- Email: [email protected]
DIAZEPAM AS TUMOUR PROMOTER
277 The comment by Dr Knott* that the inclusion of DMSO under the Medicines Act was agreed upon with the D.H.S.S. is adequately answered by Dr Griffin.Furthermore the only cooperation between the Royal Free Hospital and Dr Knott was over details of the case-report, and it is inco’rrect to assume that we intimated that work with DMSO could continue. We apologise for the inaccurate citing of data from the study by Dr de la Torre on the intravenous subacute toxicity in monkeys Gan. 17, p. 157). At the time of publication, we only.had a preprint of the work and we understand that this underwent revision before
publication.
The significance of duodenogastric reflux for the development of postgastrectomy discomfort is controversial mainly because we lack objective methods for measurement. This simple scintigraphic technique should be valuable, especially in patients considered for bile
diverting surgery.
Departments of Surgery and Radiophysics, University Hospital, S-750 14 Uppsala, Sweden
Academic Department of Medicine, Royal Free Hospital,
DIAZEPAM AS TUMOUR PROMOTER
C. GREENFIELD
London NW 32QG
NON-INVASIVE TESTS FOR DUODENOGASTRIC REFLUX
SIR,—The assessment of duodenogastric reflux should be facilitated by non-invasive and simple reflux tests such as that described by Dr Muhammed and colleagues (Nov. 29, p. 1162) and others. 1-3. The tests all involve intravenous administration of bileexcreted radiopharmaceuticals and external detection with a gamma camera. One of the major advantages of the tests is, perhaps, the possibility to study patients under physiological conditions that are normal with respect to food intake. In our experience with 61 patients (table) the test can be done with a standard gamma camera provided with a simple electronic device PRESENCE OF DUODENOGASTRIC REFLUX
permitting separate registrations of radioactivity in two rectangular regions of interest, one covering the stomach or gastric remnant and the other the biliary tree. The positioning of the window is 9"’Tc-tin-colloid conveniently done after peroral administration ofgastric (2 MBq) before injection of 99mTc-Solco-HIDA (75 MBq). Quantification of bile reflux is made by relating the registrations in the two windows. A computerised gamma camera is thus not a prerequisite for the test. The test did not reveal evidence of biliary reflux in any of our 13 , patients who had not had previous gastric surgery. This finding is in keeping with other reports 1,2 that the scintigraphic technique seldom gives positive results in patients with an intact stomach/duodenum. On the other hand a pronounced bile reflux seems to have been a characteristic finding in postgastrectomy patients studied with this technique. 1,2 However, only 27 of our 42 postgastrectomy patients had signs of bile reflux and thus the test was negative in 15 patients (36%). The discrepancy may be explained by methodological differences since we investigated our patients without a starvation period and emptying of the biliary tree was prompted by a fatty meal. Another explanation could be found in the high frequency of enteroanastomoses in our material (table). In Sweden this procedure is often performed in connection with Billroth II gastrectomy with the intention of preventing bile reflux.
M. KROG L. K. ENANDER S. GUSTAVSSON B. HEDIN B. JUNG
SIR,-Dr Jackson and Dr Harris from Roche Products (Jan. 10, p. 104) describe two studies which, they claim, refute my suggestion that diazepam may accelerate the growth of existing tumours and promote the development of cancer in response to sub-threshold doses of initiating carcinogens. I have never suggested that diazepam itself is an initiating carcinogen. The conventional carcinogenicity test in rats being done at the Huntingdon Research Centre is thus irrelevant to the issue. By definition tumour promoters do not themselves cause tumours. The Roche interpretation depends on the idea that spontaneous tumours arise because of unknown carcinogens. There is no evidence that spontaneous tumours are
caused in this way. To
test
for acceleration of tumour
growth one must compare groups of animals which all have tumours of the same size at the start of the experiment. Jackson and Harris also refer to a study of the effects of N-diethylnitrosamine (DEN) in control and diazepam treated gerbils.’ I am surprised that Roche claim this as evidence for the safety of diazepam. DEN is metabolised to an active carcinogen in the body, and diazepam blocks this process. Two groups of gerbils were given the same weekly dose ofDEN; in one group each DEN injection was preceded by a large (10 mg) diazepam dose aimed at blocking DEN activation. Not surprisingly, the group exposed to a low dose of activated DEN (plus diazepam) lived longer. What are surprising are the following results: (1) Diazepam did not reduce the frequency of nasal adenocarcinoma even though levels of activated DEN were lower. Biliary tract tumours developed in 32/40 animals in the diazepam group and in 33/39 of the DEN alone group, but the diazepam group adenomas and the DEN alone group tumours were carcinomas. Since DEN adenomas appear to progress to carcinomas,2this observation is consistent with exposure of the the diazepam group to a lower dose of activated carcinogen. (2) No hepatocellular tumours were detected in the DEN alone group but there were 5 such tumours (3 adenomas and 2 carcinomas) in the diazepam group (p<0 - 05). Even though the animals in the diazepam group were exposed to a lower dose of activated DEN a tumour of a type not usually caused by DEN developed. This is a characteristic tumour-promoting effect. Thus one study cited by Jackson and Harris is irrelevant and the other provides evidence of tumour promoting activity. Further-
tumours were
more: , in muscle similar to those of (a) Diazepam has actions on calcium movements J phorbol esters and ultraviolet radiation. (b) Diazepam at low doses accelerates the growth of the R3230AC mammary
tumour’"and of a renal Walker 256 tumour"
m rats.
1. Green U, Ketkar M. The influence of diazepam and thiouracil upon the carcinogenic effect of diethylnitrosamine in gerbils. Zeitschr Krebsforsch 1978; 92: 55-62. 2. Bannasch P, Massner B. Histogenese und cytogenese von cholangiofibromen und cholangiocarcinomen bei nitrosomorpholin-vergifteten ratten. Zeitschr Krebsforsch
1976; 87: 239-255 DF, Trosko JE. The possible effect of diazepam on cancer development and growth. Med Hypoth 1981; 7: 117-27. Karmali RA, Horrobin DF, Ghayur T, et al Influence of agents which modulate
3. Horrobin
Griffin JP. Dimethylsulphoxide. Lancet 1981; i: 41 HG, Hundeshagen H, Pichlamyr R. Die Anwendung einer neuen Methode zur Bestimmung des duodeno- under jejunogastralen Reflux nach Magenoperationen. Der Chirurg 1977; 48: 588-91. 2. Tolin RD, Malmud LS, Stelzer F, Mening R, Makler PT Jr, Applegate G, Fisher RS Enterogastric reflux in normal subjects and patients with Billroth II gastroenterostomy. Gastroenterology 1979; 77: 1027-33. 3. Gustavsson S, Enander LK, Jung B, Nilsson F, Wilen T Scintigraphic determination 7.
1 Löhlein
of biliary reflux into the 1979; suppl. 493: 14.
residual stomach after gastric surgery. Acta Chir Scand
4.
thromboxane A2 synthesis or action on the R3230AC mammary carcinoma Cancer Lett 1978; 5: 205-08. 5. Karmali RA, Volkman A, Muse P, et al The influence of diazepam administration in rats bearing the R3230AC mammary carcinoma. Prostaglandins Med 1979, 3: 193-98. 6. Karmali RA, Volkman A, Spivey W, et al. Intrarenal growth of the Walker 256 tumour and renal vein concentrations of PGE2, PGF2 alpha and TXB2 effects of diazepam. Prostaglandins Med 1980, 4: 239-46.
-
278
(c) In a test for tumour promoters diazepam gave positive results at clinically relevant concentrations.’7 ( f) Women with breast cancer who have taken minor psychotropics have an accelerated rate of tumour development.’P (e) Diazepam can cause abnormal mammary function in both animals and man.3. Without interfering with therapy it should be possible to compare development in people taking and not taking diazepam. Particular attention should be paid to tumours likely to be caused by initiating carcinogens or in which promoting factors may affect growth, such as cancers in smokers and in industrial workers exposed to carcinogens and malignant melanomas and breast cancers. cancer
PO Box 10, Nuns’ Island, Montreal H3E
D. F. HORROBIN
1JB, Canada
SIR,-In 1933 it was reported that eczematous children had decreased blood levels of unsaturated fatty acids, and several workers subsequently claimed encouraging therapeutic results from the addition of maize oil or fresh lard to the diet of patients with atopic eczema.2.4 These studies were poorly controlled, however, and in 1955 a controlled trial showed that a small daily dose of oral linoleic and linolenic acid was of no benefit in eczema. With the advent of topical steroids, dietary treatment of eczema with oral fats became outmoded and the possible role of unsaturated fatty acids in the pathogenesis of eczema has not been fully investigated. Evening primrose oil is a rich source of linoleic and y-linolenic acid, and we have shown that this preparation produces clinical improvement in atopic eczema. We studied seventeen children (aged 18 months to 13 years) and fifteen adults (aged 14-32 years), all of whom had had atopic eczema for at least 6 months. Each patient received ’Efamol’ capsules (containing 500 mg evening primrose oil, including 45 mg y-linolenic acid) on a randomised double-blind crossover basis, with similar capsules of liquid paraffin as a placebo. Each adult received four capsules twice daily of one preparation for 3 weeks, followed by the same dose of the alternative for a further 3 weeks. Children received half the adult dose. All patients also used a mild topical steroid preparation which was continued unchanged throughout the trial. At each 3 week visit the patient (or parent) was asked to record the severity of the eczema on a continuous 10 cm
8. 1. 2. 3. 4.
E (PGEI) activity6,
eczema.88
TREATMENT OF ATOPIC ECZEMA WITH EVENING PRIMROSE OIL
7.
linear scale ranging from no eczema (zero) to most severe (10 cm). One doctor made a similar independent assessment. Efamol caused no adverse reactions in either adults or children. Patients receiving efamol showed a modest but significant improvement on both the doctor’s and their own assessment (table). These preliminary observations suggest that an abnormality in fatty acid metabolism may be involved in the pathogenesis of atopic eczema. Several possible mechanisms require further investigation-e.g., y-linolenic acid isa precursor of prostaglandin 1) which is required for normal T lymphocyte and a metabolic block in the production of PGEcould account for the defective T cell function which occurs in some patients with atopic
Trosko JE, Horrobin DF. The activity of diazepam in a Chinese hamster V79 lung cell assay for tumour promoters. IRCS J Med Sci 1980; 8: 887. Stoll BA. Psychosomatic factors and tumour growth. In: Stoll BA, ed. Risk factors in breast cancer. London: William Heinemann Medical Books, 1976 193-203 Hansen AE. Serum lipid changes and therapeutic effects of various oils in infantile eczema. Proc Soc Exp Biol 1933; 31: 160-61. Cornbleet T. Use of maize oil (unsaturated fatty acids) in the treatment of eczema: Preliminary report. Arch Dermatol Syphilol 1935; 31: 224 Finnerud CW, Kesler RL, Wiese HF. Ingestion of lard in the treatment of eczema and allied dermatoses. Arch Dermatol Syphilol 1941, 44: 849. Hansen AE, Knott EM, Wiese HF, Shaperman E, McQuarrie I. Eczema and essential fatty acids. Am J Dis Child 1947; 73: 1-18.
EFFECT OF EVENING PRIMROSE OIL
(EPO) AND PLACEBO
ON CLINICAL
We thank Mr L. J. Smith of Agricultural Holdings, 40 Warton Road, London E15 2JU for supplies of’Efamol’ and placebo and the consultant dermatologists at Bristol Royal Infirmary for allowing us to study their patients.
Department of Dermatology, Bristol Royal Infirmary,
C. R. LOVELL
Bristol BS2 8HW
J. L. BURTON
P.O. Box 10, Nun’s Island, Montreal, Canada
D. F. HORROBIN
TESTING FOR AUTONOMIC NEUROPATHY
SIR,-Duncan et al.reported that the 30:15 ratio2 after a head-up tilt is an insensitive index of autonomic neuropathy among chronic alcoholics. Now Dr Borst and his colleagues claim (Jan. 10, p. 102) that analysis of the immediate heart rate reaction to tilting is unsuitable in the diagnosis of autonomic neuropathy. We disagree. The immediate heart rate reaction to standing up is characterised by an initial acceleration followed by a transient deceleration.2 We found a similar heart rate reaction after tilting in 31 healthy controls with a test procedure almost identical to that used by Duncan et al. (90 head up tilt in 2 S).3 In contrast, Borst et al. found an absent immediate reaction. The reason for the discrepancy is not clear. Patients and methods may differ. Unfortunately, no details are given by Borst et al., and the references comprise three abstracts (one unpublished). Borst’s data do not justify the conclusion that the tilt table test is without value in autonomic neuropathy. In our experience the test is very efficient, both in controls and in diabetics, alcoholics, and patients with rheumatic diseases, and it has the advantage of not being effort dependent. Dr Maisey (Jan. 3, p. 46) suggests that another ratio should be used. We agree. We found that about 50% of healthy controls had an abnormal 30:15 ratio.Maisey suggests using the ratio of maximum to minimum heart rate. Such an index, however, cannot separate the acceleration and deceleration phases. To make this possible we have introduced an "acceleration index" (the difference between resting R-R interval and shortest R-R interval expressed as a percentage of resting R-R interval) and a "brake index" (longest R-R minus shortest R-R expressed as a percentage of resting R-R).3 These indices take into account the resting heart rate, which often is raised in autonomic neuropathy.4Using these indices we have shown that
SEVERITY OF ECZEMA 5.
Pettit JHS. Use of unsaturated fatty acids in the eczemas of childhood. Br Med J 1954,i: 79-81.
DF, Manku MS, Oka M The nutritional regulation of T lymphocyte funcMed Hypoth 1979; 5: 969-85. Horrobin DF. The regulation of prostaglandin biosynthesis: Negative feedback mechanisms and the selective control of formation of 1 and 2 series prostaglandins: relevance to inflammation and immunity. Med Hypoth 1980; 6: 687-709. Byrom NA, Timlin DA. Immune status in atopic eczema. BrJ Dermatol 1979; 100:
6. Horrobin tion
7.
8.
491-98. 1 .Duncan
*Clinical
grading from 0 (no eczema) to
10
(most severe): (means ± SEM).
G, Johnson RH, Lambie DG, Whiteside E.A. Evidence ofvagal neuropathy in chronic alcoholics Lancet 1980; ii: 1053-57 2. Ewing DJ, Campbell IW, Muray A, Neilson JMM, Clarke BF. Immediate heart rate response to standing. a simple test for autonomic neuropathy in diabetes Br Med J 1978, i 145-47. 3. Sundkvist G, Lilja B, Almér L.-O. Abnormal diastolic blood pressure and heart rate reactions to tilting in diabetes mellitus. Diabetologia 1980; 19: 433-38. 4. Wheeler T, Watkins PJ Cardiac denervation in diabetes. Br Med J 1973, iv 584-86
publication.
The significance of duodenogastric reflux for the development of postgastrectomy discomfort is controversial mainly because we lack objective methods for measurement. This simple scintigraphic technique should be valuable, especially in patients considered for bile
diverting surgery.
Departments of Surgery and Radiophysics, University Hospital, S-750 14 Uppsala, Sweden
Academic Department of Medicine, Royal Free Hospital,
DIAZEPAM AS TUMOUR PROMOTER
C. GREENFIELD
London NW 32QG
NON-INVASIVE TESTS FOR DUODENOGASTRIC REFLUX
SIR,—The assessment of duodenogastric reflux should be facilitated by non-invasive and simple reflux tests such as that described by Dr Muhammed and colleagues (Nov. 29, p. 1162) and others. 1-3. The tests all involve intravenous administration of bileexcreted radiopharmaceuticals and external detection with a gamma camera. One of the major advantages of the tests is, perhaps, the possibility to study patients under physiological conditions that are normal with respect to food intake. In our experience with 61 patients (table) the test can be done with a standard gamma camera provided with a simple electronic device PRESENCE OF DUODENOGASTRIC REFLUX
permitting separate registrations of radioactivity in two rectangular regions of interest, one covering the stomach or gastric remnant and the other the biliary tree. The positioning of the window is 9"’Tc-tin-colloid conveniently done after peroral administration ofgastric (2 MBq) before injection of 99mTc-Solco-HIDA (75 MBq). Quantification of bile reflux is made by relating the registrations in the two windows. A computerised gamma camera is thus not a prerequisite for the test. The test did not reveal evidence of biliary reflux in any of our 13 , patients who had not had previous gastric surgery. This finding is in keeping with other reports 1,2 that the scintigraphic technique seldom gives positive results in patients with an intact stomach/duodenum. On the other hand a pronounced bile reflux seems to have been a characteristic finding in postgastrectomy patients studied with this technique. 1,2 However, only 27 of our 42 postgastrectomy patients had signs of bile reflux and thus the test was negative in 15 patients (36%). The discrepancy may be explained by methodological differences since we investigated our patients without a starvation period and emptying of the biliary tree was prompted by a fatty meal. Another explanation could be found in the high frequency of enteroanastomoses in our material (table). In Sweden this procedure is often performed in connection with Billroth II gastrectomy with the intention of preventing bile reflux.
M. KROG L. K. ENANDER S. GUSTAVSSON B. HEDIN B. JUNG
SIR,-Dr Jackson and Dr Harris from Roche Products (Jan. 10, p. 104) describe two studies which, they claim, refute my suggestion that diazepam may accelerate the growth of existing tumours and promote the development of cancer in response to sub-threshold doses of initiating carcinogens. I have never suggested that diazepam itself is an initiating carcinogen. The conventional carcinogenicity test in rats being done at the Huntingdon Research Centre is thus irrelevant to the issue. By definition tumour promoters do not themselves cause tumours. The Roche interpretation depends on the idea that spontaneous tumours arise because of unknown carcinogens. There is no evidence that spontaneous tumours are
caused in this way. To
test
for acceleration of tumour
growth one must compare groups of animals which all have tumours of the same size at the start of the experiment. Jackson and Harris also refer to a study of the effects of N-diethylnitrosamine (DEN) in control and diazepam treated gerbils.’ I am surprised that Roche claim this as evidence for the safety of diazepam. DEN is metabolised to an active carcinogen in the body, and diazepam blocks this process. Two groups of gerbils were given the same weekly dose ofDEN; in one group each DEN injection was preceded by a large (10 mg) diazepam dose aimed at blocking DEN activation. Not surprisingly, the group exposed to a low dose of activated DEN (plus diazepam) lived longer. What are surprising are the following results: (1) Diazepam did not reduce the frequency of nasal adenocarcinoma even though levels of activated DEN were lower. Biliary tract tumours developed in 32/40 animals in the diazepam group and in 33/39 of the DEN alone group, but the diazepam group adenomas and the DEN alone group tumours were carcinomas. Since DEN adenomas appear to progress to carcinomas,2this observation is consistent with exposure of the the diazepam group to a lower dose of activated carcinogen. (2) No hepatocellular tumours were detected in the DEN alone group but there were 5 such tumours (3 adenomas and 2 carcinomas) in the diazepam group (p<0 - 05). Even though the animals in the diazepam group were exposed to a lower dose of activated DEN a tumour of a type not usually caused by DEN developed. This is a characteristic tumour-promoting effect. Thus one study cited by Jackson and Harris is irrelevant and the other provides evidence of tumour promoting activity. Further-
tumours were
more: , in muscle similar to those of (a) Diazepam has actions on calcium movements J phorbol esters and ultraviolet radiation. (b) Diazepam at low doses accelerates the growth of the R3230AC mammary
tumour’"and of a renal Walker 256 tumour"
m rats.
1. Green U, Ketkar M. The influence of diazepam and thiouracil upon the carcinogenic effect of diethylnitrosamine in gerbils. Zeitschr Krebsforsch 1978; 92: 55-62. 2. Bannasch P, Massner B. Histogenese und cytogenese von cholangiofibromen und cholangiocarcinomen bei nitrosomorpholin-vergifteten ratten. Zeitschr Krebsforsch
1976; 87: 239-255 DF, Trosko JE. The possible effect of diazepam on cancer development and growth. Med Hypoth 1981; 7: 117-27. Karmali RA, Horrobin DF, Ghayur T, et al Influence of agents which modulate
3. Horrobin
Griffin JP. Dimethylsulphoxide. Lancet 1981; i: 41 HG, Hundeshagen H, Pichlamyr R. Die Anwendung einer neuen Methode zur Bestimmung des duodeno- under jejunogastralen Reflux nach Magenoperationen. Der Chirurg 1977; 48: 588-91. 2. Tolin RD, Malmud LS, Stelzer F, Mening R, Makler PT Jr, Applegate G, Fisher RS Enterogastric reflux in normal subjects and patients with Billroth II gastroenterostomy. Gastroenterology 1979; 77: 1027-33. 3. Gustavsson S, Enander LK, Jung B, Nilsson F, Wilen T Scintigraphic determination 7.
1 Löhlein
of biliary reflux into the 1979; suppl. 493: 14.
residual stomach after gastric surgery. Acta Chir Scand
4.
thromboxane A2 synthesis or action on the R3230AC mammary carcinoma Cancer Lett 1978; 5: 205-08. 5. Karmali RA, Volkman A, Muse P, et al The influence of diazepam administration in rats bearing the R3230AC mammary carcinoma. Prostaglandins Med 1979, 3: 193-98. 6. Karmali RA, Volkman A, Spivey W, et al. Intrarenal growth of the Walker 256 tumour and renal vein concentrations of PGE2, PGF2 alpha and TXB2 effects of diazepam. Prostaglandins Med 1980, 4: 239-46.
-
278
(c) In a test for tumour promoters diazepam gave positive results at clinically relevant concentrations.’7 ( f) Women with breast cancer who have taken minor psychotropics have an accelerated rate of tumour development.’P (e) Diazepam can cause abnormal mammary function in both animals and man.3. Without interfering with therapy it should be possible to compare development in people taking and not taking diazepam. Particular attention should be paid to tumours likely to be caused by initiating carcinogens or in which promoting factors may affect growth, such as cancers in smokers and in industrial workers exposed to carcinogens and malignant melanomas and breast cancers. cancer
PO Box 10, Nuns’ Island, Montreal H3E
D. F. HORROBIN
1JB, Canada
SIR,-In 1933 it was reported that eczematous children had decreased blood levels of unsaturated fatty acids, and several workers subsequently claimed encouraging therapeutic results from the addition of maize oil or fresh lard to the diet of patients with atopic eczema.2.4 These studies were poorly controlled, however, and in 1955 a controlled trial showed that a small daily dose of oral linoleic and linolenic acid was of no benefit in eczema. With the advent of topical steroids, dietary treatment of eczema with oral fats became outmoded and the possible role of unsaturated fatty acids in the pathogenesis of eczema has not been fully investigated. Evening primrose oil is a rich source of linoleic and y-linolenic acid, and we have shown that this preparation produces clinical improvement in atopic eczema. We studied seventeen children (aged 18 months to 13 years) and fifteen adults (aged 14-32 years), all of whom had had atopic eczema for at least 6 months. Each patient received ’Efamol’ capsules (containing 500 mg evening primrose oil, including 45 mg y-linolenic acid) on a randomised double-blind crossover basis, with similar capsules of liquid paraffin as a placebo. Each adult received four capsules twice daily of one preparation for 3 weeks, followed by the same dose of the alternative for a further 3 weeks. Children received half the adult dose. All patients also used a mild topical steroid preparation which was continued unchanged throughout the trial. At each 3 week visit the patient (or parent) was asked to record the severity of the eczema on a continuous 10 cm
8. 1. 2. 3. 4.
E (PGEI) activity6,
eczema.88
TREATMENT OF ATOPIC ECZEMA WITH EVENING PRIMROSE OIL
7.
linear scale ranging from no eczema (zero) to most severe (10 cm). One doctor made a similar independent assessment. Efamol caused no adverse reactions in either adults or children. Patients receiving efamol showed a modest but significant improvement on both the doctor’s and their own assessment (table). These preliminary observations suggest that an abnormality in fatty acid metabolism may be involved in the pathogenesis of atopic eczema. Several possible mechanisms require further investigation-e.g., y-linolenic acid isa precursor of prostaglandin 1) which is required for normal T lymphocyte and a metabolic block in the production of PGEcould account for the defective T cell function which occurs in some patients with atopic
Trosko JE, Horrobin DF. The activity of diazepam in a Chinese hamster V79 lung cell assay for tumour promoters. IRCS J Med Sci 1980; 8: 887. Stoll BA. Psychosomatic factors and tumour growth. In: Stoll BA, ed. Risk factors in breast cancer. London: William Heinemann Medical Books, 1976 193-203 Hansen AE. Serum lipid changes and therapeutic effects of various oils in infantile eczema. Proc Soc Exp Biol 1933; 31: 160-61. Cornbleet T. Use of maize oil (unsaturated fatty acids) in the treatment of eczema: Preliminary report. Arch Dermatol Syphilol 1935; 31: 224 Finnerud CW, Kesler RL, Wiese HF. Ingestion of lard in the treatment of eczema and allied dermatoses. Arch Dermatol Syphilol 1941, 44: 849. Hansen AE, Knott EM, Wiese HF, Shaperman E, McQuarrie I. Eczema and essential fatty acids. Am J Dis Child 1947; 73: 1-18.
EFFECT OF EVENING PRIMROSE OIL
(EPO) AND PLACEBO
ON CLINICAL
We thank Mr L. J. Smith of Agricultural Holdings, 40 Warton Road, London E15 2JU for supplies of’Efamol’ and placebo and the consultant dermatologists at Bristol Royal Infirmary for allowing us to study their patients.
Department of Dermatology, Bristol Royal Infirmary,
C. R. LOVELL
Bristol BS2 8HW
J. L. BURTON
P.O. Box 10, Nun’s Island, Montreal, Canada
D. F. HORROBIN
TESTING FOR AUTONOMIC NEUROPATHY
SIR,-Duncan et al.reported that the 30:15 ratio2 after a head-up tilt is an insensitive index of autonomic neuropathy among chronic alcoholics. Now Dr Borst and his colleagues claim (Jan. 10, p. 102) that analysis of the immediate heart rate reaction to tilting is unsuitable in the diagnosis of autonomic neuropathy. We disagree. The immediate heart rate reaction to standing up is characterised by an initial acceleration followed by a transient deceleration.2 We found a similar heart rate reaction after tilting in 31 healthy controls with a test procedure almost identical to that used by Duncan et al. (90 head up tilt in 2 S).3 In contrast, Borst et al. found an absent immediate reaction. The reason for the discrepancy is not clear. Patients and methods may differ. Unfortunately, no details are given by Borst et al., and the references comprise three abstracts (one unpublished). Borst’s data do not justify the conclusion that the tilt table test is without value in autonomic neuropathy. In our experience the test is very efficient, both in controls and in diabetics, alcoholics, and patients with rheumatic diseases, and it has the advantage of not being effort dependent. Dr Maisey (Jan. 3, p. 46) suggests that another ratio should be used. We agree. We found that about 50% of healthy controls had an abnormal 30:15 ratio.Maisey suggests using the ratio of maximum to minimum heart rate. Such an index, however, cannot separate the acceleration and deceleration phases. To make this possible we have introduced an "acceleration index" (the difference between resting R-R interval and shortest R-R interval expressed as a percentage of resting R-R interval) and a "brake index" (longest R-R minus shortest R-R expressed as a percentage of resting R-R).3 These indices take into account the resting heart rate, which often is raised in autonomic neuropathy.4Using these indices we have shown that
SEVERITY OF ECZEMA 5.
Pettit JHS. Use of unsaturated fatty acids in the eczemas of childhood. Br Med J 1954,i: 79-81.
DF, Manku MS, Oka M The nutritional regulation of T lymphocyte funcMed Hypoth 1979; 5: 969-85. Horrobin DF. The regulation of prostaglandin biosynthesis: Negative feedback mechanisms and the selective control of formation of 1 and 2 series prostaglandins: relevance to inflammation and immunity. Med Hypoth 1980; 6: 687-709. Byrom NA, Timlin DA. Immune status in atopic eczema. BrJ Dermatol 1979; 100:
6. Horrobin tion
7.
8.
491-98. 1 .Duncan
*Clinical
grading from 0 (no eczema) to
10
(most severe): (means ± SEM).
G, Johnson RH, Lambie DG, Whiteside E.A. Evidence ofvagal neuropathy in chronic alcoholics Lancet 1980; ii: 1053-57 2. Ewing DJ, Campbell IW, Muray A, Neilson JMM, Clarke BF. Immediate heart rate response to standing. a simple test for autonomic neuropathy in diabetes Br Med J 1978, i 145-47. 3. Sundkvist G, Lilja B, Almér L.-O. Abnormal diastolic blood pressure and heart rate reactions to tilting in diabetes mellitus. Diabetologia 1980; 19: 433-38. 4. Wheeler T, Watkins PJ Cardiac denervation in diabetes. Br Med J 1973, iv 584-86