1044

compared the two drugs with placebo. The design of the trialincorporated stratification of the patients by numbers of previousepisodes, a factor relating to prognosis which limited intake into thestudy. Even so, the numbers cannot be regarded as "too small forany conclusions to be drawn". The results presented indicate thatactive drug treatment was more effective than placebo in preventingrelapse in patients with just one episode of depression before theindex episode and that the differences between lithium and

amitryptiline in preventing relapse in unipolar depression wereminimal. The findings do not demonstrate that lithium and

amitryptiline are "equally potent in preventing relapse". As wepoint out, there was an 80% chance of detecting a relapse rate ratioas small as 2:1 on the two treatments.Your editorial concludes with a series of questions to be answered

by further studies. No doubt these are important, but meanwhile anomission from the editorial must be repaired by pointing out that nomore than a preliminary account of the M.R.C. trial, concentratingprincipally on the relapse-rates, has so far appeared. The reportconcludes with the observation that "the rational determination oftreatment must take account of other factors associated withadministration of the drug, including its impact on the naturalhistory of the disease and the quality of life of the patient and, mostimportant of all, its adverse side-effects. These, and other topics willbe discussed at length in a full account of the investigation". It

surely would be wise to suspend judgment on the implications of alarge-scale study which has taken nearly 4 years to complete until allthe results have been analysed and published in full.

Craig Dunain Hospital,Inverness IV3 6JU

M.R.C. Biostatistics Unit,M.R.C. Centre,Hills Road,Cambridge CB2 2QH

Institute of Psychiatry,London SE5 6AF

IAIN GLEN

A. L. JOHNSON

MICHAEL SHEPHERD

PASSIVE SMOKING AND NICOTINE

SIR,-Basing your view on a recent Tobacco Advisory Councilmonograph on nicotine you state that passive smoking of nicotine"does not seem to be a hazard" (Oct. 3, p. 763). Before this notionbecomes hallowed in the literature, perhaps you will allow a fewrejoinders.Nicotine can produce an atopic dermatitis in hypersensitive

individuals.’ This "anaphylaxis of the skin" seems to be due tonicotine acting as a hapten, and can be induced by a single puff oftobacco smoke entering the atmosphere. Heavy passive smoking cancause Raynaud’s phenomenon, and nicotine may be the componentof smoke responsible for this effect.2 Nicotine is a co-carcinogen3 3and the thermal decomposition of nicotine (which occurs mainly inthe side-stream) gives rise to carcinogens such as dibenzacridines,dibenzocarbazole, and nitrosamines. It would be premature to

exculpate such suspect components. As a result of passive smoking,most urban non-smokers have nicotine in their body fluids for mostof their lives,4 and the long-term consequences of this are notknown. Passive smoking by non-smoking wives5,ó and husbands 7 ofsmoking spouses may be a cause of lung cancer. Passive smokinginduces increases in heart rate and blood-pressure in patients withangina pectoris, and this is believed to be due to nicotine. Similarcardiovascular effects have been observed in children acutely

1. Sudan JL. Contribution à l’étude du rôle allergènique de la fumée du tabac La nicotineun haptène. Allergie Immunol 1978, 10 (12)/2: 36-54.

2. Bocanegra TS, Espinoza LR. Raynaud’s phenomenon in passive smokers. N Engl JMed 1980; 303: 1419.

3. Bock FG. Co-carcinogenic activity of nicotine. Proc Am Assoc Cancer Res 1976; 17: 24 Russell MAH, Feyerabend C Blood and urinary nicotine in non-smokers. Lancet 1975,

i 179-81.5. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: a

study from Japan. Br Med J 1981; 282: 183-85.6 Trichopoulos D, Kalandidi A, Sparros L, MacMahon B. Int J Cancer 1981, 27: 1-4.7. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer Br

Med J 1981, 283: 916-17.8. Aronow WS. Effect of passive smoking on angina pectoris. N Engl J Med 1978; 299:

21-24

exposed to passive smoking, and, while psychological factorscannot be excluded, the observation 10 that children from homeswhere parents smoke have higher heart rates and blood-pressuresthan those from homes where no smoking occurs suggests thatpharmacological mechanisms are at least partly responsible. .

According to the 1979 U.S. Surgeon General’s report, Smokingand Health, nicotine in the environment is of concern becausenicotine absorbed by cigarette smokers is believed to contribute totheir increased risk of developing coronary heart disease (CHD).Hirayama5 studied the effect of passive smoking on death fromCHD and found no evidence of an effect. However, death fromCHD is a stringent criterion of CHD, and fatal CHD is uncommonin the Japanese, perhaps because of their high dietary intake ofeicosapentaenoic acid.

I

On the issue of nicotine and passive smoking a more reasonablestandpoint is still that of Schmeltz et all "... we are faced withthe question of whether low levels of chronic nicotine exposureaffect the non-smoker. This question needs to be answered by futureepidemiological studies".

50 Thong Lane,Gravesend, Kent DA12 4LD SHERRIDAN L. STOCK

NICOTINE, CARBON MONOXIDE, ANDHEART DISEASE

SiR,—Dr Wald and his colleagues (Oct. 10, p. 775) report someinteresting data on cotinine levels in pipe, cigar, and cigarettesmokers. The suggestion that their findings absolve nicotine as acause of coronary heart disease (CHD) is, however, contentious.Alternative explanations for the lower risk of CHD associated withpipe or cigar smoking may be offered.The rapid absorption of nicotine through the lungs makes each

inhaled puff of cigarette smoke equivalent to an intravenous bolusinjection of nicotine. Cigarette smokers are, therefore, exposed to anintermittent series of high-nicotine boli, associated with each puff.The absorption of nicotine from pipe and cigar smoke through thebuccal mucosa is slower and does not produce puff-by-puff nicotinepeaks in blood. The pattern of exposure to nicotine in inhaling andnon-inhaling smokers is thus very different, and nicotine delivery tothe heart or other organs cannot easily be predicted.Wald et al. also fail to consider the possibility of a synergistic

relation between nicotine and carbon monoxide. The highermortality from CHD in cigarette smokers may be related to anincreased myocardial oxygen demand caused by nicotine and adecreased myocardial oxygen supply produced by carboxyhaemo-globin (COHb). Furthermore, during an episode of myocardialischaemia, both nicotine and COHb can reduce the threshold forventricular fibrillation.z Cigarette smokers are, therefore, subjectedto dual stresses while primary pipe or cigar smokers, who have lowCOHb concentrations, are not.

Anaesthetics Laboratory,St Bartholomew’s Hospital,London EC1A 7BE

Y. SALOOJEEP. V. COLE

SIR,-We support the contention of Dr Wald and his colleaguesthat carboxyhaemoglobin (CoHb) levels in the blood of smokers maycorrelate well with their risk of acquiring vascular disease. Westudied 43 male cigarette smoking patients with arteriographicevidence of peripheral vascular disease (PVD) and compared their

9. Luquette AJ, Landiss CW, Merki DJ. Some immediate effects of a smokingenvironment on children of elementary school age. J Sch Health 1970;40: 533-36.

10. Luquette AJ, Merki D, Landiss C, Giam SS Some physiological reactions in childrenfrom smoking and non-smoking homes to a smoking environment SouthernDistrict AAHPER Proceedings 1971: 103-04.

11. Hirai A, et al. Eicosapentaenoic acid and platelet function in Japanese Lancet 1980, ii1132-33.

12. Schmeltz I, Hoffmann D, Wynder EL. The influence of tobacco smoke on indooratmospheres. Prev Med 1975; 4: 66-82

1. Russell MAH, Feyerabend C. Cigarette smoking a dependence on high nicotine boli.Drug Metabolism Review 1978; 8: 29-57.

2 Aronow WS. A critical review of the effect of nicotine and carbon monoxide on

coronary heart disease World Smoking Health 1976, 1: 20-24.

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CoHb levels with 25 age, sex, and weight matched smokers withoutPVD, and a control group of 25 similarly matched non-smokerswithout PVD.I There was no significant difference in overallcigarette consumption between the two smoking groups (X2 =0-23,not significant), but those smokers with PVD had significantlygreater CoHb levels (5 - 107o) than those smokers without PVD(3.4%)(t=3’37, p<0.001).These data, with Wald’s findings, do suggest that CoHb or a

substance as yet unmeasured but with similar blood levels, doesprovide a sensitive index for the risk of development of vasculardisease.

University Surgical Unit,Southampton General Hospital,Southampton SO1 6HU

C. CLYNEP. J. ARCH

SIR,&mdash;Dr Wald and his colleagues report higher cotinine levels inpipe smokers than in cigarette smokers. Epidemiological evidenceindicates that the risk of coronary heart disease is little raised in pipesmokers but considerably raised in cigarette smokers. Theycombine these findings to argue that nicotine is unlikely to be themajor cause of the excess coronary heart disease mortality incigarette smokers. Those who have espoused a nicotine model ofsmoking would like to be able to welcome this conclusion, butcaution is necessary before accepting it.

While cotinine may be used as a marker of total nicotine intake,different forms of tobacco use involve different routes of absorption,and it cannot be assumed that a given level of cotinine implies aparticular level of circulating nicotine. For example, we recentlyreported closely similar plasma nicotine levels in daily dependentsnuff takers and cigarette smokers, but the snuffers had

considerably higher cotinine levels. 2

In pipe smokers, who keep their pipes in the mouth for longperiods, it is likely that much of the nicotine is swallowed in saliva,metabolised to cotinine in the liver, and hence never reaches thesystemic circulation as nicotine. Their cotinine levels are thereforenot a valid indicator of nicotine dose either to the brain or to thecardiovascular system. Direct measurement of nicotine levels in

plasma indicates that non-inhaled smoking, whether of pipes orcigars,3-5 gives rise to only modest doses of nicotine in the systemiccirculation, which certainly do not rival those achieved by cigarettesmokers.

The data on blood carboxyhaemoglobin as reported do not permita valid comparison of CO intake from cigarette and cigar smoking,since 89% of the cigarette smokers but only 47% of the cigarsmokers had smoked already on the day of attendance. Noninhaling,mainly primary cigar smokers absorb little CO, but those whoswitch from cigarettes often continue to inhale. Did those cigarsmokers who were ex-cigarette smokers and who had alreadysmoked on the day of their visit to the clinic have CoHb (and,indeed, cotinine) levels substantially different from those of thecigarette smokers?

This paper does not advance our understanding of whethernicotine, CO, or some other constituent of cigarette smoke is

responsible for the excess risk of coronary heart disease in smokers.

Addiction Research Unit,Department of Psychiatry,Institute of Psychiatry,London SE5 8AF

M. J. JARVISM. A. H. RUSSELL

1. Clyne CAC, Arch PJ, Webster JHH, Chant ADB. Arch Surg (in press)2. Russell MAH, Jarvis MJ, Devitt G, Feyerabend C. Nicotine intake by snuff users Br

Med J 1981; 283: 814-17.3 Turner JAMcM, Sillett RW, McNichol MW The inhaling habits ofpipe smokers. Br

J Dis Chest 1981, 75: 71-76.4 Turner JAMcM, Sillett RW, McNichol MW. The effect of cigar smoking on

carboxyhaemoglobin and plasma nicotine concentrations in primary pipe and cigarsmokers and ex-cigarette smokers. Br Med J 1977; i 1387.

5 Russell MAH, Jarvis MJ, Feyerabend C. A new age for snuff Lancet 1980; i: 474-75.

SKIN PROBLEMS IN CHRONIC ACTIVE HEPATITIS

SIR,&mdash;Dr Powell and Dr Rogers (Sept. 5, p. 525) and ProfessorRebora (Oct. 10, p. 805) describe lichen planus associated withhepatic disorders. We have seen a case of a dermatological compli-cation of chronic active hepatitis (CAH) which may throw somelight on the aetiology of the condition. Our patient presented withpalmar and plantar hyperkeratosis, and subsequent investigationsrevealed hepatitis B surface antigen (HBsAg) negative CAH.A 58-year-old man presented with a 3 month history of malaise,

weight loss, generalised pruritus, jaundice, and increased thicknessof the skin over his palms and soles. Investigations revealed anerythrocyte sedimentation rate of 73 mm/h, bilirubin 54 mmol/l,alkaline phosphatase 250 IUII, aspartate transaminase 84 IU/1,smooth muscle antibody test positive, antimitochondrial antibodynegative as was antinuclear factor. HBsAg was negative and urinaryarsenic screening was negative. Chest X-ray and barium meal were-normal.

Liver biopsy showed the typical features of CAH. Skin biopsy ofthe affected area revealed focal hyperkeratosis and parakeratosiswith irregular acanthosis. There was no evidence offungal infectionand no oral lesions were present.Rebora proposes that the underlying disorder in the cutaneous

manifestations of CAH is autoimmune and suggestive of a graft-versus-host reaction. Two of his seven cases of lichen planus hadCAH but no HBsAg results are described. Previous work has showna strong link between underlying suppressor T cell abnormality andHBsAg negative CAH but not for HBsAg positive cases, and thecutaneous manifestations may be confined to those patients whoseunderlying liver disorder is part of a generalised T cell or auto-immune defect. No T cell studies were possible in our patientbecause steroid therapy had been started.

We thank Dr J. H. Jones for permission to report this case.

Department of Medicine,University Hospital of Wales,Heath Park, Cardiff

B. CHEONG

D. B. JONES*

*Present address: Diabetes Research Laboratories, Radcliffe Infirmary, Oxford.

SIR,-Professor Rebora describes erosive lichen planus in patientswith severe chronic liver disease. We have encountered two similarcases.

A 55-year-old woman presented with a 2 month history of a soretongue. She was known to have chronic active hepatitis withcirrhotic change, proved on liver biopsy. The surface of her tonguewas white and atrophic with several erosions. The appearance wasthat of erosive lichen planus. 6 months later flat-topped violaceouspapules typical of lichen planus developed on the dorsum of her leftfoot.A 21-year-old man presented with an 8 month history of a sore

mouth. He was known to have cirrhosis and sclerosing cholangitissecondary to ulcerative colitis, confirmed by liver biopsy andcholangiography. In his mouth there was a white reticular patternon the gum margin and buccal mucosa, and his tongue was atrophic,white, and ulcerated. Oral biopsy-confirmed the diagnosis of lichenplanus. There were no skin lesions.Seehafer et al. have reported the development of lichen-planus-

like skin lesions in patients with primary biliary cirrhosis treatedwith penicillamine. Neither of our patients had received

penicillamine at any time. Over the same three year period in whichwe saw these two patients, we have had no cases of ordinary lichenplanus referred from a large unit specialising in liver disease. Thissuggests that liver disease might make lichen planus assume theerosive form.

Department of Dermatology,King’s College Hospital,London SE5 9RS

B. E. MONKA. C. PEMBROKE

1. Tremolada F, Faltorich G, Paniebiaco G, Ongaro G, Realai G. Suppressor cell activityin viral and non viral chronic active hepatitis. Clin Exp Immunol 1980, 40: 89-95.

2. Seehafer JR, Rogers RS III, Fiening CR, Dickson ER. Lichen planus-like lesionscaused by penicillamine in primary biliary cirrhosis. Arch Dermatol 1981; 117:140-42.