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REVERSIBILITY OF AIRWAYS OBSTRUCTION IN CHRONIC BRONCHITIS
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Cyclophosphamide in the dose of 2-3 mg. per kg. per day for periods exceeding 3 months by no means invariably sterilises women, as Professor Kerr’s data might suggest. A number of pregnancies have been reported during prolonged cyclophosphamide therapy,8-12 and several other unpublished cases have been recorded.13 We ourselves have had 1 patient becoming pregnant during prolonged cyclophosphamide therapy (the pregnancy was terminated). Of 15 women aged 15-45 years treated with cyclophosphamide 3 mg. per kg. per day for 12-52 weeks, all 11 who stopped treatment regained normal menstruation within 5-12 months, and 1 has subsequently become pregnant. In contrast, 4 women with lupus nephritis on prolonged cyclophosphamide therapy (25, 126, 196, and 212 weeks) now all have amenorrhcea, although it must be mentioned that 2 of these patients are also urmmic. These data suggest that the ovary is more resistant to cyclophosphamide than the testicular germinal epithelium. Our main task now is to assess the risk in prepubertal children, since at the moment these are by far the largest group of renal patients receiving cyclophosphamide, and have the longest potential survival. Because of the many to reduce the dangers, we have progressively attempted " " dosage and length of the course used in minimal-change steroid-toxic relapsing nephrotic children. The relapse-rate at 2 years after 3 mg. per kg. per day of cyclophosphamide for 8 weeks is the same as that after 5 mg. per kg. per day initially with a leucopenia maintained for 12 weeks. In a recent controlled trial,14 however, 2 weeks’ treatment with 3 mg. per kg. per day was significantly worse than 8 weeks, and scarcely better than steroid withdrawal alone. There is urgent need for evaluation of those treated for 8 weeks at 3 mg. per kg. per day, since it appears that this is near the minimum course required to induce prolonged remissions in most children. Clearly, obtaining this data will not be easy and final conclusions may not appear for a decade or more. Dr. Fairley’s paper has reminded us strongly of the need for careful and critical thought before even short courses of cyclophosphamide are used, exact definition of the conditions for which it may be indicated, controlled evaluation of its effects on the progress of the disease, and a careful watch for potential and unexpected side-effects. J. S. CAMERON
Guy’s Hospital,
C. S. OGG.
London SE1 9RT.
REVERSIBILITY OF AIRWAYS OBSTRUCTION IN CHRONIC BRONCHITIS
SIR,-Referring to the letter by Dr. Astin (May 20, p. 1128), one must question the validity of conclusions based on a study of patients labelled as " chronic bronchitic " according to the existing definitions of bronchial disease. I have previously remarked upon the confusion arising from the unsatisfactory and unscientific international definitions of " bronchial asthma " and " chronic bronchitis ".11,2 It is possible that many of the patients with " chronic bronchitis " studied in Dr. Astin’s department may in fact have allergic bronchitis and not catarrhal bronchitis. The example quoted in his letter could certainly be a case of allergic bronchitis, and it would be interesting to know whether the sputum has been examined for stigmata of allergic bronchitis. Differentiation of allergic bronchitis from catarrhal bronchitis is usually possible by appropriate examination of the sputum, which reflects the pathological process in the bronchi. West Cardiff Area Laboratory, St. David’s Hospital, Cardiff CF1 9TZ.
N. G. SANERKIN.
BIOCHEMISTRY AND DRUG TREATMENT OF DEPRESSION
SiR,—Your annotation (May 6, p. 1001) provides further on the comments made by myself (March 25, p. 682) and by Dr. Johnson (April 29, p. 966). From the remarks of Dr. Johnson and myself it could be construed that psychopharmacological drugs by themselves are infood for thought
variably successful treatments of psychiatric conditions. Unfortunately, even those psychiatric conditions which on clinical grounds seem eminently suitable for psychopharmacological treatment sometimes fail to respond. Further, if the antidepressants act by increasing the amount of free amines in the brain, then why do patients relapse into depression despite apparently adequate drug maintenance ? The findings of Coppen et al.demonstrated relapses in a proportion of patients on apparently adequate antidepressant treatment (and to a lesser extent in patients on lithium salts). Your annotation points out that there seems to be an optimum plasma concentration of tricyclic drug, and levels above or below this level are associated with a You go on to say: " It is clearly unsatisfactory to use tricyclic drugs in standard dosage ... The use of tricyclic drugs in depression is based on the statistically significant positive results of many doubleblind trials. I ask what value can we now place on these trials, many of which are blighted by at least one or two important considerations: (1) many were outpatient trials, and the work of Wilcox et awl. reminds us of the high incidence in outpatients of failure to take medication as prescribed; (2) the dosage of tricyclic drug was not based on optimum plasma concentrations. It is as well to remember that, apart from drug treatment, there are other factors which may play a part in the improvement of depression. Factors which we may not know, because our patients may not be aware of or realise the importance of these factors and thus fail to communicate them to us; or, if they do communicate them to us, then we may fail to recognise their significance. I am sure many colleagues have shared with me the following embarrassing experience. I prescribe" a tricyclic classical " drug for an outpatient with a typical or
which
are
poor response.
SHORTER CHEMOTHERAPY IN TUBERCULOSIS
SiR,—The comment in your leader (May 20, p. 1105)" This could not only get patients back to active work earlier but would also reduce the entire costs of the treatment service ..."-implies that tuberculosis patients should cease work during treatment. This is totally unnecessary for the vast majority of patients. In most areas there should be no insurmountable problems in giving streptomycin to working people. There are no epidemiological hazards. An infectious person will have had ample opportunities to infect others before treatment, but will be non-infectious very soon after the treatment begins. Ballinderry, Mullingar, MICHAEL P. FLYNN. Ireland. Greenberg, L. A., Tanáka, H. R. J. Am. med. Ass. 1964, 188, 423. Lacher, M. L., Geller, W. ibid. 1966, 195, 486. Marazzini, F., Macchi, L. Annali Ostet. Ginec. 1966, 88, 825. Coates, A. Aust. N.Z. Jl Obstet. Gynœc. 1970, 10, 33. Toledo, T. M., Harper, R. C., Moser, R. H. Ann. intern. Med. 1971, 74, 87. 13. Simister, J. M. Personal communication. 14. Barratt, T. M., Soothill, J. F., Cameron, J. S., Chantler, C., Ogg, C. S. Unpublished. 8. 9. 10. 11. 12.
1. Ann. Allergy, 1971, 29, 187. 2. Lancet, 1971, ii, 162. 3. Coppen, A., Noguera, R., Bailey, J., Burns, B. H., Swani, M. S., Hare, E. H., Gardner, R., Maggs, R. ibid. p. 275. 4. Wilcox, D. R. C., Gillan, R., Hare, E. H. Br. med. J. 1965, ii, 790.
Cyclophosphamide in the dose of 2-3 mg. per kg. per day for periods exceeding 3 months by no means invariably sterilises women, as Professor Kerr’s data might suggest. A number of pregnancies have been reported during prolonged cyclophosphamide therapy,8-12 and several other unpublished cases have been recorded.13 We ourselves have had 1 patient becoming pregnant during prolonged cyclophosphamide therapy (the pregnancy was terminated). Of 15 women aged 15-45 years treated with cyclophosphamide 3 mg. per kg. per day for 12-52 weeks, all 11 who stopped treatment regained normal menstruation within 5-12 months, and 1 has subsequently become pregnant. In contrast, 4 women with lupus nephritis on prolonged cyclophosphamide therapy (25, 126, 196, and 212 weeks) now all have amenorrhcea, although it must be mentioned that 2 of these patients are also urmmic. These data suggest that the ovary is more resistant to cyclophosphamide than the testicular germinal epithelium. Our main task now is to assess the risk in prepubertal children, since at the moment these are by far the largest group of renal patients receiving cyclophosphamide, and have the longest potential survival. Because of the many to reduce the dangers, we have progressively attempted " " dosage and length of the course used in minimal-change steroid-toxic relapsing nephrotic children. The relapse-rate at 2 years after 3 mg. per kg. per day of cyclophosphamide for 8 weeks is the same as that after 5 mg. per kg. per day initially with a leucopenia maintained for 12 weeks. In a recent controlled trial,14 however, 2 weeks’ treatment with 3 mg. per kg. per day was significantly worse than 8 weeks, and scarcely better than steroid withdrawal alone. There is urgent need for evaluation of those treated for 8 weeks at 3 mg. per kg. per day, since it appears that this is near the minimum course required to induce prolonged remissions in most children. Clearly, obtaining this data will not be easy and final conclusions may not appear for a decade or more. Dr. Fairley’s paper has reminded us strongly of the need for careful and critical thought before even short courses of cyclophosphamide are used, exact definition of the conditions for which it may be indicated, controlled evaluation of its effects on the progress of the disease, and a careful watch for potential and unexpected side-effects. J. S. CAMERON
Guy’s Hospital,
C. S. OGG.
London SE1 9RT.
REVERSIBILITY OF AIRWAYS OBSTRUCTION IN CHRONIC BRONCHITIS
SIR,-Referring to the letter by Dr. Astin (May 20, p. 1128), one must question the validity of conclusions based on a study of patients labelled as " chronic bronchitic " according to the existing definitions of bronchial disease. I have previously remarked upon the confusion arising from the unsatisfactory and unscientific international definitions of " bronchial asthma " and " chronic bronchitis ".11,2 It is possible that many of the patients with " chronic bronchitis " studied in Dr. Astin’s department may in fact have allergic bronchitis and not catarrhal bronchitis. The example quoted in his letter could certainly be a case of allergic bronchitis, and it would be interesting to know whether the sputum has been examined for stigmata of allergic bronchitis. Differentiation of allergic bronchitis from catarrhal bronchitis is usually possible by appropriate examination of the sputum, which reflects the pathological process in the bronchi. West Cardiff Area Laboratory, St. David’s Hospital, Cardiff CF1 9TZ.
N. G. SANERKIN.
BIOCHEMISTRY AND DRUG TREATMENT OF DEPRESSION
SiR,—Your annotation (May 6, p. 1001) provides further on the comments made by myself (March 25, p. 682) and by Dr. Johnson (April 29, p. 966). From the remarks of Dr. Johnson and myself it could be construed that psychopharmacological drugs by themselves are infood for thought
variably successful treatments of psychiatric conditions. Unfortunately, even those psychiatric conditions which on clinical grounds seem eminently suitable for psychopharmacological treatment sometimes fail to respond. Further, if the antidepressants act by increasing the amount of free amines in the brain, then why do patients relapse into depression despite apparently adequate drug maintenance ? The findings of Coppen et al.demonstrated relapses in a proportion of patients on apparently adequate antidepressant treatment (and to a lesser extent in patients on lithium salts). Your annotation points out that there seems to be an optimum plasma concentration of tricyclic drug, and levels above or below this level are associated with a You go on to say: " It is clearly unsatisfactory to use tricyclic drugs in standard dosage ... The use of tricyclic drugs in depression is based on the statistically significant positive results of many doubleblind trials. I ask what value can we now place on these trials, many of which are blighted by at least one or two important considerations: (1) many were outpatient trials, and the work of Wilcox et awl. reminds us of the high incidence in outpatients of failure to take medication as prescribed; (2) the dosage of tricyclic drug was not based on optimum plasma concentrations. It is as well to remember that, apart from drug treatment, there are other factors which may play a part in the improvement of depression. Factors which we may not know, because our patients may not be aware of or realise the importance of these factors and thus fail to communicate them to us; or, if they do communicate them to us, then we may fail to recognise their significance. I am sure many colleagues have shared with me the following embarrassing experience. I prescribe" a tricyclic classical " drug for an outpatient with a typical or
which
are
poor response.
SHORTER CHEMOTHERAPY IN TUBERCULOSIS
SiR,—The comment in your leader (May 20, p. 1105)" This could not only get patients back to active work earlier but would also reduce the entire costs of the treatment service ..."-implies that tuberculosis patients should cease work during treatment. This is totally unnecessary for the vast majority of patients. In most areas there should be no insurmountable problems in giving streptomycin to working people. There are no epidemiological hazards. An infectious person will have had ample opportunities to infect others before treatment, but will be non-infectious very soon after the treatment begins. Ballinderry, Mullingar, MICHAEL P. FLYNN. Ireland. Greenberg, L. A., Tanáka, H. R. J. Am. med. Ass. 1964, 188, 423. Lacher, M. L., Geller, W. ibid. 1966, 195, 486. Marazzini, F., Macchi, L. Annali Ostet. Ginec. 1966, 88, 825. Coates, A. Aust. N.Z. Jl Obstet. Gynœc. 1970, 10, 33. Toledo, T. M., Harper, R. C., Moser, R. H. Ann. intern. Med. 1971, 74, 87. 13. Simister, J. M. Personal communication. 14. Barratt, T. M., Soothill, J. F., Cameron, J. S., Chantler, C., Ogg, C. S. Unpublished. 8. 9. 10. 11. 12.
1. Ann. Allergy, 1971, 29, 187. 2. Lancet, 1971, ii, 162. 3. Coppen, A., Noguera, R., Bailey, J., Burns, B. H., Swani, M. S., Hare, E. H., Gardner, R., Maggs, R. ibid. p. 275. 4. Wilcox, D. R. C., Gillan, R., Hare, E. H. Br. med. J. 1965, ii, 790.