NO WINDOWS
1
549 ischsmic heart-disease, is it really necessary to undertake, as Dr Nichols suggests, " a large prospective clinical trial designed to study coffee consumption as a risk factor ... "? I have no doubt that the manufacturers of alternative beverages would be eager to finance such a trial, but could not the money be better spent on encouraging a more original line of investigation ? The Surgery, Newport, Pembs. J. C. BIGNALL. NO WINDOWS SiR,—Your editorial 1 leaves one feeling rather distressed on behalf of patients nursed in windowless intensive-care units. I was aware that industry was against this type of false economy and I have been told that employers in a multi-storey building, which has two windowless shopping floors below street level, are having difficulty in keeping shop assistants, and working hours are being lost because the assistants feel compelled to get up to street level to " look out " several times a day. Have researchers observed any deleterious effects on nursing personnel working in an already stressful situation, such as an intensive-care unit, where there are no windows ? If so, such so-called economy would be doubly expensive, since continuity of effective patient care would be well- nigh impossible. And anyone inclined to be claustrophobic would be unable to work in such a situation. 15 Fay Jill House, Prince Alfred Street, Pietermaritzburg, Natal. M. E. F. ALEXANDER. EFFECT OF CO-TRIMOXAZOLE ON PHENYLALANINE METABOLISM SIR,-I cannot allow the paper of Dr England and Dr Coles 2 to pass without comment. They state that " The components of co-trimoxazole (sulphamethoxazole and trimethoprim) act as antibiotics by inhibiting bacterial metabolism of folic acid". This sentence is too dogmatic. Sulphamethoxazole, like any sulphonamide, inhibits the synthesis of bacterial folic acid by competing with p-amino- benzoic acid (P.A.B.A.).3 Man uses dietary folate and is therefore immune to this action (hence the therapeutic use of sulphonamides). To my knowledge, there has been no experimental work to indicate that sulphamethoxazole inhibits bacterial metabolism of folic acid. The authors’ finding that sulphamethoxazole alone caused slight phenyl- alanine intolerance suggests that it may in fact have actions other than just competition with P.A.B.A., but further work is required to elucidate this point. The action of trimethoprim is a different matter. It seems to me unjust for Dr England and Dr Coles to refer to Hitchings’ work and then state categorically that " it is widely held that this drug combination does not interfere with human metabolism ". Hitchings did indeed show that bacterial dihydrofolate reductase is much more sensitive than the human enzyme to the action of trimethoprim, but, for all that, he did show that the latter had some effect on the human enzyme. This might well be of considerable sig- nificance in patients already folate-deficient, such as those documented in the paper of Chanarin and England.5 The latter, however, reported that Dr K. Rowe in their labora- tory could not show any effect of trimethoprim on dihydro- folate reductase from rat or human liver. Clearly the toxic 1. Lancet, 1972, ii, 1075. 2 England, J. M., Coles, M. ibid. p. 1341. 3 Lawrence, D. R. Clinical Pharmacology; p. 68. London, 1966. 4. Hitchings, G. H. Postgrad. med. J. 1969, 45, suppl. p. 7. 5. Chanarin, I., England, J. M. Br. med. J. 1972, i, 651. action of trimethoprim in man is not as straightforward as it might at first sight appear. Gastrointestinal Laboratory, St. Thomas’ Hospital, London SE1 7EH. M. ELIZABETH M. STEPHENS. PENICILLAMINE IN RHEUMATOID ARTHRITIS SIR,-It was encouraging to read the report on the treatment of severe rheumatoid arthritis with D(-) penicillamine (Feb. 10, p. 275). If the results are true a valuable new treatment for rheumatoid arthritis will be available, as the authors claim. Before this claim is sub- stantiated, however, I think two questions should be answered. Firstly, was the trial a true " double-blind trial " ? It appears from the description of the methodology that the doctors who selected the patients made a number of the assessments of the patients’ progress. At the same time, however, various indices were observed to determine whether the patient was suffering ill-effects from penicilla- mine. These included laboratory tests and side-effects. It seems likely, in view of the large number of patients taking penicillamine who had identifiable side-effects, that the doctors conducting the trial were able to pick out those on active treatment and those on placebo treatment while the trial was in progress. The second question concerns the use of concomitant therapy during the trial itself. From the figures available it appears that, of those that completed the trial, 66% of the treatment group and 63 ° of the control group were on corticosteroid therapy at the start of the trial. Apart from a mention that " adjustments of dose were permitted but were recorded and kept to a minimum " there is no state- ment about corticosteroid therapy during the trial. This must be an important point because corticosteroids, despite their disadvantages, are known to be effective in treatment Darbishire House Health Centre, Upper Brook Street, Manchester M13 0FW. G. KEELE. * * * We showed this letter to Dr Lyle, whose reply follows.-ED. L. SIR,-The laboratory staff, occupational therapists, and clinicians whose records were used in this experiment did not know at the outset which patients were receiving penicillamine. Like Dr Keele, we realised that side- effects, such as hypogeusia or proteinuria, would give the game away sometimes to the clinicians, though not to the other observers, who remained " blind " throughout and whose findings, nevertheless, were in favour of peni- cillamine. Dr Greenbury’s reports on the S.C.A.T. were not disclosed to the clinicians during the trial. We considered it neither sensible nor proper to exclude from the experiment patients who might be doing well merely because the clinician, at some stage, had found out (or had deduced) that they were in the penicillamine group. Such " unblinding ", however, had to be recorded. Of the patients who completed one year in the experi- ment, the pharmacists, by request, broke the code for 3 (of 30) patients in the penicillamine group and 1 (of 38) of the controls. 2 of the 3 on penicillamine completed the trial at a reduced dose, 1 doing well and the other showing no change. The conclusion was drawn by clinicians, but not confirmed at the time, that 8 further patients were taking penicillamine, although in fact 2 were controls. It proved more difficult than had been anticipated to deduce which patients were in the penicillamine group. There was a similar frequency of rash and minor gastro-
Transcript of NO WINDOWS
549
ischsmic heart-disease, is it really necessary to undertake,as Dr Nichols suggests,
" a large prospective clinical trial
designed to study coffee consumption as a risk factor ... "?I have no doubt that the manufacturers of alternative
beverages would be eager to finance such a trial, but couldnot the money be better spent on encouraging a moreoriginal line of investigation ?
The Surgery,Newport, Pembs. J. C. BIGNALL.
NO WINDOWS
SiR,—Your editorial 1 leaves one feeling rather distressedon behalf of patients nursed in windowless intensive-careunits. I was aware that industry was against this type offalse economy and I have been told that employers in amulti-storey building, which has two windowless shoppingfloors below street level, are having difficulty in keepingshop assistants, and working hours are being lost becausethe assistants feel compelled to get up to street level to
" look out " several times a day.Have researchers observed any deleterious effects on
nursing personnel working in an already stressful situation,such as an intensive-care unit, where there are no windows ?If so, such so-called economy would be doubly expensive,since continuity of effective patient care would be well-nigh impossible. And anyone inclined to be claustrophobicwould be unable to work in such a situation.
15 Fay Jill House,Prince Alfred Street,Pietermaritzburg,
Natal. M. E. F. ALEXANDER.
EFFECT OF CO-TRIMOXAZOLE ONPHENYLALANINE METABOLISM
SIR,-I cannot allow the paper of Dr England and DrColes 2 to pass without comment. They state that " Thecomponents of co-trimoxazole (sulphamethoxazole and
trimethoprim) act as antibiotics by inhibiting bacterialmetabolism of folic acid". This sentence is too dogmatic.Sulphamethoxazole, like any sulphonamide, inhibits the
synthesis of bacterial folic acid by competing with p-amino-benzoic acid (P.A.B.A.).3 Man uses dietary folate and istherefore immune to this action (hence the therapeuticuse of sulphonamides). To my knowledge, there has beenno experimental work to indicate that sulphamethoxazoleinhibits bacterial metabolism of folic acid. The authors’
finding that sulphamethoxazole alone caused slight phenyl-alanine intolerance suggests that it may in fact have actionsother than just competition with P.A.B.A., but further workis required to elucidate this point.The action of trimethoprim is a different matter. It
seems to me unjust for Dr England and Dr Coles to referto Hitchings’ work and then state categorically that " it iswidely held that this drug combination does not interferewith human metabolism ". Hitchings did indeed show thatbacterial dihydrofolate reductase is much more sensitivethan the human enzyme to the action of trimethoprim, but,for all that, he did show that the latter had some effect on thehuman enzyme. This might well be of considerable sig-nificance in patients already folate-deficient, such as thosedocumented in the paper of Chanarin and England.5 Thelatter, however, reported that Dr K. Rowe in their labora-tory could not show any effect of trimethoprim on dihydro-folate reductase from rat or human liver. Clearly the toxic
1. Lancet, 1972, ii, 1075.2 England, J. M., Coles, M. ibid. p. 1341.3 Lawrence, D. R. Clinical Pharmacology; p. 68. London, 1966.4. Hitchings, G. H. Postgrad. med. J. 1969, 45, suppl. p. 7.5. Chanarin, I., England, J. M. Br. med. J. 1972, i, 651.
action of trimethoprim in man is not as straightforward asit might at first sight appear.
Gastrointestinal Laboratory,St. Thomas’ Hospital,London SE1 7EH. M. ELIZABETH M. STEPHENS.
PENICILLAMINE IN RHEUMATOID ARTHRITIS
SIR,-It was encouraging to read the report on thetreatment of severe rheumatoid arthritis with D(-)penicillamine (Feb. 10, p. 275). If the results are true avaluable new treatment for rheumatoid arthritis will beavailable, as the authors claim. Before this claim is sub-
stantiated, however, I think two questions should beanswered.
Firstly, was the trial a true " double-blind trial " ?It appears from the description of the methodology thatthe doctors who selected the patients made a number ofthe assessments of the patients’ progress. At the same time,however, various indices were observed to determinewhether the patient was suffering ill-effects from penicilla-mine. These included laboratory tests and side-effects. Itseems likely, in view of the large number of patients takingpenicillamine who had identifiable side-effects, that thedoctors conducting the trial were able to pick out those onactive treatment and those on placebo treatment while thetrial was in progress.The second question concerns the use of concomitant
therapy during the trial itself. From the figures available itappears that, of those that completed the trial, 66% of thetreatment group and 63 ° of the control group were oncorticosteroid therapy at the start of the trial. Apart froma mention that " adjustments of dose were permitted butwere recorded and kept to a minimum " there is no state-ment about corticosteroid therapy during the trial. Thismust be an important point because corticosteroids, despitetheir disadvantages, are known to be effective in treatment
Darbishire House Health Centre,Upper Brook Street,
Manchester M13 0FW. G. KEELE.
* * * We showed this letter to Dr Lyle, whose replyfollows.-ED. L.
SIR,-The laboratory staff, occupational therapists, andclinicians whose records were used in this experiment didnot know at the outset which patients were receivingpenicillamine. Like Dr Keele, we realised that side-
effects, such as hypogeusia or proteinuria, would give thegame away sometimes to the clinicians, though not to theother observers, who remained " blind " throughout andwhose findings, nevertheless, were in favour of peni-cillamine. Dr Greenbury’s reports on the S.C.A.T. were
not disclosed to the clinicians during the trial.We considered it neither sensible nor proper to exclude
from the experiment patients who might be doing wellmerely because the clinician, at some stage, had found out(or had deduced) that they were in the penicillaminegroup. Such " unblinding ", however, had to be recorded.Of the patients who completed one year in the experi-
ment, the pharmacists, by request, broke the code for 3(of 30) patients in the penicillamine group and 1 (of 38) ofthe controls. 2 of the 3 on penicillamine completed thetrial at a reduced dose, 1 doing well and the other showingno change. The conclusion was drawn by clinicians, butnot confirmed at the time, that 8 further patients weretaking penicillamine, although in fact 2 were controls.
It proved more difficult than had been anticipated todeduce which patients were in the penicillamine group.There was a similar frequency of rash and minor gastro-
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