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The lymphocyte hyporesponsiveness found in pre-eclampticpatients may be a consequence rather than the cause of theirclinical disease. Any alteration in maternal response maydepend on changes in plasma suppressor factors as well aslymphocytes, so it is desirable that in vitro tests of lymphocytefunction should be carried out both in autologous and non-pregnant plasma.

Departments of Microbiologyand Obstetrics and Gynæcology,

University of OtagoDunedin, New Zealand

J. F. T. GRIFFINE. W. WILSON

EXPOSURE AND RESPONSE TO TETANUS TOXOIDIN INDIANS

SIR,-There is a danger that people in developing countriesmay transfer the data of Collier et al.l on antibody responsesto reinforcing doses of tetanus vaccines to their own environ-ment where the situation may be entirely different. Our experi-ence highlights this point.

Insufficient exposure to antigen. In India cooperation withtetanus immunisation is poor because it means a schedule ofthree spaced injections. Only 10% of a random urban popula-tion tested showed protective antitoxin titres in their blood(0-01 IU/ml).2 The educated upper class are conscious of theneed to administer triple vaccine to children in the first yearof life, but the need for booster doses is not widely recognised.Only 15% of a new batch of medical students were protectedagainst tetanus. The overriding problem in all sectors of

society is thus one of insufficient exposure to tetanus toxoid.Reactions to adsorbed toxoid are practically unknown.

Chronic antigenic stimulation.-The Indian jejunal mucosais abnormal by Western criteria. This is not genetically deter-mined because similar changes were found in American PeaceCorps workers who had lived in India for more than threemonths.3 The abnormalities may be related to chronic bac-terial contamination of the small bowel.4 Certain clostridial

organisms can be shown to excite B and T cell responses inPeyer’s patches.5 Such sensitised cells induce systemic im-munity on transport to the spleen and mesenteric lymph-nodes.6 If Clostridium tetani chronically contaminates thesmall bowel then this could be a means of inducing low-gradeantitoxin production. Indeed, we regularly find some antitoxintitre in people with no history of immunisation. Such individ-uals given tetanus toxoid may be unable to mount adequateantibody responses because they are partly desensitised. Thishypothesis requires scientific support but could explain ourfindings with booster doses of toxoid.

Effects of booster toxoid doses.-Healthy individuals with ahistory of exposure to tetanus toxoid showed only a fourfoldincrease in titre with 5 Lf adsorbed toxoid, whilst othersshowed a tenfold increase with a special 100 Lf vaccine (GlaxoLaboratories India Ltd). This quantum jump in titre happenedirrespective of the basal titre.7 Titres were estimated by themouse neutralisation test. It seems, therefore, that responses tobooster toxoid doses in India are attenuated when compared tothose demonstrated by Collier et al. and will not afford protec-tion against tetanus for as long as 5-10 years.Department of Medicine,K. E. M. Hospital,Bombay 400 012, India;and Glaxo Laboratories India Ltd,

Bombay

F. D. DASTUR

J. A. D’SAV. P. AWATRAMANIS. K. DIXIT

1. Collier LH, Polakoff S, Mortimer J. Lancet 1979; i: 1364.2. D’Sa JA. J Postgrad Med 1974; 20: 15-20.3. Baker SJ, Mathan VI. Am J Clin Nutr 1972; 25: 1045-55.4. Bhat P, Shantakumari S, Rajan D, Mathan VI, Kapadia CR, Swarnabai C,

Baker SJ. Gastroenterology 1972; 62: 11-15.5. Muller-Schoop JW, Good RA. J Immunol 1975; 114: 1752-63.6. Rothberg RM, Kraft SG, Michalities SM. J Immunol 1973; 111: 1906-19.7. Dastur FD, D’Sa JA, Badami PV, Awatramani VP, Dixit SK. J Postgrad

Med (in press).

MANAGEMENT OF CIMETIDINE OVERDOSE

SIR,-We read with interest the recent report of a case ofcimetidine and oxazepam intoxication.’ Whilst the outcomewas satisfactorv we are concerned that forced diuresis was usedfor the treatment of cimetidine poisoning. In our experience,and that of others ingestion of cimetidine in acute overdoseis not associated with serious consequences.The National Poisons Information Service has detailed

information on four children and fourteen adults admitted tohospital in the past two years after an overdose of cimetidine.None of the four children reported any symptoms and noabnormal signs were observed. All were fit and well when dis-charged. Seven adults ingested cimetidine alone; five patientsremained symptom-free, one had a sinus tachycardia, and theother had mild abdominal discomfort. Four patients took cime-tidine together with alcohol, and three of these had eitherdrowsiness or dizziness. The remaining patients had taken avariety of drugs in addition to cimetidine, and remained eithersymptom-free or had symptoms or signs attributable to the in-gestion of the other drugs. Three of the seven adults whoremained completely symptom-free had taken 20 g of cimeti-dine ; one of these had a blood cimetidine level (determined bybiochemistry department, Smith Kline and French) of 45.8 8mg/1 3 ; hours after ingestion of the overdose (contrasted witha level of 18-7 mg/l at 8 hours in van Rijthoven’s patienttreated by forced diuresis).

In view of the apparent lack of toxicity of cimetidine in over-dose we recommend that treatment consist of gastric lavage, orthe administration of syrup of ipecacuanha, provided that notmore than 4 hours have elapsed since ingestion of the drug,followed by supportive measures and symptomatic treatmentonly. We would not advise using forced diuresis, a procedurewhich is not without risk. Moreover, there is no evidence, toour knowledge, that forced diuresis enhances the excretion ofcimetidine from the body.Poisons Unit,Guy’s Hospital,London SE1 9RT

T. J. MEREDITHG. N. VOLANS

PHENYLPROPANOLAMINE AND MENTALDISTURBANCES

SIR,-Phenylpropanolamine (PPA) is commonly used as asystemic nasal decongestant in upper respiratory infectionsand in secretory otitis media, either alone or in combinationwith an antihistamine. It is also available in a number of prep-arations as an appetite suppressant.3 PPA is structurally verysimilar to amphetamine, a potent central stimulant drug whichalso can induce paranoid psychosis.’

During 1979 the Swedish Adverse Drug Reaction Com-mittee has received several reports of psychic disturbances dur-ing treatment with preparations containing PPA. Sixty-onecases have been reported, forty-eight in children aged 0-15.The dominant symptoms were restlessness, irritability, aggres-siveness (especially in younger children), and sleep distur-bances.

Five cases of psychotic episodes during PPA intake have alsobeen reported. Two boys, aged 3 and 8, were mentally affecteda few hours after ingestion of PPA (’Rinexin’; Leo) with confu-sion and inability to recognise their parents. The symptomsdeclined over a couple of hours. A 4-year-old girl had episodesof visual hallucinosis and a grand-mal seizure after PPA

together with the antihistamine brompheniramine (’Lunerin’;Draco). A 25-year-old woman became increasingly excited and

1. van Rijthoven AWAM. Cimetidine intoxication. Lancet 1979; ii: 370.2. Illingworth RN, Jarvie DR. Absence of toxicity in cimetidine overdosage. Br

Med J 1979; i: 453-54.3. Med Lett Drugs Ther 1979; 21: 16, 65.4. Kalant OJ. The amphetamines. Toronto: University of Toronto Press, 1973.

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lacking in concentration with sleep/wakefulness disturbancesduring treatment with PPA (’Monydrin’; Draco). After ninedays she had vivid paranoid misconceptions and episodic mus-cular twitchings in the legs. The symptoms disappeared within24 h after cessation of the drug. A 17-year-old was admittedto a mental hospital three times within a few months withsigns and symptoms of acute mania-like psychosis with exces-sive motor excitement, aggressive behaviour, and elevatedmood with uncontrollable thought and speech. During thethird admission he deteriorated with hallucinosis and confu-sion. After recovery it was revealed that he had taken largequantities of PPA (rinexin) and PPA and brompheniramine(’Rinomar’; Leo) before each episode.The therapeutic and prophylactic effects of PPA in upper

respiratory tract infections and in serous otitis media havebeen questioned. 1-6 Since psychic disturbances, including psy-chotic episodes, seem to be a problem, the prescribing of drugscontaining PPA should be more restricted.

Paediatrics Clinic I,Östra Sjukhuset,S-416 85 Gothenburg, Sweden GUNNAR NORVENIUS

Department of Drugs,National Board of Health and Welfare,Box 607, S-751 25 Uppsala

ERIK WIDERLÖVGUDMAR LÖNNERHOLM

VILOXAZINE AND MIGRAINE

SIR,-During an open study of the bicyclic tetrahydroxa-zine antidepressant viloxazine hydrochloride (’Vivalan’) wefound a high frequency of severe headache. Thirty depressedpatients started treatment with viloxazine at 150 mg/day individed doses, increasing by 50 mg/day every week to 300 mg/day if well tolerated. We asked about side-effects each week.Fourteen patients continued on the drug for the 6-week trialperiod, and nine of them complained of headaches. Among thesixteen drop-outs, ten withdrew because of adverse effects, ofwhom six had severe headaches. Three patients describedclassical migraine symptoms.

Case .—An 18-year-old woman was referred after an epsiode ofself-poisoning. She had a 3-month history of social withdrawal, tear-fulness, and poor attention, following a broken romance. After 5 daysof treatment with viloxazine she had several severe left supraorbitalheadaches accompanied by nausea and visual disturbances "likeflashes". The headaches were followed by a feeling of "slowness".Viloxazine was continued without recurrence of these symptoms.

Case 2.-A 54-year-old man presented with social withdrawal, tear-fulness, diurnal variation of mood, and suicidal ideation. A previousepisode of depression had responded to antidepressants. During thethird week of treatment with viloxazine he had a severe right-sidedheadache associated with "difficulty in seeing things properly". Withcontinued medication there was no recurrence.

Case 3.-A 31-year-old woman presented in the outpatient clinicwith a history of tearfulness, diurnal variations of mood, suicidalideas, and sleep and appetite disturbances. She complained of severeheadache throughout the trial. During the sixth week of viloxazinetreatment she awoke early on several occasions with a severe one-sidedheadache accompanied by nausea.None of these three patients had a personal or family history

of migraine. Three other patients had severe one-sided head-aches which did not recur after spontaneous omission of theirmedication. One of them had a history of migraine, and sheclaimed that while taking viloxazine her right-sided headaches

3. Kjellman N-I M, Harder H, Lindwall L. Synnerstad B. Long-term treatmentwith brompheniramine and phenylpropanolamine in recurrent otitismedia: a double-blind study. Otolaryngol 1978; 7: 257-61.

4. Meistrup-Larsen KI, Mygind N, Thomsen J, Sørensen H, Vesterhauge S.Oral norephedrine in the treatment of acute otitis media. Results of a doub-le-blind, placebo-controlled trial. Acta Otolaryngol 1978; 86: 248-50.

5. Olson AL, Klein SW, Charney E, JB, McInerny TK, MillerRL, Nazarian LF, Cunningham D. Prevention and therapy of serous otitismedia by oral decongestant: A double-blind study in pediatric practice.Pediatrics 1978; 61: 679-84.

6. Randall JE, Hendley JO. A decongestant-antihistamine mixture in the pre-vention of otitis media in children with colds. Pediatrics 1979; 63:483-85.

with blurring of vision were accompanied by new symptoms ofmild photophobia, weakness, and nausea. Her headache remit-ted after one day without tablets.Thus in a group of thirty patients on viloxazine 50% had

headaches, in several cases accompanied by nausea. The threepatients described in detail and two others with severe one-sided headaches had a migraine-like syndrome in the absenceof any history of migraine, suggesting a causal relationship tothe viloxazine treatment. Nausea and vomiting have beenreported with viloxazine,’ though the nausea is generallyascribed to a local gastrointestinal action; its association withheadache suggests cerebrovascular or central mechanism.The biological basis of migraine remains unresolved, but

there is general agreement on the involvement of cranial andextracranial blood vessels. An initial vasoconstriction, prob-ably due to a local release of noradrenaline acting on

a-adrenoreceptors, seems to be associated with the prodromalphase of the syndrome, while a secondary vasodilatation (orreactive hyperxmia) is a feature of the headache phase of anattack. Factors known to precipitate migraine include drugswhich potentiate or mimic the effects of the monoamines nor-adrenaline and 5-hydroxytryptamine (5-HT). Viloxazine in-hibits noradrenaline reuptake in both central and peripheralnervous tissue24 and potentiates certain effects of 5-HT, prob-ably by a presynaptic releasing action,3,5 These propertiesmight, in susceptible individuals, induce cerebrovascular vaso-constriction and lead to side-effects characteristic of migraine.Other centrally acting drugs with pharmacological propertiessimilar to those of viloxazine can also cause headache-e.g.,tricyclic antidepressants’ (most of which block noradrenalinereuptake) and fenfluramine a potent 5-HT releasing agent.Although in our trial with viloxazine the side-effects tended toemerge after several days of treatment, the headache problemwas transitory and subsided with continued medication.

Academic Unit for Clinical

Psychopharmacology,Guy’s Hospital Medical School,London SE1

T. R. E. BARNES*T. KIDGER

Research (Biology) Department,I.C.I. Pharmaceuticals Division,Alderley Park, Macclesfield,Cheshire D. T. GREENWOOD

*Present address: Department of Psychiatry, University of Cambridge ClinicalSchool, New Addenbrookes Hospital, Cambridge CB2 2QQ.

ANTIDEPRESSANTS AND CONVULSIONS

SIR,-Reports by Dr Tyrer and his colleagues (Oct. 13, p.798) and by Dr Mikhail (Nov. 3, p. 969) of seizures in patientstaking mianserin call for a fresh look at the incidence of seiz-ures and related problems in patients taking antidepressants.The number of cases of convulsions reported to the Com-

mittee on Safety of Medicines (C.S.M.) up to November, 1979,is shown in the table, which also gives the percentage share ofthe 8 812 000 prescriptions for antidepressants issued betweenApril, 1978, and June, 1979. The figures give some idea of the

1. Pinder RM, Brogden RN, Speight TM, Avery GS. Viloxazine A review ofits pharmacological properties and therapeutic efficacy in depressive ill-ness. Drugs 1977; 13: 401-21,

2. Greenwood DT. Animal pharmacology of viloxazine (vivalan). J Int Med Res1975; 3 suppl 3: 18-28.

3. Lippmann W, Pugsley TA. Effects of viloxazine, an antidepressant agent, onbiogenic uptake mechanisms and related activities. Can J Physiol Pharma-col 1976; 54: 494-509.

4. Blackburn TP, Foster GA, Greenwood DT, Howe R. Effects of viloxazine,its optical isomers and its ma)or metabolites on biogenic amine uptakemechanisms in vitro and in vivo. Eur J Pharmaol 1978; 52: 367-74.

5. Martin IL, Baker GB, Mitchell PR. The effects of viloxazine on the transportof noradrenaline, dopamine, 5-hydroxytryptamine and gamma-amino-butyric acid in rat brain tissue. Neuropharmacology 1978; 17: 421-23.

6. Wheatley D. Psychopharmacology in family practice. London: Heinemann,1973.

7. Sicuteri F, Del Berne E, Anselmi B. Fenfluramine headache. Headache1976; 16: 185-88.