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illustrating the aids and appliances which can be helpful. Because there are few children with osteogenesis imperfecta in any area, doctors, therapists, and social workers are seldom familiar with their needs. The demonstrations on television helped many parents to know what was possible. This is just one of the ways in which television can be of real help to us in medicine. To exploit the medium we need more insight into its workings. I suspect that many of the difficulties described by your correspondent arose because we fail to speak in a language the public understands or because we do not appreciate that the producers, reporters, and researchers are professionals in their own right. The words of Cromwell that we should "think it possible that we are mistaken" apply with as much force to ourselves. C R PATERSON University Department of Biochemical Medicine, Ninewells Hospital and Medical School, Dundee

Fatal chlormethiazole poisoning in chronic alcoholics

SIR,-I would like to draw your attention to two basic errors in the article by Dr Joan M Horder (3 September 1977, p 614), one of which significantly affects the conclusions drawn while the other must give rise to considerable confusion. Dr Horder, in referring to the findings of Fischler et al,' states that "the ingestion of two 500-mg tablets of chlormethiazole edisylate produces a maximum concentration of about . . 10 mg/100 ml plasma after 70 minutes. " It would appear that Dr Horder misread the original data, which indicated that this dosage produced a maximum level of about 1 ,ug/ml (0-1 mg/100 ml), a tenfold difference. We have checked with one of the authors (Ortengren), who has confirmed that the mean maximum concentration at the time stated was 0-122 mg chlormethiazole base/100 ml. There is thus a much wider margin between the therapeutic plasma concentration of chlormethiazole and the lowest recorded fatal level (2-5 mg/100 ml) than appeared from Dr Horder's paper, and her statement that her findings "question the statement that the drug is of low toxicity" is hardly justified. The second error concerns the substance (molar) concentrations of the drug given throughout Dr Horder's paper. It must be assumed that the concentrations measured by Dr Horder were, like those of Fischler et al, those of chlormethiazole base and that they were originally expressed in mass units, as is customary, so that the values given in parentheses in the paper are the original ones obtained. The substance concentrations (,umol/ 1) given, however, appear to have been calculated from the mass concentrations by means of a factor derived from the molecular weight of chlormethiazole edisylate (513 5), which differs very considerably from that of chlormethiazole base (16165). This miscalculation has thus given values which are approximately one-third of the true substance concentrations of chlormethiazole base, an anomaly which makes them incomprehensible and confusing. The reliability of drug concentration findings in samples of blood taken post mortem is doubtful.2 This is perhaps also a point where Dr Horder's findings might be questioned

BRITISH MEDICAL JOURNAL

in the light of the number of tablets reported to be recovered post mortem. Concerning the criticism of Dr Horder's article with regard to certain misleading statements made about medical indications for chlormethiazole in alcoholics, we fully endorse the views expressed by Dr J J Bradley (17 September, p 774) and Dr M M Glatt (22 October, p 1088). We do not consider chlormethiazole to possess specific antidepressant properties. It is a sedative/hypnotic and anticonvulsant.3 It has also been shown to have anxiolytic properties.4 Its use in alcoholism should be reserved for the management of acute withdrawal symptoms, including delirium tremens, preferably in a hospital-type setting where there are adequate facilities for supervision. The length of treatment should be limited to about eight days. Under such treatment conditions Glatt,5 6 as reaffirmed in his recent letter (22 October, p 1088), found there was no justification to contraindicate the use of chlormethiazole in the presence of depression. However, long-term outpatient treatment with sedative/hypnotics of an alcoholic patient suffering from depression may constitute a risk. Finally, I would like to thank Dr Horder for reporting her cases. Through her article the medical profession has been rightly warned of the risk involved in combining alcohol with sedative/hypnotics in outpatients suffering from alcoholism and depression. These at-risk patients should not be prescribed large quantities of any sedative/hypnotic., IAN M SLESSOR Medical Adviser, On behalf of Astra Chemicals Ltd, Watford, England, and Astra Lakemedel AB, Sweden

18 MARCH 1978

chlormethiazole alone and 0-5 mg/100 ml of chlormethiazole when taken with alcohol.)' The amount of a drug found in the stomach merely indicates the minimum quantity ingested and bears no relation to levels of drug attained in the plasma. Those intent on suicide invariably take far more of a noxious substance than is required to kill. I did not state that chlormethiazole was an antidepressant (19 November, p 1354). Since, however, clarity seems to have suffered in the condensation of the report I have rephrased the offending sentences in the revised version. I do not agree with Dr Slessor that "long term outpatient treatment with sedative/ hypnotics of an alcoholic patient suffering from depression may constitute a risk" (my italics). It clearly does, as five fatal cases in one district over a 22-year period shows. I note that since October 1977 local pharmacists and the hospital pharmacy have received supplies of chlormethiazole in bottles which now bear a warning label to the effect that it is additive with alcohol. I hope that the revised version of the article with the drug concentrations expressed in the form as originally submitted to the BM7, together with this letter, will correct the errors and misunderstandings which have occurred. J M HORDER Department of Pathology, Bedford General Hospital (South Wing),

Bedford

Jakobsson, S, and Moller, M, in Abstracts of the Sixth International Meeting of Forensic Sciences, Edinburgh, 1972, p 150. London, Association of the British Pharmaceutical Industry.

Watford, Herts

2

3

Fischler, S, Frisch, P, and Ortengren, B, Acta Pharmacologica Suecica, 1973, 10, 483. Gee, D J, Ciba Foundation Symposium 27 (new series), p 239. Amsterdam, Excerpta Medica, 1974. Lechat, P, Acta Psychiatrica Scandinavica, 1966, 42, suppl 192, p 15. Haslam, M T, Pharmatherapeutica, 1976, 1, 2. Glatt, M M, and George, H R, British MedicalJournal, 1964, 2, 445. Glatt, M M, George, H R, and Frisch, E P, British Medical J7ournal, 1965, 2, 201.

***Dr Slessor is quite correct in his diagnosis of the mistake that was made, in this office, in converting Dr Horder's original mass concentrations of chlormethiazole base (in mg/100 ml) into substance concentrations of the edisylate (in tmol/l). This was a subeditorial error for which we apologise and accept full responsibility (see leading article, p 668). Dr Horder's own reply to Dr Slessor's letter is printed below, while a revised version of her original short report appears at p 693ED, BMJ. SIR,-In replying to Dr Slessor's letter I shall deal with the points in the order in which they are raised, with the exception of the error in conversion of the chlormethiazole concentrations into SI units, to which you have already replied. Dr Slessor is quite correct when he states that the figures quoted from the paper of Fischler et al were misread. A poor-quality photostat was mainly responsible. I sincerely regret the error and apologise to Astra Chemicals for any embarrassment caused to them. There is indeed a wider margin between the therapeutic plasma concentration of chlormethiazole when taken in tablet form and the lowest recorded fatal levels (2-5 mg/100 ml of

College of Anaesthetists SIR,-I write in response. to the letter from Professor Donald Campbell and others (4 March, p 574) on the subject of a College of Anaesthetists. They suggest that the new charter of the Royal College of Surgeons of England offers complete independence to anaesthetists within the college. The new charter certainly does not offer parity-the number of fellows of the Faculty of Anaesthetists on the college council is not equal to the number of surgical fellows. Indeed, it would be unreasonable to expect our surgical colleagues to agree to this intrusion in their own college. They have conceded as much as they can and we are grateful to them for so much help in our adolescent years as a specialty. However, anaesthesia has now fully matured as a specialty. and, as the letter from the President of the Royal College of Surgeons and the deans of its faculties recently sent to all fellows points out, it is not unreasonable for many anaesthetists to aspire to complete independence in the form of their own college. The matter has already been under debate within the specialty for some 10 years, and the majority of those who have been unconvinced about the wisdom of establishing a college are concerned on financial grounds. The matter of finance is now being put to the test and the success or otherwise of the fund-raising activities will surely provide for a sensible and proper decision to be made as to whether a college should be founded or not. It is to be hoped that, when the decision is made, the verdict will be graciously accepted and supported by all anaesthetists whatever their current views.

BRITISH MEDICAL JOURNAL

18 MARCH 1978

In the meantime the Board of Faculty remains our academic body whose aims are to foster and encourage education and high standards of practice. No doubt it is supported in these activities by all those elected to the board. To suggest that any elected member who supports the concept of a separate college is acting disruptively is surely casting an unjust slur on individuals. If some of these individuals genuinely believed that the best way for anaesthetists to further the activities required of their academic body is through a College of Anaesthetists, then many of us believe that they are being truly loyal to their principles, their electors, and their specialty. PETER BASKETT

but there is the additional safeguard (mentioned in the appeal letter) that the trustees are charged with seeing that the money is used in a way which accords with the wishes of the majority of the specialty. Although the appeal is designed to raise funds for the foundation, the response it attracts will-given its objective-indicate the support for that objective. In a democratic society one has to accept that, while there are bound to be those who dissent, the will of the majority must prevail. It is to be hoped that this is conceded and opposition will not remain "adamant" if its numerical strength is less than its obvious ardour. The message to those who have considered all the facts and accept the desirability of Departmenit of Anaesthetics, Frenchay Hospital, establishing an independent College of Bristol Anaesthetists is clearly to respond to the appeal letter as soon and as generously as possible to SIR,-As a successful candidate in the recent assert their commitment. JAMES M B BURN election to the Board of Faculty of Anaesthetists Shackleton Department of of the Royal College of Surgeons of England Anaesthetics. General Hospital, may I reply to the letter from Professor D Southampton Southampton Campbell and others (4 March, p 574) ? The letter suggests that those elected to the board will be "willing to disregard their Cimetidine prophylaxis after renal declaration of loyalty to that body which, in transplantation fact, they clearly plan to disrupt." May I reassure the authors and others that I have no SIR,-The paper by Dr R H Jones and others prior intention to "disrupt" the board and (18 February, p 398) concerning the use of shall pursue the highest standards of repre- cimetidine to prevent upper gastrointestinal sentation in academic anaesthesia to the best haemorrhage after renal transplantation conof my ability and according to the dictates of tains misleading statements regarding the my conscience. pathophysiology of peptic ulcer disease in JOHN ZORAB transplant patients, and I cannot agree with the Departmenit of Anaesthetics, recommendation that cimetidine should be Frenchay Hospital, Bristol given as a matter of routine after transplantation. The authors state that the recent findings of SIR,-I cannot muster the authority of the AlcGeown et all in renal transplant recipients platoon of professors who were signatories to reinforces the view that patients treated with the letter under the above heading (4 March, steroids have a significantly higher incidence of p 574). However, I can say that feeling among peptic ulceration. Nowhere does the quoted my colleagues in this locality is strongly pro- paper state this point of view or allow such a college, particularly among senior registrars conclusion. A comprehensive review of the and recently appointed consultants. Among literature2 convincingly shows a higher such colleagues the letter from the Royal prevalence of peptic ulcer disease in patients College of Surgeons signed by the president with chronic renal failure-especially those and deans produced a very strongly adverse undergoing dialysis. Furthermore, there is reaction, giving rise to such expressions as experimental evidence of a mechanism whereby "humbug," "mealy-mouthed," and worse. the two diseases are connected.:' Peptic ulcer in The most important aspect of this affair is transplant recipients is therefore a complication that the Faculty of Anaesthetists is not self- of the chronic uraemia which has gone before. accounting and the moneys raised by and from Post-transplant steroid therapy brings the anaesthetists is spent by a body with a large ulcer disease to light by causing bleeding and majority of surgeons, and it is this which has perforation, and its contribution to de-novo determined a very large number of anaes- ulcer disease is probably minimal. Prethetists to break away. transplant endoscopy identifies patients with JOHN HURDLEY ulcer disease, who are therefore at risk of Royal Gwent Hospital, bleeding after transplantation and likely to Newport, Gwent benefit from prophylactic cimetidine. More often, however, such bleeding is due to gastric SIR,-Professor Donald Campbell and others erosions, and endoscopy is of no value in (4 March, p 574) state that they find the predicting which patients will develop this editorial in Anaesthesia and the appeal letter lesion. However, the majority of such gastric from the Anaesthetists' Academic Foundation erosions occur when massive doses of misleading in that both give the impression prednisone are given for acute rejection that the proposal to form a separate college is episodes and also (in some centres) in the early generally accepted by anaesthetists. As a post-transplant phase. It is worth noting that signatory to that letter I do indeed believe that in the series reported by Dr Jones and his the majority of anaesthetists wish to establish colleagues the prednisone dosage started at 10 a college of their own, provided it is financially times that used in the Belfast series' and feasible, since full equality and independence continued at a relatively much higher dosage with the Royal College of Surgeons of England for the first four months; the respective have proved impracticable. All the evidence incidence of gastrointestinal bleeding in the (including a referendum in 1972 and subse- two series was 18O% and 7o%.4 Prevention of upper gastrointestinal haemorquent discussions at annual general meetings and linkman conferences) supports this belief, rhage after renal transplantation may therefore

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be achieved by (1) pretransplant endoscopic assessment; (2) sparing use of steroid; and (3), for those with ulcer, use of cimetidine in the early post-transplant stage and also when antirejection treatment is necessary. It does not make sense to add a second drug to prevent the undesirable side effects of the first without first examining other ways of minimising the side effects of the first drug. Surely the questions should be: are massive doses of prednisone really necessary, and do the benefits (if any) outweigh the substantial hazards ? A comparative trial of different prednisone regimens is at least as necessary as further trials with cimetidine. CIARAN C DOHERTY Renal Unit, Belfast City Hospital, Belfast

McGeown, M G, et al, Lancet, 1977, 2, 648. 2 Doherty, C C. In preparation. 3Doherty, C C, Kidney International. In press. 4Doherty, C C, et al, in Proceedings of the XIVth European Dialysis and Transplant Association, 1977, p 386.

Cimetidine and serum prolactin SIR,-Dr S K Majumdar and his colleagues (18 February, p 409) report normal serum prolactin concentrations in five male patients treated with cimetidine 1 g/day for between one and six months. We have studied the prolactin response to cimetidine in healthy male subjects.' An intravenous bolus injection of cimetidine 400 mg resulted in high blood concentrations of cimetidine. The measured peak mean concentration (+ SEM) was achieved 22 min after injection (84-6+7 4 [rmol/l (2 13 +0-19 mg/ 100 ml)) and there was a concurrent three-fold increase in serum prolactin which returned to pretreatment values after 70 to 95 minutes. These data are in agreement with those from Carlson and Ippoliti. We found no increase in serum prolactin when subjects were treated with bromocriptine prior to injection of cimetidine 400 mg, nor in subjects given single oral doses of cimetidine 800 mg, after which peak mdan blood cimetidine concentrations (14 0+3.5 glmol/l (0 35 +0 09 mg/100 ml)) was < 20 °' of that achieved after intravenous injection. The serum prolactin concentration has been abnormally increased in only three of seven patients with gynaecomastia or galactorrhoea in whom it was measured. We concluded that at high blood concentrations cimetidine may be acting directly or indirectly at the dopamine receptor in the pituitary to produce hyperprolactinaemia or on the uptake of prolactin in peripheral tissues. Hyperprolactinaemia may be a rare idiosyncratic response at the lower blood concentrations normally associated with oral therapeutic dosage regimens of cimetidine. W L BURLAND R I GLEADLE R M LEE D ROWLEY-JONES Research Institute, Smith, Kline, and French Laboratories Ltd, Welwyn Garden City, Herts

G V GROOM Tenovus Institute,

University Hospital of Wales, Cardiff

Burland, W L, et al, British Journal of Clinical Pharmacology. In press. 2Carlson, H E, and Ippoliti, A F, Journal of Clinical Endocrinology and Metabolism, 1977, 45, 367.

College of Anaesthetists.

716 illustrating the aids and appliances which can be helpful. Because there are few children with osteogenesis imperfecta in any area, doctors, ther...
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