903 tinal propulsion produced by bromocriptine.S We cannot explain the transient effects of bromocriptine on the gastrointestinal tract, but side-effects in man are also transient.*’ The rise in basal serum-gastrin found in cats may explain, at least in part, the potentiation of pentagastrinstimulated acid secretion3 and may also explain the slight rise in basal acid output reported by Major Cowan. We have suggested that bromocriptine acts on the stomach via 5-hydroxytryptamine or a-adrenergic antagonism,j both actions being properties of bromocriptine.3 The data reported here need confirmation in man, but provide further justification for Major Cowan’s suggestion that bromocriptine be used with care in patients with a history of peptic ulceration. We thank the Science Research Council (B.H.H.) and Luccock of Newcastle upon Tyne
Scholarship Committee of the University (’.K.L.) for financial support. Department of Physiology, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU
B. H. HIRST P. K. LUND J. D. REED
D. J. SANDERS
to be diagnosed rapidly so that chlamydia-negative, ureaplasma-positive cases may be studied in detail.
infections
Division of Communicable Diseases, M.R.C. Clinical Research Centre, Harrow, Middlesex, and Central Middlesex Hospital, London NW10.
D. TAYLOR-ROBINSON G. W. CSONKA M. J. PRENTICE
MEDICAL ONCOLOGY
SiR,-Skilled management of the psychological and social problems of the patient with malignant disease, as urged by Mr Ouslander and Dr Barker (April 9, p. 801), is not the sole preserve of the medical oncologist. Much experience in these aspects of oncology is gained by working in a busy radiotherapy department, which should be part of the training of every aspiring medical oncologist. Each member of the oncological team has his own contribution to make to the care of the cancer patient. The medical oncorogist must offer expert knowledge of the design and improvement of chemotherapeutic regimens and the management of specific medical problems. At the same time, physicians, surgeons, and radiotherapists must all be clinicians first, giving the fullest care and support to the patient throughout his illness.
CHLAMYDIAL AND UREAPLASMA-ASSOCIATED URETHRITIS
StR,-1’he role of ureaplasmas, formerly termed T-strain T
B. S. MANTELL
or
mycoplasmas,
in non-specific urethritis (N.S.u.) has been a bone of contention for many years. It was therefore with interest that we read the paper by Bowie et al.’ in which they reported the results of using either sulphonamides or aminocyclitols to treat N.s.u. Sulphonamides, active against chlamydix but not ureaplasmas, were effective in treating chlamy-
and
dia-positive aminocyclitols, active against ureaplasmas but not chlamydiae, were successful in ureaplasma-positive cases. These results give some support to the idea that ureaplasmas do cause some cases of N.s.u. Further supJ. port comes from our placebo-controlled trial of minocycline. The results indicated that chlamydix had an important part to play and also suggested, albeit less convincingly, that ureacases,
plasmas were implicated. Lately two of us (D.T.-R. and G.W.C.) inoculated ourselves intraurethrally with ureaplasmas, each with a different strain. These had been isolated as the only organisms from two patients whose N.s.u. had responded to tetracycline. Inoculation resulted in infection followed by symptoms and signs compatible with N.S.U. In one subject the disease responded rapidly to tetracycline; in the other, urinary threads of epithelial cells and polymorphonuclear leucocytes persisted for at least six months after the symptoms and other signs had disappeared and after the ureaplasmas had been eliminated from the urogenital tract. The details of these experiments will be published elsewhere.3 sufficient evidence to conclude that of N.s.u. The question which ureaplasmas remains, however, is whether they are a prominent or an insignificant cause. This will only be solved by the further use of differential antibiotics, by an assessment of the extent to which the number of infectinj organisms might be important, and by the development of techniques which will enable chlamydial We feel that there is
now
are one cause
5.
Department of Radiotherapy and Oncology, London Hospital, E 1
SUPPORT FOR RESEARCH IN DERMATOLOGY
SIR,-All dermatologists will agree with Professor Greaves’ (April 9, p. 793) on the need to increase research in der-
views
Our two charities hope that dermatologists will note that we are trying to help research by providing financial aid when we can. But we in turn need the help of dermatologists to inform patients of our existence and to hand out our literature in their departments, so that we can recruit members who will aid us in our fund-raising and whose subscriptions will also support our nationwide activities.
matology.
SAM CHAPLAIN, National chairman
National Eczema
Society Psoriasis Association, 7 Milton Street, Northampton NN2 7JG
RICHARD B. COLES, National vice-chairman
ARSENIC IN OPIUM
SiR,—Dr Datta (Feb. 26, p. 484) reports arsenic-induced neuropathy resulting from the consumption of 10-20 g opium per day with an arsenic content of less than 7$[ig/100 g. This concentration is below the acceptable upper limits for all foods (normally set at 1 part per million or 100 g/100 g) and is little more than a tenth of the acceptable limit for fish (5 p.p.m.). The total daily intake of arsenic from such a dose of opium is minute and could not possibly be responsible for neurological change. If Dr Datta’s patient had neurological changes due to arsenic then I think he must look elsewhere for the arsenic source.
Charles Camsell Hospital, Edmonton, Alberta T5M 3A4, Canada
R. D. P. EATON
Flückinger,
E. Paper read at symposium on Pharmacological and Clinical Aspects of Bromocriptine (’Parlodol’), held in London on May 14, 1976. (In the press.) 6 Sachdev, Y., Gomez-Pan, A., Tunbridge, W. M. G., Duns, A., Weightman, D. R., Hall, R., Goolamali, S. K. Lancet, 1975, ii, 1164. 1 Bowie, W. R., Alexander, E. R., Floyd, J. F., Holmes, J., Miller, Y., Holmes, K K. Lancet, 1976, ii, 1276. 2 Prentice, M. J., Taylor-Robinson, D., Csonka, G. W. Br. J.ven. Dis. 1976, 52, 269. 3 Taylor-Robinson, D., Csonka, G. W., Prentice, M. J. Q. Jl Med. (in the press).
*
**This letter has been shown lows.-ED. L.
SIR,-Ithank
to
Dr
Datta, whose reply fol-
Dr Eaton for his critical comment. Besides
methodological difficulties, there are many gaps in our knowledge of arsenic metabolism. However, our results compare well with those obtained by spectrophotometry. The toxicity of
904 arsenic depends on whether it is taken in organic or inorganic form (pentavalent or trivalent).’ I have extended the work to which Dr Eaton refers and confirmed that opium is adulterated by some unknown arsenic compound to increase its aphrodisiac activity and that the arsenic concentration can be very high. It is mostly in salt form and can be extracted without boiling with hydrochloric acid, in contrast to the arsenic present in food (see figure). Arsenic compounds prepared in
TOTAL
Total arsenic content in arsenic.
INORGANIC FREE
opium compared
with
inorganic,
free
our area are based on the trivalent oxide form known as Bhasma. Since no history of arsenic intake from any other source was available and in view of the nature of the arsenic with which the opium was adulterated, I am convinced that the adulteration was responsible for the neuropathy. In this area the syndrome of "arsenicosis" is not uncommon2 consisting of neuropathy, skin pigmentation, exfoliation of skin and hepatomegaly; and contaminated water adulterated chewing tobacco, indigenous drugs,3 and adulterated opium are some of’ the sources of arsenic. We have found higher arsenic concentrations in 20% of livers obtained after accidental death, when compared with concentrations in normal liver reported from the West.4 These high-arsenic livers often show portal fibrosis, which has been reported by others.5
for levodopa this figure can be lowered further still by combination with a decarboxylase inhibitor. Amantadine, but not levodopa or bromocriptine, sometimes causes ankle cedema, and may cause a cardiomyopathy.’ However, an association between amantadine and heart-failure is not proven. Amantadine 100-300 mg daily for 2-6 weeks causes livedo reticularis, a mottled blue discoloration of the skin due to prominence of the normal pattern of venous drainage, in approximately 50% of all elderly patients. Livedo is accompanied by redema in 5-10% of cases, but oedema is unlikely to be due to heartfailure, being accompanied by a redistribution of body fluid between different fluid compartments rather than by an increase in total body water or by an electrolyte disturbance.2 Livedo and cedema are normally confined to the legs and may result from the catecholamine-releasing action of amantadine in certain vascular beds. Oedema responds to salt restriction and/or diuretics. We have not seen it get worse or more extensive in any parkinsonian patient treated with amantadine for up to seven years. 4 of 89 parkinsonian patients on amantadine 100-600 mg daily, and 2 of 64 patients not on amantadine but taking levodopa 0 5-8 g daily, have developed angina, dyspnoea, pulmonary congestion, or distension of neck veins during treatment. 1 of these 6 patients had a cardiac arrhythmia, 2 had angina, 3 had myocardial infarction, and 5 had electrocardiographic evidence of ischasmic heart-disease. All these patients were aged over sixty. 2 of the 4 on amantadine had had ankle cedema before heart-failure developed but 2 had not. All 4 patients were also taking levodopa alone or combined with a decarboxylase inhibitor, and 3 were also taking anticholinergic drugs. The signs of cardiac failure responded to diuretics and digoxin, and amantadine and levodopa were continued. Treatment for Parkinson’s disease increases the patient’s mobility and may have been indirectly responsible for the signs of ischaemic heart-disease. However, we have not observed any patient in whom heart-failure seemed to be due directly to depletion of catecholamines in the heart by amantadine and in whom there was no other obvious cause for heart-failure. Theoretically amantadine could deplete myocardial noradrenaline stores, and this possibility may, perhaps, be avoided by the addition of levodopa. On balance, the benefits of antiparkinsonian treatment outweigh the risk of provoking cardiac disorders, and if necessary to restore mobility, levodopa, bromocriptine, or amantadine should not be witheld in parkinsonian patients who also have heart-disease. J. D. PARKES University Department of Neurology, C. D. MARSDEN King’s College Hospital, London SE5. P. PRICE
LEVAMISOLE AND AGRANULOCYTOSIS
SIR,-Agranulocytosis has developed
Institute of Medical Education and Research, Chandigarh 160011, India
D. V. DATTA
patients on levami-
as a fall in granulocyte levels to of the granulocyte/lymphocyte reversal 600/ul ratio. 12 This condition should be distinguished from the leukopenia which is spontaneously reversible even when levamisole is continued. Levamisole-induced agranulocytosis has the characteristics
We
regard agranulocytosis or
Postgraduate
in
sole.3-11 It is potentially fatal if unrecognised and untreated.
less, with
a
AMANTADINE-INDUCED HEART-FAILURE
SiR,—It is difficult
bromocriptine,
or
to
know whether
to
prescribe levodopa,
amantadine for patients with Parkinson’s
disease who also have heart-disease, because all these drugs may be cardiotoxic. However, levodopa and bromocriptine cause cardiac arrhythmias in less than 1% of all patients, and 1. Schroeder, H. A.,
Balassa, J. J. J. chron. Dis. 1966, 19, 85. 2. Datta, D V , Kaul, M. K. J. Ass.Physns India, 1976, 24, 599. 3. Datta, D. V., Singh, I., Kaul, M. K. Postgrad.Inst.Bull. (in the press). 4. Kingslay, G. R., Schaffert, R. R. Analyt. Chem. 1951, 23, 914. 5. Morris, J. S., Schmid, M., Newmen, S., Schene, P. J., Path, M. R. C., Sherlock, S. Gastroenterology, 1974, 66, 86.
1. Vale, J. A., Maclean, K. S. Lancet, 1976, i, 548. 2. Parkes, J. D., Baxter, R. C. H., Curzon, G., Knill-Jones, R. P., Knott, P J., Marsden, C. D., Tattersall, R., Vollum, D. ibid. 1971, i, 1083. 3. Rosenthal, M., Trabert, U., Müller, W.Lancet, 1976, i, 369. 4. Graber, H., Takacs, L., Vedrödy, K. ibid. 1976, u, 1248. 5. Sany, J., Morlock, G., Kalfa, G., Serre, H.Nouv.Presse méd. 1976, 5, 1148. 6. Leca, A. P., Le Porrier, M., Prier, A., Camus, J. P.ibid.p. 1212. 7. Ruuskanen, O., Remes, M., Mäkelä, A. L., Isomäki, H., Toivanen, A Lancet, 1976, ii, 958. 8. Williams, I. A. ibid. 1976, i, 1080. 9. Clara, R., Germanes, J. ibid. 1977, i, 47. 10. Vanholder, R., Van Hove, W. ibid. p. 100. 11. Willoughby, M L. N., Baird, G. M., Campbell, A. M. ibid.p. 657. 12. Pisciotta, A. V. Clin. Pharm. Ther. 1971, 12, 13.
Scholarship Committee of the University (’.K.L.) for financial support. Department of Physiology, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU
B. H. HIRST P. K. LUND J. D. REED
D. J. SANDERS
to be diagnosed rapidly so that chlamydia-negative, ureaplasma-positive cases may be studied in detail.
infections
Division of Communicable Diseases, M.R.C. Clinical Research Centre, Harrow, Middlesex, and Central Middlesex Hospital, London NW10.
D. TAYLOR-ROBINSON G. W. CSONKA M. J. PRENTICE
MEDICAL ONCOLOGY
SiR,-Skilled management of the psychological and social problems of the patient with malignant disease, as urged by Mr Ouslander and Dr Barker (April 9, p. 801), is not the sole preserve of the medical oncologist. Much experience in these aspects of oncology is gained by working in a busy radiotherapy department, which should be part of the training of every aspiring medical oncologist. Each member of the oncological team has his own contribution to make to the care of the cancer patient. The medical oncorogist must offer expert knowledge of the design and improvement of chemotherapeutic regimens and the management of specific medical problems. At the same time, physicians, surgeons, and radiotherapists must all be clinicians first, giving the fullest care and support to the patient throughout his illness.
CHLAMYDIAL AND UREAPLASMA-ASSOCIATED URETHRITIS
StR,-1’he role of ureaplasmas, formerly termed T-strain T
B. S. MANTELL
or
mycoplasmas,
in non-specific urethritis (N.S.u.) has been a bone of contention for many years. It was therefore with interest that we read the paper by Bowie et al.’ in which they reported the results of using either sulphonamides or aminocyclitols to treat N.s.u. Sulphonamides, active against chlamydix but not ureaplasmas, were effective in treating chlamy-
and
dia-positive aminocyclitols, active against ureaplasmas but not chlamydiae, were successful in ureaplasma-positive cases. These results give some support to the idea that ureaplasmas do cause some cases of N.s.u. Further supJ. port comes from our placebo-controlled trial of minocycline. The results indicated that chlamydix had an important part to play and also suggested, albeit less convincingly, that ureacases,
plasmas were implicated. Lately two of us (D.T.-R. and G.W.C.) inoculated ourselves intraurethrally with ureaplasmas, each with a different strain. These had been isolated as the only organisms from two patients whose N.s.u. had responded to tetracycline. Inoculation resulted in infection followed by symptoms and signs compatible with N.S.U. In one subject the disease responded rapidly to tetracycline; in the other, urinary threads of epithelial cells and polymorphonuclear leucocytes persisted for at least six months after the symptoms and other signs had disappeared and after the ureaplasmas had been eliminated from the urogenital tract. The details of these experiments will be published elsewhere.3 sufficient evidence to conclude that of N.s.u. The question which ureaplasmas remains, however, is whether they are a prominent or an insignificant cause. This will only be solved by the further use of differential antibiotics, by an assessment of the extent to which the number of infectinj organisms might be important, and by the development of techniques which will enable chlamydial We feel that there is
now
are one cause
5.
Department of Radiotherapy and Oncology, London Hospital, E 1
SUPPORT FOR RESEARCH IN DERMATOLOGY
SIR,-All dermatologists will agree with Professor Greaves’ (April 9, p. 793) on the need to increase research in der-
views
Our two charities hope that dermatologists will note that we are trying to help research by providing financial aid when we can. But we in turn need the help of dermatologists to inform patients of our existence and to hand out our literature in their departments, so that we can recruit members who will aid us in our fund-raising and whose subscriptions will also support our nationwide activities.
matology.
SAM CHAPLAIN, National chairman
National Eczema
Society Psoriasis Association, 7 Milton Street, Northampton NN2 7JG
RICHARD B. COLES, National vice-chairman
ARSENIC IN OPIUM
SiR,—Dr Datta (Feb. 26, p. 484) reports arsenic-induced neuropathy resulting from the consumption of 10-20 g opium per day with an arsenic content of less than 7$[ig/100 g. This concentration is below the acceptable upper limits for all foods (normally set at 1 part per million or 100 g/100 g) and is little more than a tenth of the acceptable limit for fish (5 p.p.m.). The total daily intake of arsenic from such a dose of opium is minute and could not possibly be responsible for neurological change. If Dr Datta’s patient had neurological changes due to arsenic then I think he must look elsewhere for the arsenic source.
Charles Camsell Hospital, Edmonton, Alberta T5M 3A4, Canada
R. D. P. EATON
Flückinger,
E. Paper read at symposium on Pharmacological and Clinical Aspects of Bromocriptine (’Parlodol’), held in London on May 14, 1976. (In the press.) 6 Sachdev, Y., Gomez-Pan, A., Tunbridge, W. M. G., Duns, A., Weightman, D. R., Hall, R., Goolamali, S. K. Lancet, 1975, ii, 1164. 1 Bowie, W. R., Alexander, E. R., Floyd, J. F., Holmes, J., Miller, Y., Holmes, K K. Lancet, 1976, ii, 1276. 2 Prentice, M. J., Taylor-Robinson, D., Csonka, G. W. Br. J.ven. Dis. 1976, 52, 269. 3 Taylor-Robinson, D., Csonka, G. W., Prentice, M. J. Q. Jl Med. (in the press).
*
**This letter has been shown lows.-ED. L.
SIR,-Ithank
to
Dr
Datta, whose reply fol-
Dr Eaton for his critical comment. Besides
methodological difficulties, there are many gaps in our knowledge of arsenic metabolism. However, our results compare well with those obtained by spectrophotometry. The toxicity of
904 arsenic depends on whether it is taken in organic or inorganic form (pentavalent or trivalent).’ I have extended the work to which Dr Eaton refers and confirmed that opium is adulterated by some unknown arsenic compound to increase its aphrodisiac activity and that the arsenic concentration can be very high. It is mostly in salt form and can be extracted without boiling with hydrochloric acid, in contrast to the arsenic present in food (see figure). Arsenic compounds prepared in
TOTAL
Total arsenic content in arsenic.
INORGANIC FREE
opium compared
with
inorganic,
free
our area are based on the trivalent oxide form known as Bhasma. Since no history of arsenic intake from any other source was available and in view of the nature of the arsenic with which the opium was adulterated, I am convinced that the adulteration was responsible for the neuropathy. In this area the syndrome of "arsenicosis" is not uncommon2 consisting of neuropathy, skin pigmentation, exfoliation of skin and hepatomegaly; and contaminated water adulterated chewing tobacco, indigenous drugs,3 and adulterated opium are some of’ the sources of arsenic. We have found higher arsenic concentrations in 20% of livers obtained after accidental death, when compared with concentrations in normal liver reported from the West.4 These high-arsenic livers often show portal fibrosis, which has been reported by others.5
for levodopa this figure can be lowered further still by combination with a decarboxylase inhibitor. Amantadine, but not levodopa or bromocriptine, sometimes causes ankle cedema, and may cause a cardiomyopathy.’ However, an association between amantadine and heart-failure is not proven. Amantadine 100-300 mg daily for 2-6 weeks causes livedo reticularis, a mottled blue discoloration of the skin due to prominence of the normal pattern of venous drainage, in approximately 50% of all elderly patients. Livedo is accompanied by redema in 5-10% of cases, but oedema is unlikely to be due to heartfailure, being accompanied by a redistribution of body fluid between different fluid compartments rather than by an increase in total body water or by an electrolyte disturbance.2 Livedo and cedema are normally confined to the legs and may result from the catecholamine-releasing action of amantadine in certain vascular beds. Oedema responds to salt restriction and/or diuretics. We have not seen it get worse or more extensive in any parkinsonian patient treated with amantadine for up to seven years. 4 of 89 parkinsonian patients on amantadine 100-600 mg daily, and 2 of 64 patients not on amantadine but taking levodopa 0 5-8 g daily, have developed angina, dyspnoea, pulmonary congestion, or distension of neck veins during treatment. 1 of these 6 patients had a cardiac arrhythmia, 2 had angina, 3 had myocardial infarction, and 5 had electrocardiographic evidence of ischasmic heart-disease. All these patients were aged over sixty. 2 of the 4 on amantadine had had ankle cedema before heart-failure developed but 2 had not. All 4 patients were also taking levodopa alone or combined with a decarboxylase inhibitor, and 3 were also taking anticholinergic drugs. The signs of cardiac failure responded to diuretics and digoxin, and amantadine and levodopa were continued. Treatment for Parkinson’s disease increases the patient’s mobility and may have been indirectly responsible for the signs of ischaemic heart-disease. However, we have not observed any patient in whom heart-failure seemed to be due directly to depletion of catecholamines in the heart by amantadine and in whom there was no other obvious cause for heart-failure. Theoretically amantadine could deplete myocardial noradrenaline stores, and this possibility may, perhaps, be avoided by the addition of levodopa. On balance, the benefits of antiparkinsonian treatment outweigh the risk of provoking cardiac disorders, and if necessary to restore mobility, levodopa, bromocriptine, or amantadine should not be witheld in parkinsonian patients who also have heart-disease. J. D. PARKES University Department of Neurology, C. D. MARSDEN King’s College Hospital, London SE5. P. PRICE
LEVAMISOLE AND AGRANULOCYTOSIS
SIR,-Agranulocytosis has developed
Institute of Medical Education and Research, Chandigarh 160011, India
D. V. DATTA
patients on levami-
as a fall in granulocyte levels to of the granulocyte/lymphocyte reversal 600/ul ratio. 12 This condition should be distinguished from the leukopenia which is spontaneously reversible even when levamisole is continued. Levamisole-induced agranulocytosis has the characteristics
We
regard agranulocytosis or
Postgraduate
in
sole.3-11 It is potentially fatal if unrecognised and untreated.
less, with
a
AMANTADINE-INDUCED HEART-FAILURE
SiR,—It is difficult
bromocriptine,
or
to
know whether
to
prescribe levodopa,
amantadine for patients with Parkinson’s
disease who also have heart-disease, because all these drugs may be cardiotoxic. However, levodopa and bromocriptine cause cardiac arrhythmias in less than 1% of all patients, and 1. Schroeder, H. A.,
Balassa, J. J. J. chron. Dis. 1966, 19, 85. 2. Datta, D V , Kaul, M. K. J. Ass.Physns India, 1976, 24, 599. 3. Datta, D. V., Singh, I., Kaul, M. K. Postgrad.Inst.Bull. (in the press). 4. Kingslay, G. R., Schaffert, R. R. Analyt. Chem. 1951, 23, 914. 5. Morris, J. S., Schmid, M., Newmen, S., Schene, P. J., Path, M. R. C., Sherlock, S. Gastroenterology, 1974, 66, 86.
1. Vale, J. A., Maclean, K. S. Lancet, 1976, i, 548. 2. Parkes, J. D., Baxter, R. C. H., Curzon, G., Knill-Jones, R. P., Knott, P J., Marsden, C. D., Tattersall, R., Vollum, D. ibid. 1971, i, 1083. 3. Rosenthal, M., Trabert, U., Müller, W.Lancet, 1976, i, 369. 4. Graber, H., Takacs, L., Vedrödy, K. ibid. 1976, u, 1248. 5. Sany, J., Morlock, G., Kalfa, G., Serre, H.Nouv.Presse méd. 1976, 5, 1148. 6. Leca, A. P., Le Porrier, M., Prier, A., Camus, J. P.ibid.p. 1212. 7. Ruuskanen, O., Remes, M., Mäkelä, A. L., Isomäki, H., Toivanen, A Lancet, 1976, ii, 958. 8. Williams, I. A. ibid. 1976, i, 1080. 9. Clara, R., Germanes, J. ibid. 1977, i, 47. 10. Vanholder, R., Van Hove, W. ibid. p. 100. 11. Willoughby, M L. N., Baird, G. M., Campbell, A. M. ibid.p. 657. 12. Pisciotta, A. V. Clin. Pharm. Ther. 1971, 12, 13.
