapid-eye-movement sleep but increases in stages I and II; zolpidem, however, increases slow-wave sleep without any alteration in rapid-eye-movement sleep. In other words zolpidem prolongs sleep more naturally. The effect of zopiclone on slow-wave sleep is controversial.6-8 Whether or not the production of a more normal EEG pattern of sleep influences the likelihood of dependence and withdrawal remains to be demonstrated, but at least this would seem to be a step in the right direction. Stress Clinic,

Maudsley Hospital, London SE5 8AZ, UK

DAVID WHEATLEY

D. Zopiclone: a non-benzodiazepine hypnotic controlled comparison to temazepam in insomnia. Br J Psychiatry 1985; 146: 312-14. 2. Deary IJ, Tait R. Effects of sleep disruption on cognitive performance and mood in medical house officers. Br Med J 1987; 295: 1513-16. 3. Wheatley D. Zolpldem: a new imidazopyridine hypnotic. Psychopharmacol Bull 1989; 25: 124-27. 4. Langer SZ, Arbilla S, Scatton B, Niddam R, Dubois A. Receptors involved m the mechanisms of action of zolpidem. In: Sauranet JP, Langer SZ, Morseli PL, eds. Imidazopyridine in sleep disorders: a novel experimental and therapeutic approach. New York: Raven Press, 1988: 55-70. 5. Wheatley D, ed. The anxiolytic jungle: where next? Chichester: John Wiley (in press). 6. Jovanovic UJ, Dreyfus JF. Polygraphical sleep recordings in insomniac patients under zopiclone or nitrazepam. Int Pharmacopsychiatry 1982; 17 (suppl 2): 136-45. 7. Wright NA, Belyavin A, Borland RG, Nicholason AN. Modulation of delta activity by hypnotics in middle-aged subjects: studies with a benzodiazepine (flurazepam) and a cyclopyrrolone (zopiclone). Sleep 1986; 9: 348-52. 8. Mamelak M, Scima A, Price V. Effects of zopiclone on the sleep of chronic insomniacs. Int Pharmacopsychiatry 1982; 17 (suppl 2); Pharmacology 1983; 27 (suppl 2): 156-64.

1. Wheatley

Antibody avidity test for recent infection with hepatitis C virus SIR,-Low-avidity antibody is the predominant antibody produced in the first few months after infection with many viruses.1-3 We have looked for such antibodies to hepatitis C virus (HCV) in sequential sera from a patient with post-transfusion hepatitis after blood transfusion. The patient was given eight units of blood in August, 1988, and raised levels of alanine aminotransferase, consistent with post-transfusion non-A, non-B hepatitis, developed 46 days later. Sera taken from the patient and stored sera from all eight donors were tested in the Ortho Diagnostics System anti-HCV enzyme immunoassay.4 The samples collected on the dates shown in the table were tested according to the manufacturer’s instructions and also with a modification in which 8 mol/1 urea was added to the wash fluid for the first wash step in the assay. An additional wash with the manufacturer’s recommended wash solution to remove the urea was then done. The urea dissociates low-avidity antibody from antigen. This early antibody is detected in the unmodified assay but not detected in the presence of 8 mol/1 urea. As the immune response matures, more avid antibodies develop which are not dissociated from the antigen by treatment with urea. Low-avidity antibody was predominant in the sample collected 116 days after blood transfusion, although this result was just below ANTI-HCV ASSAYS BY ORTHO ELISA WITH AND WITHOUT UREA WASH

*6 months before and 13 months after donation. tAfter transfusion.

positive cut-off. A sample collected at 179 days also contained significant low-avidity anti-HCV although high-avidity antibody was also present. Potent high-avidity antibody predominated by day 415, and would have masked any low-avidity antibody present. These findings are consistent with a recent infection with

the

HCV. We did not have enough serum from the implicated donation it by the modified technique but samples collected from the donor 6 months earlier and 1 year later were tested in this way. The HCV antibody in these samples was predominantly of high avidity, which is consistent with infection months or years to test

previously. We suggest that the presence of low-avidity HCV antibody can be used as an indication of recent infection, in the absence of a specific IgM test, albeit over the limited time span of acute infection. Clinical Microbiology and Public Health Laboratory, Addenbrooke’s Hospital, Cambridge CB2 2QW, UK

T. G. WREGHITT

J. J. GRAY S. ALOYISUS M. CONTRERAS J. A. J. BARBARA

North London Blood Transfusion Centre, Edgware, Middlesex

Changes in the avidity and specificity of early IgM and IgG antibodies. Immunology 1968, 14: 39-52. Morgan-Capner P, Thomas HIJ. Serological distinction between primary rubella and

1. Webster RG. The immune response to influenza III.

2. 3. 4.

reinfection. Lancet 1988; i: 1397. Gray JJ, Wreghitt TG. Immunoglobulin G avidity in Epstein-Barr virus infections in organ transplant recipients. Serodiag Immunother Infect Dis 1989; 3: 389-93. Kuo G, Choo Q-L, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244: 362-64.

Migraine and visual evoked potentials SIR,-We agree with Dr Peatfield (Feb 24, p 480) that a migraine replace the clinical diagnosis of headache. However, it is

test cannot

difficult

from a young child. in clinical use have been descriptions, unsupported by readily available diagnostic markers.1,2 Markers and correct definitions are fundamental to the evaluation of research and treatment.2 We can report that there is no correlation between VER (visual evoked response) amplitude and the duration of headache history. However, whether cause or consequence of migraine can be interpreted from this data is questionable because of the paroxysmal nature of migraine and what we know so far about the pathophysiology of migraine. The subject of patient personality is very interesting. In our study most patients were invited to attend the clinic from general practice, so the consultation was doctor initiated. Preliminary results from a study comparing childen with tension headache or migraine and controls indicate no increase in fast-wave activity in children with tension headache over that in controls. The diagnosis of common or classical migraine using VER with stimuli of different wavelengths is possible (unpublished). In reply to Dr van Dijk and colleagues’ letter (Feb 24, p 480) we believe that the reason why our VER analysis technique is more specific in terms of migraine diagnosis is that we have greatly amplified the EEG, on both x and y axes, after transient flash and pattern stimulation. Such a recording clearly differentiates the beta rhythm from other background activity such as electromyographic artifact. Other workers may have failed to notice enhanced beta rhythm in migraineurs because of the difficulties of quantifying beta rhythm with conventional EEG techniques. The VEPs consisted of averaged responses to five consecutive stimuli, and no attempt was made to analyse responses from individual stimuli. This was repeated four times for each stimulus parameter, and amplitudes and frequencies were averaged to quantify fast-wave activity (FWA). All analysis was made by peak-to-peak measurements in the last 250 ms of the recording. Analyses were done "blind", with no prior knowledge of clinical to

obtain

a

reliable

history

Furthermore, the migraine definitions