699 DISPOSABLES FOR DIABETICS
SiR,—Why cannot insulin-dependent diabetics be given the advantages of disposable syringes and needles? If the answer is economy, then it is false economy. If it is difficulty of supply, then this should be
If it is merely that the British willing to press for this, then they
overcome.
Diabetic Association is should be overcome.
not
unilateral lesions did not benefit from nephrectomy. Thus the success-rate from renal surgery was just better than 1% (4/336), of the same order as the other reports cited by Swales. The hypotensive drugs available when my series began were very much less tolerable than those of today, so that one looked for surgical aid if possible. The Manor
It does seem wrong that those of us who are diabetics dependent upon insulin should be denied the free issue, with insulin, of a supply of disposable syringes and needles. A needle used for a week and kept under sterile conditions does become, even in the hands of an expert pathologist when used on himself, a painful instrument, and this must make the administration of insulin to children a severe ordeal. Upper Wimpole Street,
DAVID HALER
London Wl
LABELLING VARICOSE-VEIN FLUID
SIR,-The injection of varicose-vein fluid called S.T.D. is tabelid for "intravenous fluids" on the bottle and the carton, and the fluid is available in theatres. Although this method of labelling has apparently been passed by the Medicines Commission, I consider it to be extremely dangerous because the fluid could be drawn up into a syringe and handed to an anaesthetist or surgeon in an emergency and injected into an arm vein where it might produce morbidity and could be fatal. These cartons should be labelled for varicose veins only. Peterborough District Hospital, Peterborough, PE3 6DA
D. W. BRACEY
HEALTH: A DEMYSTIFICATION OF MEDICAL TECHNOLOGY
SIR,-Dr Lawson’s reply (Feb. 28, p. 481) to Dr Moore is well stated. Moore’s mythopceic presentation of the modern physician as an innocent ("Someone who, by a press of the hand or a look in the eye, seals an unwritten contract saying, ’I will take care of you"’) would be hilarious if it were not so sad. Moore’s declaration (Jan. 10, p. 83) to the contrary notwithstanding, modern medical work is, increasingly, a set of planned responses to a group of predictable requests. Modern medicine creates wants and needs to which it responds. For example, Phillipe Aries has commented, in Western Attitudes Toward Death, "... one dies in the hospital because the hospital has become the place to receive care which can no longer be given at home." To characterise as unresponsive to needs of individual patients Mahler’s call’ for extension of technical skills down the hierarchic chain of professional specialisation is a sad mis-reading of the W.H.O. Director-General’s timely message.
House, Wolferton, King’s Lynn, Norfolk PE31 6HA
C. P. PETCH
MONITORING SERUM-PHENYTOIN
’SIR,-We have pointed
out the importance of taking into the saturable nature of phenytoin metabolism in calculating dose increments from serum levels of this antiepileptic drug.Failure to do this can be disastrous. A 39-year-old man had, 6 years earlier, been admitted to a neurological unit with severe headache, vomiting, and leftsided weakness and sensory disturbance. Intracerebral haemorrhage was diagnosed, but hxmatoma could not be located. He slowly recovered, and was discharged with a residual spastic weakness of hia left leg. A year later he had attacks of long-lasting paraesthesiae in his left hand followed 3 years later by several episodes of loss of consciousness preceded by flashing lights in his left visual field. Primidone was prescribed, but shortly afterwards he developed explosive jerks in his left leg which caused him to fall. He was readmitted for assessment and discharged on phenytoin 300 mg daily, primidone 750 mg daily, pheneturide 400 mg daily, and diazepam 10 mg daily. When his leg jerks continued he was put on baclofen 30 mg daily. Several months later, in June 1974, his seizures and leg jerks were still uncontrolled. His serum-phenytoin, measured while on 300 mg daily, was 12 mol/1 (3 g/ml), which was below the optimal range of 40-80 p.moI;1. The dose was doubled. The patient seemed to improve and was discharged. In September, 1974, he took up studying for A levels in an attempt to retrain for clerical work, but had to give up because of intense diplopia; orthoptic treatment was unsuccessful. By July, 1975, he was spending most of his day in a wheelaccount
1.
Richens, A., Dunlop, A. Lancet, 1975, ii, 247.
90 La Cuesta
Drive, Greenbrae, California 94904, U.S.A.
WILLIAM A. SILVERMAN
HUNT FOR RENAL HYPERTENSION
SIR,-Professor Swales (March 13, p. 577) reviews the findings of several specialised groups. Perhaps the results from a general medical unit before the days of plasma-renin estimations would be of interest. During the twenty-five years up to 1975 I investigated in hospital 336 cases of severe hypertension, renal radiology and some measure of catecholamine production being included in each. As a result, my surgical colleagues were able to operate on 2 patients with phsochromocytoma and 5 with unilateral renal lesions. The first 2 1
are not
relevant
to
Mahler, H. Lancet, 1975, ii,
the argument, and 1 of the 5 with
829.
Dose/serum-level relationship.
O=serum-phenytoin on 300 and 600 mg/day. A=serum-phenytoin on 600 mg/day predicted by
first-order kine-
tics. Q=doses
levels of 60
predicted by nomogram’
mol/1.
to
give
serum
or
80
700 chair. His wife was terrified to let him out of her sight lest he should fall, and she herself had "broken down psychologic-
ally". In November he was interviewed for possible admission to the National Hospitals-Chalfont Centre for Epilepsy. He was found to have gross ataxia, diplopia, and coarse nystagmus on lateral gaze. His slurring dysarthria was worst 2-3 h after a dose of his tablets. His serum-phenytoin was 160 mol/1, well into the toxic range. An electroencephalogram was consistent with drug intoxication. His phenytoin was stopped for 4 days and then restarted at 300 mg/day. By the third day he could walk without falling, his speech became normal, and he lost his double vision. Presumably, the neurological unit which doubled the phenytoin dose to 600 mg assumed that the serum level is linearly related to dose. This is not so. The figure shows the dose required to give therapeutic serum-phenytoin levels of 60 or 80 .mol/1, the doses being 550 and 580 mg/day. A dose of 600 mg/day would be expected to be toxic. The monitoring of serum-phenytoin levels is a step forward in the management of epilepsy but can be disastrous if the clinician fails to understand the pharmacokinetics of phenytoin. Dr Ludden and his colleagues (Feb. 7, p. 307) consider that individual Km values would be better than our average values.’ We agree, but a single estimation at two different doses does not necessarily provide adequate data. Our data were means of up to eight individual estimations at each dose level. We have applied Ludden’s procedure using the highest and lowest single (i.e., not averaged) estimations, for the lowest two dose-rates in three of our patients. The Michaelis parameters derived from the two opposed limit cases of these four points can differ widely from those obtained by computer fitting of the complete data set. The best of the three cases gave Km=47 mol/1, Vmax=503 mg/day and Km=5.4 fLDloI;1, Vmax=254 mg/day as the two limit cases. The other two patients gave negative parameters in one limit. Thus, chance ’
opposed
errors can
give grossly misleading predictions using
Ludden’s procedure. Department of Clinical Pharmacology, St. Bartholomew’s Hospital, London EC1A 7BE
ALAN RICHENS ANDREW DUNLOP
National Hospitals-Chalfont Centre for Epilepsy, Chalfont St. Peter, Bucks SL9 0RJ
SUHAIL AHMAD JOHN LAIDLAW
than a localised lesion of the gastrointestinal tract which might be important in considering aaiology and also explain the high incidence of recurrent disease after surgical resection of all macroscopically involved bowel. R. N. ALLAN Nutritional and Intestinal Unit, B. T. COOPER General Hospital, W. T. COOKE B4 6NH Birmingham
CHENODEOXYCHOLIC-ACID TREATMENT OF RHEUMATOID ARTHRITIS
SIR,- The joint symptoms of rheumatoid arthritis (R.A.) improve in patients with jaundice of parenchymatous and ocdusive origin.This antirheumatic effect may be related to the increased serum concentrations of bile acids’2 which are found concomitantly with raised serum-bilirubin concentrations in these forms of jaundice. This hypothesis is supported by the observation that addition of bile acids to R.A. synovial fluid in vitro resulted in plasmin digestion of the abnormal fibrin/fibrinogen degradation products, otherwise resistant to plasmin.3 In R.A. the bile-acid pool size is diminishedresulting in a lower postprandial rise in the serum concentration of bile acids, analogous to what happens after ileal resection.’ Chenodeoxycholic acid (c.D.c.) administered intravenously caused a definite, although insufficient and short-term, improvement of the joint symptoms in R.A.,2 but because of the development of phlebitis this treatment had to be abandoned. We have tried oral C.D.C. in R.A. patients. Sixteen patients have been treated with C.D.C. in a dose of 0.75 to 1.0 g/day, for 3-11 weeks. The characteristic course during treatment has been an initial deterioration of the joint pains and general condition, sometimes rather severe and accompanied by fever, followed by obvious remission of the disease and falling ery-
throcyte-sedimentation
rates. The turning-point was usually after about 6 weeks of treatment. Long-term follow-up is needed to evaluate fully the value of c.D.c. therapy in R.A. In the treatment of cholesterol gallstones, C.D.C. has proved to be a safe drug at the doses we used.6’ Consequently, we recommend the initiation of controlled trials on a large scale to confirm our preliminary promising results.
Department of Medicine, Frederiksberg Hospital, DK-2000 Copenhagen F,
ARNE BRUUSGAARD
Denmark
Department of Physical Medicine and Rheumatology,
BOWEL MUCOSA IN CROHN’S DISEASE
SIR,-Dr Goodman and his colleagues (Feb. 7,
275) apparently
Hvidovre Hospital, DK-2650 Copenhagen Hvidovre, Denmark
report abnormal cell-counts and enzyme activity in normal colonic mucosa of patients with Crohn’s disease, even if macroscopic and histological examination showed no abnor-
mality. We have been aware for some time of abnormalities in apparently uninvolved proximal small-bowel mucosa in Crohn’s disease. In this unit we have demonstrated an increased inflammatory-cell infiltrate in the lamina propria of otherwise normal proximal jejunal mucosa compared with healthy subjects’ and a reduction of bidirectional sodium flux across the small-intestinal mucosa of patients with Crohn’s disease treated in the past by panproctocolectomy and ileostomy with no evidence of recurrent disease compared with a similarly treated group of patients with ulcerative colitis.2 We are now studying the apparently normal proximal jejunal mucosa by measuring cytophsmic and brush-border enzymes and surface pH. Preliminary results suggest that these indices are also abnormal in Crohn’s disease. These studies suggest that Crohn’s disease is a diffuse rather 1. 2.
RASMUS BACH ANDERSEN
p.
Ferguson, R., Allan, R. N., Cooke, W. T. Gut, 1975, 16, 205. Allan, R. N., Steinberg, D. M., Dixon, K., Cooke, W. T. ibid. p. 201.
MACROPHAGE ALLOGRAFTS IN MAN?
SIR,-Mr Fakhri and his colleagues (Jan. 10, p. 94) raise the possibility of macrophage allografting in man: they may be advocating appropriate therapy for unsound reasons. They suggest that, -since in their experience the macrophage seems to lack expression of certain gene products of the major histocompatibility complex (M.H.C.), it may, at least antigenically, be immunologically "privileged" and thus able to evade allograft rejection upon adoptive transfer. However, cells of the
monocyte/macrophage lineage and 1. 2. 3. 4. 5.
they
may be
as
are not
fundamental
to
antigenically deficient,
rejection
as are
certain
Hench, P. S. Proc. Staff Meet. Mayo Clin. 1933, 8, 430. Bruusgaard, A., Andersen, R. B. Scand. J. Rheum. 1975, 4, 169. Andersen, R. B., Bruusgaard, A. ibid. p. 158. Bruusgaard, A., Andersen, R. B. Dan. med. Bull. (in the press).
LaRusso, N. F., Korman, M. G., Hoffman, N. E., Hofmann, A. F. New Engl. J. Med. 1974, 291, 689. 6. Bell, G. D., Mok, H. Y. I., Thwe, M., Murphy, G. M., Henry, K., Dowling, R. H. Gut, 1974, 15, 165. 7. Hofmann, A. F., Paumgartner, G. (editors) Chenodeoxycholic Acid Therapy of Gallstones, p. 57. Stuttgart, 1974.
SiR,—Why cannot insulin-dependent diabetics be given the advantages of disposable syringes and needles? If the answer is economy, then it is false economy. If it is difficulty of supply, then this should be
If it is merely that the British willing to press for this, then they
overcome.
Diabetic Association is should be overcome.
not
unilateral lesions did not benefit from nephrectomy. Thus the success-rate from renal surgery was just better than 1% (4/336), of the same order as the other reports cited by Swales. The hypotensive drugs available when my series began were very much less tolerable than those of today, so that one looked for surgical aid if possible. The Manor
It does seem wrong that those of us who are diabetics dependent upon insulin should be denied the free issue, with insulin, of a supply of disposable syringes and needles. A needle used for a week and kept under sterile conditions does become, even in the hands of an expert pathologist when used on himself, a painful instrument, and this must make the administration of insulin to children a severe ordeal. Upper Wimpole Street,
DAVID HALER
London Wl
LABELLING VARICOSE-VEIN FLUID
SIR,-The injection of varicose-vein fluid called S.T.D. is tabelid for "intravenous fluids" on the bottle and the carton, and the fluid is available in theatres. Although this method of labelling has apparently been passed by the Medicines Commission, I consider it to be extremely dangerous because the fluid could be drawn up into a syringe and handed to an anaesthetist or surgeon in an emergency and injected into an arm vein where it might produce morbidity and could be fatal. These cartons should be labelled for varicose veins only. Peterborough District Hospital, Peterborough, PE3 6DA
D. W. BRACEY
HEALTH: A DEMYSTIFICATION OF MEDICAL TECHNOLOGY
SIR,-Dr Lawson’s reply (Feb. 28, p. 481) to Dr Moore is well stated. Moore’s mythopceic presentation of the modern physician as an innocent ("Someone who, by a press of the hand or a look in the eye, seals an unwritten contract saying, ’I will take care of you"’) would be hilarious if it were not so sad. Moore’s declaration (Jan. 10, p. 83) to the contrary notwithstanding, modern medical work is, increasingly, a set of planned responses to a group of predictable requests. Modern medicine creates wants and needs to which it responds. For example, Phillipe Aries has commented, in Western Attitudes Toward Death, "... one dies in the hospital because the hospital has become the place to receive care which can no longer be given at home." To characterise as unresponsive to needs of individual patients Mahler’s call’ for extension of technical skills down the hierarchic chain of professional specialisation is a sad mis-reading of the W.H.O. Director-General’s timely message.
House, Wolferton, King’s Lynn, Norfolk PE31 6HA
C. P. PETCH
MONITORING SERUM-PHENYTOIN
’SIR,-We have pointed
out the importance of taking into the saturable nature of phenytoin metabolism in calculating dose increments from serum levels of this antiepileptic drug.Failure to do this can be disastrous. A 39-year-old man had, 6 years earlier, been admitted to a neurological unit with severe headache, vomiting, and leftsided weakness and sensory disturbance. Intracerebral haemorrhage was diagnosed, but hxmatoma could not be located. He slowly recovered, and was discharged with a residual spastic weakness of hia left leg. A year later he had attacks of long-lasting paraesthesiae in his left hand followed 3 years later by several episodes of loss of consciousness preceded by flashing lights in his left visual field. Primidone was prescribed, but shortly afterwards he developed explosive jerks in his left leg which caused him to fall. He was readmitted for assessment and discharged on phenytoin 300 mg daily, primidone 750 mg daily, pheneturide 400 mg daily, and diazepam 10 mg daily. When his leg jerks continued he was put on baclofen 30 mg daily. Several months later, in June 1974, his seizures and leg jerks were still uncontrolled. His serum-phenytoin, measured while on 300 mg daily, was 12 mol/1 (3 g/ml), which was below the optimal range of 40-80 p.moI;1. The dose was doubled. The patient seemed to improve and was discharged. In September, 1974, he took up studying for A levels in an attempt to retrain for clerical work, but had to give up because of intense diplopia; orthoptic treatment was unsuccessful. By July, 1975, he was spending most of his day in a wheelaccount
1.
Richens, A., Dunlop, A. Lancet, 1975, ii, 247.
90 La Cuesta
Drive, Greenbrae, California 94904, U.S.A.
WILLIAM A. SILVERMAN
HUNT FOR RENAL HYPERTENSION
SIR,-Professor Swales (March 13, p. 577) reviews the findings of several specialised groups. Perhaps the results from a general medical unit before the days of plasma-renin estimations would be of interest. During the twenty-five years up to 1975 I investigated in hospital 336 cases of severe hypertension, renal radiology and some measure of catecholamine production being included in each. As a result, my surgical colleagues were able to operate on 2 patients with phsochromocytoma and 5 with unilateral renal lesions. The first 2 1
are not
relevant
to
Mahler, H. Lancet, 1975, ii,
the argument, and 1 of the 5 with
829.
Dose/serum-level relationship.
O=serum-phenytoin on 300 and 600 mg/day. A=serum-phenytoin on 600 mg/day predicted by
first-order kine-
tics. Q=doses
levels of 60
predicted by nomogram’
mol/1.
to
give
serum
or
80
700 chair. His wife was terrified to let him out of her sight lest he should fall, and she herself had "broken down psychologic-
ally". In November he was interviewed for possible admission to the National Hospitals-Chalfont Centre for Epilepsy. He was found to have gross ataxia, diplopia, and coarse nystagmus on lateral gaze. His slurring dysarthria was worst 2-3 h after a dose of his tablets. His serum-phenytoin was 160 mol/1, well into the toxic range. An electroencephalogram was consistent with drug intoxication. His phenytoin was stopped for 4 days and then restarted at 300 mg/day. By the third day he could walk without falling, his speech became normal, and he lost his double vision. Presumably, the neurological unit which doubled the phenytoin dose to 600 mg assumed that the serum level is linearly related to dose. This is not so. The figure shows the dose required to give therapeutic serum-phenytoin levels of 60 or 80 .mol/1, the doses being 550 and 580 mg/day. A dose of 600 mg/day would be expected to be toxic. The monitoring of serum-phenytoin levels is a step forward in the management of epilepsy but can be disastrous if the clinician fails to understand the pharmacokinetics of phenytoin. Dr Ludden and his colleagues (Feb. 7, p. 307) consider that individual Km values would be better than our average values.’ We agree, but a single estimation at two different doses does not necessarily provide adequate data. Our data were means of up to eight individual estimations at each dose level. We have applied Ludden’s procedure using the highest and lowest single (i.e., not averaged) estimations, for the lowest two dose-rates in three of our patients. The Michaelis parameters derived from the two opposed limit cases of these four points can differ widely from those obtained by computer fitting of the complete data set. The best of the three cases gave Km=47 mol/1, Vmax=503 mg/day and Km=5.4 fLDloI;1, Vmax=254 mg/day as the two limit cases. The other two patients gave negative parameters in one limit. Thus, chance ’
opposed
errors can
give grossly misleading predictions using
Ludden’s procedure. Department of Clinical Pharmacology, St. Bartholomew’s Hospital, London EC1A 7BE
ALAN RICHENS ANDREW DUNLOP
National Hospitals-Chalfont Centre for Epilepsy, Chalfont St. Peter, Bucks SL9 0RJ
SUHAIL AHMAD JOHN LAIDLAW
than a localised lesion of the gastrointestinal tract which might be important in considering aaiology and also explain the high incidence of recurrent disease after surgical resection of all macroscopically involved bowel. R. N. ALLAN Nutritional and Intestinal Unit, B. T. COOPER General Hospital, W. T. COOKE B4 6NH Birmingham
CHENODEOXYCHOLIC-ACID TREATMENT OF RHEUMATOID ARTHRITIS
SIR,- The joint symptoms of rheumatoid arthritis (R.A.) improve in patients with jaundice of parenchymatous and ocdusive origin.This antirheumatic effect may be related to the increased serum concentrations of bile acids’2 which are found concomitantly with raised serum-bilirubin concentrations in these forms of jaundice. This hypothesis is supported by the observation that addition of bile acids to R.A. synovial fluid in vitro resulted in plasmin digestion of the abnormal fibrin/fibrinogen degradation products, otherwise resistant to plasmin.3 In R.A. the bile-acid pool size is diminishedresulting in a lower postprandial rise in the serum concentration of bile acids, analogous to what happens after ileal resection.’ Chenodeoxycholic acid (c.D.c.) administered intravenously caused a definite, although insufficient and short-term, improvement of the joint symptoms in R.A.,2 but because of the development of phlebitis this treatment had to be abandoned. We have tried oral C.D.C. in R.A. patients. Sixteen patients have been treated with C.D.C. in a dose of 0.75 to 1.0 g/day, for 3-11 weeks. The characteristic course during treatment has been an initial deterioration of the joint pains and general condition, sometimes rather severe and accompanied by fever, followed by obvious remission of the disease and falling ery-
throcyte-sedimentation
rates. The turning-point was usually after about 6 weeks of treatment. Long-term follow-up is needed to evaluate fully the value of c.D.c. therapy in R.A. In the treatment of cholesterol gallstones, C.D.C. has proved to be a safe drug at the doses we used.6’ Consequently, we recommend the initiation of controlled trials on a large scale to confirm our preliminary promising results.
Department of Medicine, Frederiksberg Hospital, DK-2000 Copenhagen F,
ARNE BRUUSGAARD
Denmark
Department of Physical Medicine and Rheumatology,
BOWEL MUCOSA IN CROHN’S DISEASE
SIR,-Dr Goodman and his colleagues (Feb. 7,
275) apparently
Hvidovre Hospital, DK-2650 Copenhagen Hvidovre, Denmark
report abnormal cell-counts and enzyme activity in normal colonic mucosa of patients with Crohn’s disease, even if macroscopic and histological examination showed no abnor-
mality. We have been aware for some time of abnormalities in apparently uninvolved proximal small-bowel mucosa in Crohn’s disease. In this unit we have demonstrated an increased inflammatory-cell infiltrate in the lamina propria of otherwise normal proximal jejunal mucosa compared with healthy subjects’ and a reduction of bidirectional sodium flux across the small-intestinal mucosa of patients with Crohn’s disease treated in the past by panproctocolectomy and ileostomy with no evidence of recurrent disease compared with a similarly treated group of patients with ulcerative colitis.2 We are now studying the apparently normal proximal jejunal mucosa by measuring cytophsmic and brush-border enzymes and surface pH. Preliminary results suggest that these indices are also abnormal in Crohn’s disease. These studies suggest that Crohn’s disease is a diffuse rather 1. 2.
RASMUS BACH ANDERSEN
p.
Ferguson, R., Allan, R. N., Cooke, W. T. Gut, 1975, 16, 205. Allan, R. N., Steinberg, D. M., Dixon, K., Cooke, W. T. ibid. p. 201.
MACROPHAGE ALLOGRAFTS IN MAN?
SIR,-Mr Fakhri and his colleagues (Jan. 10, p. 94) raise the possibility of macrophage allografting in man: they may be advocating appropriate therapy for unsound reasons. They suggest that, -since in their experience the macrophage seems to lack expression of certain gene products of the major histocompatibility complex (M.H.C.), it may, at least antigenically, be immunologically "privileged" and thus able to evade allograft rejection upon adoptive transfer. However, cells of the
monocyte/macrophage lineage and 1. 2. 3. 4. 5.
they
may be
as
are not
fundamental
to
antigenically deficient,
rejection
as are
certain
Hench, P. S. Proc. Staff Meet. Mayo Clin. 1933, 8, 430. Bruusgaard, A., Andersen, R. B. Scand. J. Rheum. 1975, 4, 169. Andersen, R. B., Bruusgaard, A. ibid. p. 158. Bruusgaard, A., Andersen, R. B. Dan. med. Bull. (in the press).
LaRusso, N. F., Korman, M. G., Hoffman, N. E., Hofmann, A. F. New Engl. J. Med. 1974, 291, 689. 6. Bell, G. D., Mok, H. Y. I., Thwe, M., Murphy, G. M., Henry, K., Dowling, R. H. Gut, 1974, 15, 165. 7. Hofmann, A. F., Paumgartner, G. (editors) Chenodeoxycholic Acid Therapy of Gallstones, p. 57. Stuttgart, 1974.
