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.
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.
