732

Advertising acyclovir p 288) of Wellcome Foundation implies that the Medicines Control Agency endorsed the company’s recent promotion of the use of ’Zovirax’ (acyclovir) in post-herpetic neuralgia. This is not the case. Zovirax is indicated for the treatment of herpes zoster infections. The clinical trials presented to the Medicines Control Agency were not sufficient to support claims that acyclovir "lessens the suffering or reduces the chances of post-herpetic neuralgia", as stated in the company’s promotion. The company have agreed to withdraw promotional material making this claim.

SIR,-Dr Williams (Feb 3,

Limited

Medicines Control Agency, Market Towers, London SW8 5NQ, UK

Mechanism of

K. JONES

paracetamol toxicity

SIR,-Studies of paracetamol (acetaminophen) induced liver damage in laboratory animals suggest that toxicity results from oxidation of paracetamol to a reactive metabolite, N-acetyl-pbenzoquinone imine. After therapeutic doses this species is detoxified by hepatic glutathione to form 3-(glutathione-S-yl)paracetamol, which is readily excreted. However, after an overdose the glutathione detoxification mechanism is overwhelmed and the toxic metabolite binds to available cysteine groups on proteins to form 3-(cystein-S-yl)paracetamol protein adducts.1-3 We have developed an immunoassay for 3-(cystein-S-yl)paracetamol derivatives that does not rely on radioisotopes and is insensitive to free paracetamol and metabolites.4,5 In laboratory animals 3-(cystein-S-yl)paracetamol protein adducts increase in hepatic cytosol after paracetamol overdose and then decline. In parallel with this decline, the adducts appear in the serum, accompanied by the appearance of serum alanine aminotransferase (AlaT). We hypothesised that the adducts in serum were of hepatic origin, being derived from liver cells damaged by hepatotoxicity, and we suggested that serum 3-(cystein-S-yl)paracetamol protein adducts are a specific marker for paracetamol hepatotoxicity.6 From thirty patients presenting with paracetamol poisoning at Rigshospitalet, Copenhagen, plasma obtained at admission was stored at - 20°C until analysis for 3-(cysteine-S-yl)paracetamol. All patients, except the one admitted 58 h after stated overdose, were immediately treated with N-acetylcysteine (NAC) 300 mg/kg body weight intravenously. Blood samples were monitored for serum AlaT and for plasma paracetamol concentrations. Eleven patients were at high risk of severe liver damage on the Prescott classification?,8Five (group I) were treated with NAC within 8 h of overdose; five were treated later than 8 h and one was untreated (group II). Three patients were at moderate risk (group III) and sixteen were at low risk of hepatotoxicity (group IV). Data for the four groups are shown in the table. In paracetamol overdose patients at severe risk, the relation between plasma AlaT and 3-(cystein-S-yl)paracetamol protein adducts at the time of admission is highly suggestive of a dominant mechanistic role of this binding (figure). This is the first direct evidence of a similar mechanism of paracetamol-induced hepatic necrosis in man and in laboratory animals. The indirect evidence of an identical mechanism of paracetamolinduced liver damage in man and animals prompted treatment of paracetamol intoxicated patients with NAC (1, 2, 7, 8). Although CONCORDANCE BETWEEN HEPATOTOXICITY AND PARACETAMOL PROTEIN ADDUCTS

*Median

(range) at admission. tOnly one patient had measurable

levels

(0 19)

Adduct and AlaT levels in

severe

risk paracetamol

poisoning.

this treatment has never been evaluated in a controlled trial, there is substantial evidence for its beneficial effect. This is a classic example of a treatment based on mechanistic insight. The assay based on antibody to 3-(cystein-S-yl)paracetamol derivatives should provide further insight into the processes leading to cell death after binding of the toxic benzoquinone imine to hepatic proteins. This insight may lead to new treatments which are needed in patients presenting too late for treatment with NAC. J. A. HINSON D. W. ROBERTS National Center for Toxicological Research, R. W. BENSON Jefferson, Arkansas, USA Department of Medicine, Rigshospitalet, University of Copenhagen Department of Pharmacology, University of Copenhagen, DK-2100

Copenhagen,

Denmark

K. DALHOFF S. LOFT H. E. POULSEN

1. Mitchell

JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Kaiser H Acetaminophenhepatic injury: Protective role of glutathione in man and rationale for therapy, Clin Pharmacol Ther 1974; 16: 676-84. 2. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med 1988; 319: 1557-62 3. Dahlin DC, Miwa GT, Lu AYH, Nelson SD. N-acetyl-p-benzoquinone imine: a cytochrome P-450 mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 1984; 81: 1327-31. 4. Roberts DW, Pumford NR, Potter DW, Benson RW, Hinson JA. A sensitive induced

immunochemical assay for acetaminophen-protein adducts. J Pharmacol Exp Ther 1987; 241: 527-33. 5. Potter DW, Pumford NR, Hinson JA, Benson RW, Roberts DW. Epitope characterization of acetaminophen bound to protein and nonprotein sulfhydryl groups by an enzyme linked immunosorbent assay. J Pharmacol Exp Ther 1988; 248: 186-90. 6. Pumford NR, Hinson JA, Potter DW, Rowland KL, Benson RW, Roberts DW. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophen treated mice. J Pharmacol Exp Ther 1989; 248: 190-96. 7. Prescott LF, Illingworrh RN, Critchley JAJH, Steward MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcysteine: The treatment of choice for paracetamol poisoning. Br Med J 1979; ii: 1097-100. 8. Prescott LF, Wright N, Roscoe P, Brown SS. Plasma paracetamol half-life and hepatic necrosis in patients with paracetamol overdose. Lancet 1971; i: 519-22.

Treatment failure in

meningococcal meningitis

SIR,-Neisseria meningitis with reduced sensitivity to penicillin has been recorded in the UK.1 We report a case of meningococcal meningitis which relapsed clinically 5 days after treatment with benzylpenicillin. N meningitidis was reisolated from the cerebrospinal fluid (CSF) obtained on repeat puncture. An 18-year-old man presented with a 2-day history of malaise and headache, followed by photophobia and vomiting. He was apyrexial and had a widespread purpuric rash and severe neck stiffness. He was given 1 MU of benzylpenicillin intravenously immediately before lumbar puncture, then 0-5 MU 6-hourly. The CSF contained 13 760 x 106 white cells/1 (100% polymorphs), protein 6.1 g/1, and glucose 0-88 mmol/1. Numerous gram-negative diplococci were seen in a gram-stained film. N meningitidis, initially reported sensitive on disc testing to penicillin and chloramphenicol, was cultured from the CSF.

733

Despite an initial response he had persistent pyrexia with worsening headache on days 2 and 3 of treatment. On day 5 he had neck rigidity, vomited, and became peripherally cyanosed. The antibiotic therapy was changed to chloramphenicol 500 mg 6-hourly. The CSF contained 240 x 106 white cells/1 (50% polymorphs), protein 28 g/1, and glucose of 15 mmol/1. No organisms were seen in the gram-stained film but culture yielded a scanty growth of N meningitidis. Within 24 hours his clinical state had improved and his temperature settled. He was discharged 1 week later. There have been reports of N merzingitidis with reduced sensitivity to penicillin from other countries/,3 and some of these organisms have been penicillinase producers. The organism in this case was N rneningitidis, group C, type 2B. The meningococcus isolated from both CSF specimens had a minimum inhibitory concentration to benzylpenicillin of 0-64 mg/1 (expected value, if fully sensitive less than 008). Both isolates were penicillinase negative. The dose of benzylpenicillin used was low by some recommendations,"but has given satisfactory results in this unit and elsewhere.s This case suggests the advisability of using high-dose benzylpenicillin in the initial treatment of meningococcal infection. Ifa satisfactory response is not obtained, a further antibiotic, such as chloramphenicol, should be started pending sensitivity results. Connrmadon of grouping, typing, and MIC values were kindly done by the meningococcus reference laboratory of Manchester Public Health

Laboratory. Leeds Regional Public Health Leeds LS15 7TR, UK

Laboratory,

P. C. TURNER K. W. SOUTHERN

Department of Infectious Disease,

N. J. B. SPENCER

Seacroft Hospital. Leeds

H. PULLEN

Sutcliffe EM, Jones DM, El-Sheikh S, Percival A. Penicillin-insensitive meningococci in the UK. Lancet 1988; i: 657-58. 2. Saex-Nieto JA, Fontals D, Garcia De Jalon J, et al. Isolation of Neiserria meningitidis strains with increase of penicillin minimal inhibitory concentrations. Epidemiol Infect 1987; 99: 463-69. 3. Botha P. Penicillin-resistant Neisseria meningitidis in South Africa. Lancet 1988; i: 54. 4. Macleod J, Edwards S, Bouchier J, eds. Davidson’s principle and practice of medicine, 15th ed. Edinburgh: Churchill Livingstone, 1987: 639. 5. Sangster G, Murdoch J, Gray JA. Bacterial meningitis 1940-79. J Infect 1982; 5: 1.

245-55.

Treatment of acute lymphoblastic leukaemia after relapse SIR,-Professor Graham-Pole (Dec 23/30, p 1517) describes an unsuccessful study in America attempting to evaluate the role of megatherapy with bone-marrow rescue in children with relapsed acute lymphoblastic leukaemia (ALL). The trial was stopped because of the low number of patients who reached the stage of receiving an allograft. Of 100 patients enrolled only 16 had HLA-matched donors and of these only 7 eventually had

transplants. Although allogeneic transplant procedures have received considerable publicity in recent years these data exemplify the limited role that this procedure has in practice’ and there is clearly an urgent need to seek alternative methods of second-line treatment.

Until better ways of reducing the morbidity from mismatched or matched unrelated donors are found clinicians must rely on retreatment with slightly modified conventional

donor either

chemotherapy

or

megatherapy

with

autologous

bone-marrow

rescue.

Authors of reports of small, often single-centre, studies have claimed encouraging results with the latter approach,2,3 but in view of the considerable cost and potential morbidity of high-dose chemotherapy/radiotherapy it is essential, as Graham-Pole suggests, to evaluate this treatment in a randomised fashion. The Medical Research Council working party on leukaemia in childhood plans to embark on such a study later this year. All children (excluding late isolated testicular relapse) who relapse after the standardised UKALL ALL regimens and who do not have an allogeneic donor will be eligible for study. Because prior therapy will be the same in all patients, the limitation present in many previous studies of patient selection and heterogeneous

chemotherapy regimens should be avoided. The study will probably receive widespread support from paediatric oncologists and haematologists who treat most children with leukaemia in the UK, with referral of patients to paediatric transplant centres as necessary. After first

marrow or extramedullary relapse patients will undergo reinduction therapy with a standard four-drug regimen. They then will receive an "extended consolidation" phase based on the German BFM protocols and following this be randomised to either megatherapy with cyclophosphamide, total body irradiation, and unpurged autologous bone-marrow rescue, or 18 months’

continuing chemotherapy. The latter will be based on the St Jude’s rotating drug regimen, which has the best reported non-transplant results in childhood ALL.4 In the UK about 100 children per

annum have relapses in the bone marrow and would be eligible for the study. This study would be one of the few prospective randomised evaluations of megatherapy and it is hoped should provide an answer within 3-4

years. Department of Haematology, Children’s Hospital,

DARBYSHIRE

Birmingham

P.

Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK

C. R. PINKERTON

Royal Manchester Children’s Hospital, Manchester

R. F. STEVENS

J.

Royal Hospital for Sick Children,

A. OAKHILL

Bristol

1. Chessells J, Rogers DW, Leiper AD, et al. Bone marrow transplantation has a limited

role in prolonging second marrow remission in childhood lymphoblastic leukaemia. Lancet 1986; i: 1239-41. 2. Kersey JH, Weisdorf D, Nerbet ME, et al. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med 1987; 317: 461-67. 3. Sallan SE, Niemeyer CM, Billet AL, et al. Autologous bone marrow transplantation for acute lymphoblastic leukemia. J Clin Oncol 1989; 7: 1594-601. 4. Rivera GK, Buchanan G, Boyett JM, et al. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse: a pediatric oncology group study. N Engl J Med 1986; 315: 273-78.

Prodromal cutaneous lesions in adult T-cell

leukaemia/lymphoma SIR,-Dr Bunker and colleagues (Feb 17, p 426) report the use of the polymerase chain reaction (PCR) to identify proviral human T-lymphotropic virus type-1 (HTLV-1) integration during both the indolent cutaneous and lymphomatous phase of HTLV-1 infection. We report a similar case, albeit with a shorter prodrome, which

was

identified when adult T-cell

leukaemia/lymphoma

(ATLL) developed 5 years later. A 56-year-old Jamaican woman resident in the UK since 1955 presented in October, 1984, with intermittent crops of pruritic papules on her upper arms, back, and buttocks. She had flesh coloured, hyperpigmented papules 3-5 mm in diameter with overlying lichenification secondary to scratching. Identical papules recurred and in 1988 skin biopsy of the upper arm showed hyperkeratosis, mild acanthosis, and negligible perivascular infiltrate of lymphocytes; prurigo was diagnosed. Her skin problems fluctuated but in January, 1990, the same eruptions appeared on the forehead and cheeks as discrete soft dermal papules 3-5mm in diameter, in addition to those on the arms, back, and buttocks. Malaise, vomiting, and abdominal pain necessitated admission to hospital, when she proved to have supraclavicular, paratracheal, and hilar nodes. Serum calcium was 5-09 mmol/l. Biopsy of a non-excoriated papule and a supraclavicular lymph node showed ATLL. She had mild leucocytosis (13-6 x 109/1); however, large pleomorphic T cells showing multilobed nuclei were present. Bone marrow was not infiltrated. Fluorescence cytometry showed the T cells were of helper (CD4) phenotype with expression of IL2 receptor (CD25) and HLA-DR characteristic of ATLL. Seropositivity to HTLV-1was confirmed by ELISA. She is having intensive chemotherapy. Subclinical ATLL associated with cutaneous lesions, antibody to HTLV-1, mild abnormal lymphocytosis, and long-term survival is