45 after mianserin ingestion has been closely monitored in depressed cardiac patients" and volunteers,12 and the drug’s lack of cardiotoxicity has been confirmed.
tients with affective disorders not on lithium and in 29 normal controls. As there was no significant difference between those not on lithium and the normal controls these groups have been combined. None of our lithium patients had had episodes of toxicity. Lithium-treated patients as a group had increased urinary output, but volumes greater than 3 litres were uncommon. In the male and female lithium-treated patients there was no significant correlation between the duration of lithium therapy and urinary volume (men, r=0-26, women, r=0.09). We suggest that, given proper surveillance, lithium therapy is not likely to cause any serious problems during surgery.
E.C.G.
Laboratories Ltd., Morden, Surrey SM4 5DZ
Organon
RIFAMPICIN AND THE LIVER
SIR,-We would like to comment on the letter of Dr Di Piazza and colleagues.’ Clinical and experimental evidence suggests that the use of rifampicin in patients with severe liver impairment, including cirrhosis, is indicated only in cases of absolute necessity, and then at doses lower than those used in patients with normal liver function. In fact, as a result of both reduced functional capacity of the hepatocyte and the portacaval anastomosis present in cirrhosis the amount of antibiotic reaching the blood of the general circulation is higher than
Deparment of Nephrology, St Bartholomew’s Hospital, London EC1
W. R. CATTELL
M.R.C. Neuropsychiatry Laboratory, West Park Hosptial,
A. COPPEN J. BAILEY
Epsom, Surrey
V. A. RAMA RAO
WILLIAM L. SHAW
normal. 2.3 A further reason for using reduced rifampicin doses in these patients is that, in patients with liver cirrhosis, the serum-antibiotic concentrations tend to increase during the early phase of treatment, in contrast to what normally happens.4 Finally, the risk of symptomatic hepatitis is higher in patients with liver disease than in patients with normal liver function, particularly when combined antibiotic (antitubercular) treatment is given.s Caution is therefore indicated when rifampicin is administered to patients with liver disease, and liver function should be monitored. This precaution is clearly stated in the leaflet accompanying this antibiotic preparation, and had it been followed, the reactions observed and reported in Di Piazza’s letter would probably have been avoided. IA G. ACOCELLA Medical Department, A. LUVARÀ Gruppo Lepetit Spa, M. GUAGLIANONE 20124 Milan, Italy
MIANSERIN
SiR,-Dr Tulloch’ has described two clinical syndromes which may have been related to mianserin therapy. The first seems to be a case of patient idiosyncrasy. From ample information available on the clinical use of mianserin at doses of up to 200 mg per day, I find it difficult to relate 14 h of unconsciousness to a single 10 mg tablet; the evidence incriminating mianserin is tenuous. Tulloch’s second patient had taken an overdose of dothiepin. When mianserin was started a week later, the patient was already showing E.C.G. changes, perhaps due to the previous ingestion of the tricyclic. Could not the E.C.G. abnormalities have been secondary to the left-ventricular failure or the aspiration pneumonia? The cardiac picture had not improved when mianserin therapy started and the E.C.G. was unchanged three weeks after mianserin was
stopped. There is little evidence to support the view that mianserin is implicated in either case. Tricyclics can affect the cardiovascular system by direct action in three ways-anticholinergic activity, adrenergic activity, and by a direct myocardial depressant effect. Mianserin has no anticholinergic effects,3 and it does not block the reuptake mechanism4.5 (i.e., there is no peripheral adrenergic effect such as the tyramine pressor
CIMETIDINE-INDUCED COMA 200
response6). Tulloch refers to three reports of cardiotoxicity in mianserin overdose. In the first’ the patient took twenty mianserin tablets and an unknown quantity of lorazepam. Whereas the plasma level of mianserin showed therapeutic dosage, the lorazepam levels indicated overdosage. The patient died of bronchopneumonia from an aspiration so her death was not directly related to either of these drugs. The second report8 showed no E.C.G. changes relating to drug therapy, and here the mianserin level was the highest so far reached, corresponding to the ingestion of ninety tablets. The third report9 referred to first-degree heart block lasting 8 h. Information about other drugs consumed was scanty; heart block in this case may have been associated with mianserin, although this is difficult to accept in view of mianserin’s safety record. A survey of constant E.c.G. recordings in 86 healthy volunteers" revealed that 12% had disturbances of rhythm which were believed to be of serious prognostic significance. The
‘
1. Tulloch, A. E. Lancet, 1978, i, 1097. 2. Jefferson, J. W. Psychosomat. Med. 1975, 37, 160. 3. Kopera, H. Br. J clin. Pharmac. 1978, 5, 29 (suppl.). 4. Kafoe, W. F., Leonard, B. E. Archs int. Pharmacodyn. Ther. 1973, 206, 389. 5. Leonard, B. E Psychopharmacologica, 1974, 36, 221. 6. Ghose, K. Br. J clin Pharmac. 1976, 3, 666. 7. Crome, P., Newman, B. Br. med. J. 1977, ii, 260. 8. Jansen, H. Br. J. clin. Pharmac. 1978, 5, 91 (suppl.). 9. Green, S. D R., Kendall-Taylor, P. Br. med. J. 1977, ii, 1190. 10. Clarke, J. M., Hamer, J., Shelton, J. R., Taylor, S., Venning, G. R. Lancet,
1976, ii, 508.
pretreated with cyclophosphamide mg/kg given allogeneic HLA-identical bonemarrow for severe aplastic anxmia. The patient was unable to take liquids or food for 20 days because of nausea and vomiting. The gastralgia and vomiting became progressively more severe and did not respond to conventional antacid and antiemetic therapy. On day 20 gastric bleeding was noted and 2 mg/kg cimetidine was given by slow intravenous injection; gastric pain and vomiting resolved in 10 min and the patient fell asleep. After 2 h she woke up and asked for food, but 4 h after the cimetidine injection nausea and vomiting returned. The patient was given a second i.v. injection of cimetidine 2 mg/kg over a period of 3 min: after 15 min the patient fell "asleep", but this time a neurological examination revealed a stage-m coma; the patient was unable to respond to any kind of stimulus, all reflexes, except for the corneal reflex, were absent, pupils were miotic and non-reactive, and muscular tone was absent; blood-pressure 90/60 mm Hg, respiration 40/min, pulse 180/min (before cimetidine blood-pressure 115/80, respiration 20, pulse 148). Exactly 2 h after the second cimetidine injection the patient woke up and asked for food. Cimetidine was continued by slow i.v. drip (6 mg/kg/ SIR,-An 11-year-old girl
11. 12.
was
and
Kopera, H., Schenk, H. Br. med. J. 1977, ii, 773. Burgess, C. D., Turner, P., Wadsworth, J. Br. J. (suppl.).
clin. Pharmac. 1978,
1. Di Piazza, S., and others Lancet, 1978, i, 774. 2. Capelle, P., Dhumeaux, D., Mora, M., Feldman,
5, 21
G., Berthelot, P. Gut,
1972, 13, 366. 3. Jeanes, C. W. L., Jessamine, A. G., Eidus, L. Can. med. Ass. J. 1972, 106, 884. 4. Acocella, G., Bonollo, L., Garimoldi, M., Mainardi, M., Tenconi, L. T., Nicolis, F. B. Gut, 1972, 13, 47. 5. Girling, D. J. J. antimicrob. Chemother. 1977, 3, 115.
46 for 7 days with no neurological complications and with resolution of gastric bleeding and vomiting. The patient’s glomerular filtration-rate was normal before and after treatment, as were all biochemical indices. ANDREA BACIGALUPO Department of Hæmatology, MARIA T. VAN LINT Ospedale S.Martino, ALBERTO M. MARMONT 16132 Genoa, Italy
day)
LEUCOENCEPHALOPATHY IN PATIENTS ON METHOTREXATE
SIR,-Dr Abelson and colleagues (Jan. 28, p. 184) suggest that in the treatment ofc.N.s. tumours it may be of value "to maintain c.s.F. levels [of methotrexate] with probenecid and to use carboxypeptidase G1 to prevent peripheral toxicity". The main side-effect of methotrexate is leucoencephalopathy when methotrexate is given intrathecally or intraventricularly.1-4 Our experience of leucoencephalopathy in children with primary c.N.s. tumours treated with intrathecal or intraventricular methotrexate suggests that such treatment may be dangerous. DETAILS OF PATIENTS ON METHOTREXATE WITH
LEUCOENCEPHALOPATHY
(A-D)
OR FROM WHOM METHOTREXATE
WAS WITHDRAWN
(E-H)
must
be undertaken with
Department of Clinical Hæmatology and Oncology, Royal Children’s Hospital, Parkville, Victoria 3052, Australia
In 1975
with
we
at
mg/m2 intrathecally
receive
or not
receive methotrexate 6
or
cycles (84 weeks). Eight patients were randomised to receive intrathecal methotrexate. Leucoencephalopathy developed in four (table). This was diagnosed by clinical findings and computerised tomography. In the other four patients intrathecal methotrexate was withdrawn when the unacceptably high incidence of methotrexate toxicity became apparent. In view of the high incidence of leucoencephalopathy any 1. 2. 3.
use
of methotrexate in children with
W. R., Chernik, W. L., Posner, Rubenstein, L. J., and others Cancer, 1975, Price, R. A., Jamieson, P. A. ibid, 1975, 35, 4. Mellor, D. Devel. Med. Child Neurol. 1976,
Shapiro,
J. B. Archs 35, 291.
306. 18, 90.
Abelson
et
al.
KEITH D. WATERS
a great need for an objective test for the and progress of infarctive sickle-cell crisis. The diagnosis observations of Professor White and his colleagues’ of raised a-hydroxybutyrate dehydrogenase (a-H.B.D.) during crises, and a sharp fall preceding clinical improvement by 48 h, need to be confirmed in other centres and in other environments. However, necrosis of the heart and skeletal muscle and liver disease are not the only conditions apart from sickle-cell crisis in which a-H.B.D. is increased. The enzyme activity is raised to up to 20 times the upper limit of normal in patients with megaloblastic erythropoiesis,2 which is considerably higher than the values reported by White et al. in sickle-cell crisis. The high activity of serum enzyme seems to stem from the intramedullary destruction of blood-cell precursors in both megaloblastosis3 and sickle-cell infarction crisis. Folate deficiency of varying severity is a feature of almost all patients with sickle-cell disease in tropical Africa when they are seen for the first time or if they are not receiving folic-acid supplements. A rise in a-H.B.D. and a fall after treatment with folic acid will be difficult to interpret in a patient with sicklecell disease and megaloblastic erythropoiesis.
SiR,—There is
A. F. FLEMING
STRUCTURE OF CHOLECALCIFEROL DERIVATIVES
intraventricularly on days 1 and 15 of a maintenance chemotherapy cycle of vincristine 1-5 mg/m2 i.v. on days 1, 8 and 15 and lomustine (C.C.N.U.) 100 mg/m2 orally on day 1, repeated every 49 days. Prior treatment consists of surgery and standard irradiation according to tumour type. Vincristine 1.5mg/m2 i.v. is given once a week during irradiation therapy, 4 weeks after completion of irradiation, maintenance chemotherapy is started and is planned for twelve
future
as
this number of doses
began randomising newly diagnosed patients
c.N.s. tumours to
caution. If,
SERUM-&agr;-HYDROXYBUTYRATE IN SICKLE-CELL DISEASE
Department of Hæmatology, Ahmadu Bello University, Zaria, Nigeria
*Intrathecal methotrexate (M.T.X.) withdrawn and vincristine and lomustine continued. 1,=local C=Craniospinal. Patients B, C, and D recovered completely.
extreme
tetrahydrobiopterin is decreased during methotrexate therapy then prevention of the leucoencephalopathy may be possible with oral neurotransmitter derivatives5 or intravenous tetrahydrobiopterinwithout decreasing the antitumour effect via inhibition of dihydrofolate reductase. This possibility should be explored in future clinical trials in view of the clinical efficacy of methotrexate. 7,8 suggest,
c.N.s. tumours
Neurol.
1973, 28, 96.
SIR,-In your editorial of May 6 (p. 973) you state that the only difference in structure between ’One-Alpha’ (la-hydroxycholecalciferol) and 1,25-dihydroxycholecalciferol was the absence of a 25-hydroxyl group, but the diagrams accompanying your editorial indicate a difference in orientation of the hydroxyl bonds at the carbon-3 position. Edgware General Hospital, Edgware, Middlesex HAS OAD
J. G. LEWIS
*** In the natural parent of vitamin D3, 7-dehydrocholesterol, 3-hydroxyl is in theposition and is drawn, by convention,
the
with a solid line. When ultraviolet irradiation ruptures ring B the A ring turns over to adopt a more comfortable position, altering the projection of the bonds and moving the 1-position from the apex of the ring to the bottom right-hand corner: ;s projections now get the broken lines and x projections the solid. The solid/broken line convention is a chemical device 5 6. 7.
Bartholomé, K., Byrd, D. J. Lancet, 1975, ii, 1042. Danks, D. M., Cotton, R. G. H , Schlesinger, P. ibid, 1975, ii, 1043. Rosen, G., Ghavimi, F., Nirenberg, A., Mosende, C., Mehta, B. C. Cancer Treat. Rep. 1977, 61, 684. 8. Shapiro, W. R ibid p. 753. 1. White, J. M., Billimoria, F., Muller, M. A., Davis, L. R., Stroud, C. E. Lancet, 1978, i, 532. 2. Fleming, A. F., Elliott, B. A. Br. med. J. 1964, ii, 1108. 3. Elliott, B. A., Fleming, A. F. ibid. 1965, i, 626.
tients with affective disorders not on lithium and in 29 normal controls. As there was no significant difference between those not on lithium and the normal controls these groups have been combined. None of our lithium patients had had episodes of toxicity. Lithium-treated patients as a group had increased urinary output, but volumes greater than 3 litres were uncommon. In the male and female lithium-treated patients there was no significant correlation between the duration of lithium therapy and urinary volume (men, r=0-26, women, r=0.09). We suggest that, given proper surveillance, lithium therapy is not likely to cause any serious problems during surgery.
E.C.G.
Laboratories Ltd., Morden, Surrey SM4 5DZ
Organon
RIFAMPICIN AND THE LIVER
SIR,-We would like to comment on the letter of Dr Di Piazza and colleagues.’ Clinical and experimental evidence suggests that the use of rifampicin in patients with severe liver impairment, including cirrhosis, is indicated only in cases of absolute necessity, and then at doses lower than those used in patients with normal liver function. In fact, as a result of both reduced functional capacity of the hepatocyte and the portacaval anastomosis present in cirrhosis the amount of antibiotic reaching the blood of the general circulation is higher than
Deparment of Nephrology, St Bartholomew’s Hospital, London EC1
W. R. CATTELL
M.R.C. Neuropsychiatry Laboratory, West Park Hosptial,
A. COPPEN J. BAILEY
Epsom, Surrey
V. A. RAMA RAO
WILLIAM L. SHAW
normal. 2.3 A further reason for using reduced rifampicin doses in these patients is that, in patients with liver cirrhosis, the serum-antibiotic concentrations tend to increase during the early phase of treatment, in contrast to what normally happens.4 Finally, the risk of symptomatic hepatitis is higher in patients with liver disease than in patients with normal liver function, particularly when combined antibiotic (antitubercular) treatment is given.s Caution is therefore indicated when rifampicin is administered to patients with liver disease, and liver function should be monitored. This precaution is clearly stated in the leaflet accompanying this antibiotic preparation, and had it been followed, the reactions observed and reported in Di Piazza’s letter would probably have been avoided. IA G. ACOCELLA Medical Department, A. LUVARÀ Gruppo Lepetit Spa, M. GUAGLIANONE 20124 Milan, Italy
MIANSERIN
SiR,-Dr Tulloch’ has described two clinical syndromes which may have been related to mianserin therapy. The first seems to be a case of patient idiosyncrasy. From ample information available on the clinical use of mianserin at doses of up to 200 mg per day, I find it difficult to relate 14 h of unconsciousness to a single 10 mg tablet; the evidence incriminating mianserin is tenuous. Tulloch’s second patient had taken an overdose of dothiepin. When mianserin was started a week later, the patient was already showing E.C.G. changes, perhaps due to the previous ingestion of the tricyclic. Could not the E.C.G. abnormalities have been secondary to the left-ventricular failure or the aspiration pneumonia? The cardiac picture had not improved when mianserin therapy started and the E.C.G. was unchanged three weeks after mianserin was
stopped. There is little evidence to support the view that mianserin is implicated in either case. Tricyclics can affect the cardiovascular system by direct action in three ways-anticholinergic activity, adrenergic activity, and by a direct myocardial depressant effect. Mianserin has no anticholinergic effects,3 and it does not block the reuptake mechanism4.5 (i.e., there is no peripheral adrenergic effect such as the tyramine pressor
CIMETIDINE-INDUCED COMA 200
response6). Tulloch refers to three reports of cardiotoxicity in mianserin overdose. In the first’ the patient took twenty mianserin tablets and an unknown quantity of lorazepam. Whereas the plasma level of mianserin showed therapeutic dosage, the lorazepam levels indicated overdosage. The patient died of bronchopneumonia from an aspiration so her death was not directly related to either of these drugs. The second report8 showed no E.C.G. changes relating to drug therapy, and here the mianserin level was the highest so far reached, corresponding to the ingestion of ninety tablets. The third report9 referred to first-degree heart block lasting 8 h. Information about other drugs consumed was scanty; heart block in this case may have been associated with mianserin, although this is difficult to accept in view of mianserin’s safety record. A survey of constant E.c.G. recordings in 86 healthy volunteers" revealed that 12% had disturbances of rhythm which were believed to be of serious prognostic significance. The
‘
1. Tulloch, A. E. Lancet, 1978, i, 1097. 2. Jefferson, J. W. Psychosomat. Med. 1975, 37, 160. 3. Kopera, H. Br. J clin. Pharmac. 1978, 5, 29 (suppl.). 4. Kafoe, W. F., Leonard, B. E. Archs int. Pharmacodyn. Ther. 1973, 206, 389. 5. Leonard, B. E Psychopharmacologica, 1974, 36, 221. 6. Ghose, K. Br. J clin Pharmac. 1976, 3, 666. 7. Crome, P., Newman, B. Br. med. J. 1977, ii, 260. 8. Jansen, H. Br. J. clin. Pharmac. 1978, 5, 91 (suppl.). 9. Green, S. D R., Kendall-Taylor, P. Br. med. J. 1977, ii, 1190. 10. Clarke, J. M., Hamer, J., Shelton, J. R., Taylor, S., Venning, G. R. Lancet,
1976, ii, 508.
pretreated with cyclophosphamide mg/kg given allogeneic HLA-identical bonemarrow for severe aplastic anxmia. The patient was unable to take liquids or food for 20 days because of nausea and vomiting. The gastralgia and vomiting became progressively more severe and did not respond to conventional antacid and antiemetic therapy. On day 20 gastric bleeding was noted and 2 mg/kg cimetidine was given by slow intravenous injection; gastric pain and vomiting resolved in 10 min and the patient fell asleep. After 2 h she woke up and asked for food, but 4 h after the cimetidine injection nausea and vomiting returned. The patient was given a second i.v. injection of cimetidine 2 mg/kg over a period of 3 min: after 15 min the patient fell "asleep", but this time a neurological examination revealed a stage-m coma; the patient was unable to respond to any kind of stimulus, all reflexes, except for the corneal reflex, were absent, pupils were miotic and non-reactive, and muscular tone was absent; blood-pressure 90/60 mm Hg, respiration 40/min, pulse 180/min (before cimetidine blood-pressure 115/80, respiration 20, pulse 148). Exactly 2 h after the second cimetidine injection the patient woke up and asked for food. Cimetidine was continued by slow i.v. drip (6 mg/kg/ SIR,-An 11-year-old girl
11. 12.
was
and
Kopera, H., Schenk, H. Br. med. J. 1977, ii, 773. Burgess, C. D., Turner, P., Wadsworth, J. Br. J. (suppl.).
clin. Pharmac. 1978,
1. Di Piazza, S., and others Lancet, 1978, i, 774. 2. Capelle, P., Dhumeaux, D., Mora, M., Feldman,
5, 21
G., Berthelot, P. Gut,
1972, 13, 366. 3. Jeanes, C. W. L., Jessamine, A. G., Eidus, L. Can. med. Ass. J. 1972, 106, 884. 4. Acocella, G., Bonollo, L., Garimoldi, M., Mainardi, M., Tenconi, L. T., Nicolis, F. B. Gut, 1972, 13, 47. 5. Girling, D. J. J. antimicrob. Chemother. 1977, 3, 115.
46 for 7 days with no neurological complications and with resolution of gastric bleeding and vomiting. The patient’s glomerular filtration-rate was normal before and after treatment, as were all biochemical indices. ANDREA BACIGALUPO Department of Hæmatology, MARIA T. VAN LINT Ospedale S.Martino, ALBERTO M. MARMONT 16132 Genoa, Italy
day)
LEUCOENCEPHALOPATHY IN PATIENTS ON METHOTREXATE
SIR,-Dr Abelson and colleagues (Jan. 28, p. 184) suggest that in the treatment ofc.N.s. tumours it may be of value "to maintain c.s.F. levels [of methotrexate] with probenecid and to use carboxypeptidase G1 to prevent peripheral toxicity". The main side-effect of methotrexate is leucoencephalopathy when methotrexate is given intrathecally or intraventricularly.1-4 Our experience of leucoencephalopathy in children with primary c.N.s. tumours treated with intrathecal or intraventricular methotrexate suggests that such treatment may be dangerous. DETAILS OF PATIENTS ON METHOTREXATE WITH
LEUCOENCEPHALOPATHY
(A-D)
OR FROM WHOM METHOTREXATE
WAS WITHDRAWN
(E-H)
must
be undertaken with
Department of Clinical Hæmatology and Oncology, Royal Children’s Hospital, Parkville, Victoria 3052, Australia
In 1975
with
we
at
mg/m2 intrathecally
receive
or not
receive methotrexate 6
or
cycles (84 weeks). Eight patients were randomised to receive intrathecal methotrexate. Leucoencephalopathy developed in four (table). This was diagnosed by clinical findings and computerised tomography. In the other four patients intrathecal methotrexate was withdrawn when the unacceptably high incidence of methotrexate toxicity became apparent. In view of the high incidence of leucoencephalopathy any 1. 2. 3.
use
of methotrexate in children with
W. R., Chernik, W. L., Posner, Rubenstein, L. J., and others Cancer, 1975, Price, R. A., Jamieson, P. A. ibid, 1975, 35, 4. Mellor, D. Devel. Med. Child Neurol. 1976,
Shapiro,
J. B. Archs 35, 291.
306. 18, 90.
Abelson
et
al.
KEITH D. WATERS
a great need for an objective test for the and progress of infarctive sickle-cell crisis. The diagnosis observations of Professor White and his colleagues’ of raised a-hydroxybutyrate dehydrogenase (a-H.B.D.) during crises, and a sharp fall preceding clinical improvement by 48 h, need to be confirmed in other centres and in other environments. However, necrosis of the heart and skeletal muscle and liver disease are not the only conditions apart from sickle-cell crisis in which a-H.B.D. is increased. The enzyme activity is raised to up to 20 times the upper limit of normal in patients with megaloblastic erythropoiesis,2 which is considerably higher than the values reported by White et al. in sickle-cell crisis. The high activity of serum enzyme seems to stem from the intramedullary destruction of blood-cell precursors in both megaloblastosis3 and sickle-cell infarction crisis. Folate deficiency of varying severity is a feature of almost all patients with sickle-cell disease in tropical Africa when they are seen for the first time or if they are not receiving folic-acid supplements. A rise in a-H.B.D. and a fall after treatment with folic acid will be difficult to interpret in a patient with sicklecell disease and megaloblastic erythropoiesis.
SiR,—There is
A. F. FLEMING
STRUCTURE OF CHOLECALCIFEROL DERIVATIVES
intraventricularly on days 1 and 15 of a maintenance chemotherapy cycle of vincristine 1-5 mg/m2 i.v. on days 1, 8 and 15 and lomustine (C.C.N.U.) 100 mg/m2 orally on day 1, repeated every 49 days. Prior treatment consists of surgery and standard irradiation according to tumour type. Vincristine 1.5mg/m2 i.v. is given once a week during irradiation therapy, 4 weeks after completion of irradiation, maintenance chemotherapy is started and is planned for twelve
future
as
this number of doses
began randomising newly diagnosed patients
c.N.s. tumours to
caution. If,
SERUM-&agr;-HYDROXYBUTYRATE IN SICKLE-CELL DISEASE
Department of Hæmatology, Ahmadu Bello University, Zaria, Nigeria
*Intrathecal methotrexate (M.T.X.) withdrawn and vincristine and lomustine continued. 1,=local C=Craniospinal. Patients B, C, and D recovered completely.
extreme
tetrahydrobiopterin is decreased during methotrexate therapy then prevention of the leucoencephalopathy may be possible with oral neurotransmitter derivatives5 or intravenous tetrahydrobiopterinwithout decreasing the antitumour effect via inhibition of dihydrofolate reductase. This possibility should be explored in future clinical trials in view of the clinical efficacy of methotrexate. 7,8 suggest,
c.N.s. tumours
Neurol.
1973, 28, 96.
SIR,-In your editorial of May 6 (p. 973) you state that the only difference in structure between ’One-Alpha’ (la-hydroxycholecalciferol) and 1,25-dihydroxycholecalciferol was the absence of a 25-hydroxyl group, but the diagrams accompanying your editorial indicate a difference in orientation of the hydroxyl bonds at the carbon-3 position. Edgware General Hospital, Edgware, Middlesex HAS OAD
J. G. LEWIS
*** In the natural parent of vitamin D3, 7-dehydrocholesterol, 3-hydroxyl is in theposition and is drawn, by convention,
the
with a solid line. When ultraviolet irradiation ruptures ring B the A ring turns over to adopt a more comfortable position, altering the projection of the bonds and moving the 1-position from the apex of the ring to the bottom right-hand corner: ;s projections now get the broken lines and x projections the solid. The solid/broken line convention is a chemical device 5 6. 7.
Bartholomé, K., Byrd, D. J. Lancet, 1975, ii, 1042. Danks, D. M., Cotton, R. G. H , Schlesinger, P. ibid, 1975, ii, 1043. Rosen, G., Ghavimi, F., Nirenberg, A., Mosende, C., Mehta, B. C. Cancer Treat. Rep. 1977, 61, 684. 8. Shapiro, W. R ibid p. 753. 1. White, J. M., Billimoria, F., Muller, M. A., Davis, L. R., Stroud, C. E. Lancet, 1978, i, 532. 2. Fleming, A. F., Elliott, B. A. Br. med. J. 1964, ii, 1108. 3. Elliott, B. A., Fleming, A. F. ibid. 1965, i, 626.
