923
characteristics of patients with primary depression; their symptoms more
closely resemble those
seen
with
primary medical disorders.5 Kendell laments the "fact" that patients with CFS refuse
antidepressant therapy. Our review of 565 patients with CFS diagnosed in our tertiary referral service revealed that 38% had received antidepressant therapy while 34% had taken some other form of psychotropic medication concurrently or alternatively. He suggests that depressive disorders "have the great merit of being eminently treatable", unlike the viral infection thought to underlie postviral fatigue syndrome. While many treated patients with depression do improve in the short-term, studies of the outcome decades show that four-fifths of patients admitted to hospital with depression can be expected to have recurrent depressive disorder.6 By contrast, the median duration of symptoms from onset to sampling in our prevalence study1 was 30 months, suggesting self-limiting natural history in many cases. Only 3 of 42 cases (7%) in this sample had symptoms for more than 20 years. Kendell makes no reference to immunological studies in CFS. He states that "depression itself may predispose to subsequent infection by an effect on immune mechanisms", a highly contentious hypothesis since immune disturbances seem to be limited to patients with severe depressive disorders who are older and often admitted for treatment.7,8Disturbances of cell-mediated immunity have been found in CFS,9,10 and these changes are not likely to be attributable to concurrent depression. Immunological therapy alone has been shown to resolve associated depressive symptoms in patients whose chronic fatigue responded to treatment.’1 We agree that patients labelled as having CFS are likely to be heterogeneous in character and that research demands more homogeneous groups, but we do not support the Centers for Disease Control definition that, by excluding patients with current or past psychological disorder, institutionalises the exact dualistic thinking of which Kendell is so critical. Manu et al12 found that 67% of patients referred with chronic fatigue did not meet CDC criteria because of concurrent psychiatric diagnoses. Further work is clearly required to categorise patients who present with both chronic fatigue and the strong conviction that they are physically ill.4 Premature and largely unwarranted assertions that patients with CFS resemble those with primary depression and will therefore respond to conventional antidepressant treatments may hinder progress towards an understanding of the pathophysiology of CFS and the development of effective therapy.
over
Mood Disorders Unit, Division of Psychiatry, Prince Henry Hospital, Little Bay, NSW 2036, Australia
Departments of Infectious Diseases and Immunology, Division of Medicine, Prince Henry Hospital
Mitochondrial inclusions and Creutzfeldt-Jakob disease
depression complicating
IAN HICKIE
ANDREW LLOYD DENIS WAKEFIELD
AR, Hickie I, Boughton CR, Spencer O, Wakefield D. The prevalence of chronic fatigue syndrome in an Australian population. Med J Aust 1990; 153: 522-28. 2 Wessely S, Powell R. Fatigue syndromes: a comparison of chronic "postviral" fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry 1989; 52: 940-48. 3. Taerk GS, Toner BB, Salit IE, et al. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med 1987; 17: 49-56. 4 Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with chronic fatigue syndrome. Br J Psychiatry 1990; 156: 534-40. 5 Rodin G, Voshart K. Depression in the medically ill: an overview. Am J Psychiatry 1986; 143: 696-705. 6 Kiloh LG, Andrews G, Nielsen M. The long term outcome of depressive illness. Br J 1. Lloyd
SIR,-Dr Lewin and Mr Edwards (Jan 26, p 236) report the presence of an electronmicroscopic mitochondrial inclusion body in a biopsy sample from a patient with Creutzfeldt-Jakob-like dementia. They suggest that the inclusion body is the agent
responsible for the disease. Various inclusion bodies have been suggested as the agent for Creutzfeldt-Jakob disease and other scrapie-like diseases. A candidate that has been researched for many years is the synaptic inclusion body.1 A drawback to the identification of inclusion bodies in mitochondria is that these organelles are notoriously sensitive to postmortem change, especially in brain material. Even in animals whose brains have been perfused mitochondria can be abnormal. Typically they become enlarged, rounded in cross section, and their cristae are disorganised. The cristae may be largely absent and form paracrystalline structures identical to those Lewin and Edwards describe. Control material is essential. In all material from patients with degenerative diseases, whether biopsied or not, there is some degree of lysis of organelles before tissue sampling. Since an agent responsible for scrapie-like disease has never been isolated its electronmicroscopic identification poses great difficulties. Many structures thought to have pathological significance for Creutzfeldt- Jakob2 and other diseases have later proved to be artifacts or non-specific .3’4 Any suggestion that a structure of importance might be artifact has to be taken seriously. 46
Craighouse Avenue, Edinburgh EH10 5LN, UK
PETER H. GIBSON
PH, Doughty LA. An electron microscopic study of inclusion bodies in the synaptic boutons of scrapie affected animals. Acta Neuropathol 1989; 77: 420-25. 2. Liberski PP, Gibson PH. Cerebellar lamellar body in two strains of murine scrapie. J Comp Pathol 1989; 97: 491-93. 3. Gibson PH. Scrapie-associated fibrils and AIDS encephalopathy. Lancet 1985; ii: 1. Gibson
612-13. 4. Gibson PH, Tomlinson BE. Numbers of Hirano bodies in the hippocampus of normal and demented people with Alzheimer’s disease. J Neurol Sci 1977; 27: 199-206.
**Thisletter has been shown - ED.L.
to
Dr
Lewin, whose reply follows.
SIR,-We agree that artifactual changes can be seen in mitochondria, even in rapidly fixed biopsy material, and that these changes have sometimes been implicated as the underlying causal factors in some disease processes. However, artifactual changes in mitochondria are often accompanied by many other intracellular changes1 that were not noted in our case. Nuclear membranes were intact, and neighbouring mitochondria with their cristae looked normal. The mitochondrial crystalloid arrays that we observed were well organised and exhibited a repetitive pattern. Further, the mitochondria containing crystalloid inclusions had intact membranes and cristae, and did not show swelling, variation in matrix density, or disruption of membranes. We feel that the inclusions noted are not artifacts and are related to the underlying spongiform encephalopathy. However, definitive characterisation will only be possible after further histochemical, biochemical, and immunological analyses. Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
PETER LEWIN VERN EDWARDS
BF, Ericsson JLE. The effect of the fixative solution on the ultrastructure of cells and tissue. Lab Invest 1965; 14: 1245-323.
1. Trump
Psychiatry 1988; 153: 752-57. 7. Hickie
I, Hickie C, Silove D, Wakefield D, Lloyd A. Is there significant immune dysfunction in depressive disorders? Psychol Med 1990; 20: 755-61 8. Schleifer SJ, Keller SE, Bond R, Cohen J, Stein M. Major depressive disorder and immunity. Arch Gen Psychiatry 1989; 46: 81-87 9 Lloyd A, Wakefield D, Boughton C, Dwyer J. Immunological abnormalities in the chronic fatigue syndrome. Med J Aust 1989; 151: 122-24. 10. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990; 28: 1403-10. 11 Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J. High dose intravenous immunoglobulin therapy in the chronic fatigue syndrome: a double-blind, placebo-controlled trial. Am J Med 190; 89: 561-68. 12 Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988; 109: 554-56.
Mutations in
amyloid precursor protein gene and disease SIR,-Dr Nieto et al (March 9, p 622) note similarities in the molecular genetics of familial amyloidotic polyneuropathy and familial prion disease. In both these conditions one of several mutations in the relevant precursor protein leads to the deposition of &bgr;-pleated sheets of amyloid fibrils. Dutch-type amyloid angiopathy has a similar molecular pathology except that only one mutation in the amyloid precursor protein has been described.’ In
924
these three disorders the deposition of amyloid is presumably central to the disease process. New findings have suggested that a point mutation in the amyloid precursor protein gene is associated Z with familial Alzheimer’s disease in two unrelated families If this mutation in the familial Alzheimer’s pedigrees proves causative then all four diseases show striking similarities in their molecular aetiology. Alzheimer’s Disease Research Group,
Departments of Biochemistry and Neurology, St Mary’s Hospital Medical School, London W2 1 PG, UK 1.
JEREMY BROWN
Levy E, Carman M, Fernandez-Madrid I, et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral haemorrhage, Dutch type Science 1990; 248:
1124-26. 2. Goate A, Chartier-Harlin M, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991; 349: 704-06.
Rarity of systemic lupus erythematosus after oral iron chelator L1 SIR,-Dr Mehta and colleagues report (Feb 2, p 298) fatal systemic lupus erythematosus in a patient taking oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (Ll). We are presently continuing a prospective evaluation of the safety and efficacy of the oral iron chelator Ll in iron-loaded patients who are not achieving net negative iron balance with nightly subcutaneous desferrioxamine.1 It is noteworthy that arthropathy, associated with both positive and negative tests for antinuclear antibodies (ANA), has been reported in a total of 15 of 36 patients receiving Ll in the Bombay studyZ but, in striking contrast, none of the 12 patients receiving a similar regimen of Ll therapy in Toronto for up to one year have had similar complaints. A more important observation may be that laboratory testing in all our patients, before initiation of L1 therapy, has revealed several abnormalities. Of the 12 patients, all of whom had erratically received desferrioxamine as the only chelating agent, 5 had high titres for ANA-2 of these had a positive test for rheumatoid factor (RF)—and 3 were positive for RF and negative for ANA. Neither antidouble stranded DNA antibodies nor antibodies to nuclear histones were detected in any of the 12 patients. No patient had a history or symptoms of arthralgias or arthritis, or any other clinical manifestations of drug-related lupus.3 Taken together these results provide no clinical or serological evidence for drug-induced lupus erythematosus in our patients treated with L 1. Although our findings do not rule out the possibility of Ll-induced lupus, they do confirm that antibodies to nuclear antigens, as well as RF, are not an infrequent finding in patients with thalassaemia major, in both those who are unchelated or those treated with desferrioxamine only, and cannot be attributed to L 1. Divisions of Haematology/Oncology, Clinical Pharmacology, and Immunology, Hospital for Sick Children, Toronto, Canada M5G IX8
NANCY F. OLIVIERI GIDEON KOREN MELVIN H. FREEDMAN CHAIM ROIFMAN
1. Olivieri NF, Koren G, Hermann C, et al Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. Lancet 1990; 336: 1275-79. 2. Agarwal MB. Second international meeting on oral iron chelation, Bombay, India, November, 1990. 3. Solinger AM Drug-related lupus: clinical and etiologic considerations Rheum Dis Clin N Am 1988; 14: 187-202.
Calcium
antagonists and hypercalcaemia
SIR,-Dr Samani (Feb 9, p 372) reports on the worsening of hypercalcaemia in a patient with primary hyperparathyroidism who was given nifedipine. He claimed that the underlying mechanism is unclear. We have seen, in three patients with breast cancer taking calcium antagonists (two diltiazem, one nifedipine), hypercalcaemia that improved when the drug was stopped. Serum calcium fell from 3-1to 2-7, from 3-4 to 28, and from 32 to 2-5 mmol/1. These results indicate at least a contributory role of calcium antagonists.
Two of five patients with malignant disease without bone metastasis (scintigraphy) who were given calcium antagonists showed an apparent increase in serum calcium within 3 weeks when the drug was started (2-4 to 2-7 mmol/1 [verapamil]; 24 to 29
mmol/1 [nifedipine]). Calcium antagonists stimulate prostacyclin generation1 which, like prostaglandin E2,may increase circulatory calcium’ by mobilising it in a parathyroid-hormone-like effect from the bonesS.4 Hypercalcaemia as a paraneoplastic syndrome in malignant disease, especially breast cancer, can be successfully treated by aspirin or indomethacin5,6-ie, by blocking prostaglandin synthesis via cyclooxygenase inhibition. This evidence, together with Samani’s fmdings, indicates that although rare and usually mild in form, hypercalcaemia may be induced or promoted by agents that stimulate prostaglandin
synthesis. Wilhelm Auerswald Atherosclerosis Research Group (ASF), A-1090 Vienna, Austria
H. SINZINGER
Department of Cardiology, University of Vienna
F. RAUSCHA
2nd Department of Internal Medicine, Policlinic, Vienna
P. FITSCHA
Department of Pharmacology, University of Bochum, Bochum, Germany
B. A. PESKAR
1. Weiss
K, Fitscha P, O’Grady, Sinzinger H. Israpidine: a potent calcium blocker with beneficial effects on platelet function and vascular prostacyclin production. Thromb Res 1989; 54: 311-17. 2. Raisz LG, Dietrich JW, Simmons HA, Seyberth HW, Hubbard W, Oates JA Effect of prostaglandin endoperoxides and metabolites on bone resorption in vitro Nature 1977; 267: 532-34. 3. Robin JC, Brown MJ, Weinfeld M, Dziek R. Prostacyclin. effect on cAMP in bone cells Res Commun Chem Pathol Pharmacol 1982, 35: 43-46. 4. Seyberth HW, Segre GV, Morgan JL, Sweetman BJ, Potts JT, Oates JA. Prostaglandins as mediators of hypercalcemia associated with certain types of
5
6.
cancer. N Engl J Med 1975; 293: 1278-83 Seyberth HW. Prostaglandin-mediated hypercalcemia
a
Klin Wschr 1978; 56: 373-87 Tashijan AH, Voelkel EF, Goldhaber P, Levine L. metabolism and cancer Fed Proc 1974; 33: 81.
paraneoplastic syndrome. Prostaglandins,
calcium
Agents for diarrhoea in children SIR,- The World Health Organisation’s booklet on drugs in the management of acute diarrhoea in children’ (summarised in your issue of Jan 19, p 169) would, it seems, have recommended a drug, in addition to oral rehydration solution, if it proved safe and effective. WHO is also concerned about the cost of drugs for people attending primary health care centres. Safety, efficacy, and cost are major concerns of all responsible doctors. Nevertheless, WHO concludes that a drug that is safe and reduces the duration of diarrhoea, but not the volume of diarrhoeal stools, should not be recommended. We question this conclusion. The drug in question is smectite, tested in a double-blind study by Madkour et a1,2from EI-Shatby Hospital, Alexandria, Egypt, a centre designated by WHO for clinical trials in acute diarrhoea. "... the duration of diarrhoea was significantly reduced in children given Smectite (53 hrs compared with 73 hrs in the placebo; p < 0’00 1)", though smectite had little effect on stool output during the early phase of treatment. Why should a drug with such an effect not be recommended, provided it is safe? The answer may be either that 20 h extra duration of diarrhoea is negligible in the life of a child attending a primary health care centre, or that the cost of the drug for poor people is not worth the effect. Neither answer, however, takes into account the value of time, and both may prove expensive and possibly unethical, for the following reasons. The time for which a child has diarrhoea is not negligible in the light of the WHO estimate of 1000 million episodes of diarrhoea in children less than 5 years of age.’ The time of the mother who cares for her sick child is usually forgotten.3 We did a pilot study in 14 Algerian families last summer, to evaluate, by the budget-time method,4 how long the mothers spent treating their children with oral rehydration solution to relieve acute diarrhoea.
characteristics of patients with primary depression; their symptoms more
closely resemble those
seen
with
primary medical disorders.5 Kendell laments the "fact" that patients with CFS refuse
antidepressant therapy. Our review of 565 patients with CFS diagnosed in our tertiary referral service revealed that 38% had received antidepressant therapy while 34% had taken some other form of psychotropic medication concurrently or alternatively. He suggests that depressive disorders "have the great merit of being eminently treatable", unlike the viral infection thought to underlie postviral fatigue syndrome. While many treated patients with depression do improve in the short-term, studies of the outcome decades show that four-fifths of patients admitted to hospital with depression can be expected to have recurrent depressive disorder.6 By contrast, the median duration of symptoms from onset to sampling in our prevalence study1 was 30 months, suggesting self-limiting natural history in many cases. Only 3 of 42 cases (7%) in this sample had symptoms for more than 20 years. Kendell makes no reference to immunological studies in CFS. He states that "depression itself may predispose to subsequent infection by an effect on immune mechanisms", a highly contentious hypothesis since immune disturbances seem to be limited to patients with severe depressive disorders who are older and often admitted for treatment.7,8Disturbances of cell-mediated immunity have been found in CFS,9,10 and these changes are not likely to be attributable to concurrent depression. Immunological therapy alone has been shown to resolve associated depressive symptoms in patients whose chronic fatigue responded to treatment.’1 We agree that patients labelled as having CFS are likely to be heterogeneous in character and that research demands more homogeneous groups, but we do not support the Centers for Disease Control definition that, by excluding patients with current or past psychological disorder, institutionalises the exact dualistic thinking of which Kendell is so critical. Manu et al12 found that 67% of patients referred with chronic fatigue did not meet CDC criteria because of concurrent psychiatric diagnoses. Further work is clearly required to categorise patients who present with both chronic fatigue and the strong conviction that they are physically ill.4 Premature and largely unwarranted assertions that patients with CFS resemble those with primary depression and will therefore respond to conventional antidepressant treatments may hinder progress towards an understanding of the pathophysiology of CFS and the development of effective therapy.
over
Mood Disorders Unit, Division of Psychiatry, Prince Henry Hospital, Little Bay, NSW 2036, Australia
Departments of Infectious Diseases and Immunology, Division of Medicine, Prince Henry Hospital
Mitochondrial inclusions and Creutzfeldt-Jakob disease
depression complicating
IAN HICKIE
ANDREW LLOYD DENIS WAKEFIELD
AR, Hickie I, Boughton CR, Spencer O, Wakefield D. The prevalence of chronic fatigue syndrome in an Australian population. Med J Aust 1990; 153: 522-28. 2 Wessely S, Powell R. Fatigue syndromes: a comparison of chronic "postviral" fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry 1989; 52: 940-48. 3. Taerk GS, Toner BB, Salit IE, et al. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med 1987; 17: 49-56. 4 Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with chronic fatigue syndrome. Br J Psychiatry 1990; 156: 534-40. 5 Rodin G, Voshart K. Depression in the medically ill: an overview. Am J Psychiatry 1986; 143: 696-705. 6 Kiloh LG, Andrews G, Nielsen M. The long term outcome of depressive illness. Br J 1. Lloyd
SIR,-Dr Lewin and Mr Edwards (Jan 26, p 236) report the presence of an electronmicroscopic mitochondrial inclusion body in a biopsy sample from a patient with Creutzfeldt-Jakob-like dementia. They suggest that the inclusion body is the agent
responsible for the disease. Various inclusion bodies have been suggested as the agent for Creutzfeldt-Jakob disease and other scrapie-like diseases. A candidate that has been researched for many years is the synaptic inclusion body.1 A drawback to the identification of inclusion bodies in mitochondria is that these organelles are notoriously sensitive to postmortem change, especially in brain material. Even in animals whose brains have been perfused mitochondria can be abnormal. Typically they become enlarged, rounded in cross section, and their cristae are disorganised. The cristae may be largely absent and form paracrystalline structures identical to those Lewin and Edwards describe. Control material is essential. In all material from patients with degenerative diseases, whether biopsied or not, there is some degree of lysis of organelles before tissue sampling. Since an agent responsible for scrapie-like disease has never been isolated its electronmicroscopic identification poses great difficulties. Many structures thought to have pathological significance for Creutzfeldt- Jakob2 and other diseases have later proved to be artifacts or non-specific .3’4 Any suggestion that a structure of importance might be artifact has to be taken seriously. 46
Craighouse Avenue, Edinburgh EH10 5LN, UK
PETER H. GIBSON
PH, Doughty LA. An electron microscopic study of inclusion bodies in the synaptic boutons of scrapie affected animals. Acta Neuropathol 1989; 77: 420-25. 2. Liberski PP, Gibson PH. Cerebellar lamellar body in two strains of murine scrapie. J Comp Pathol 1989; 97: 491-93. 3. Gibson PH. Scrapie-associated fibrils and AIDS encephalopathy. Lancet 1985; ii: 1. Gibson
612-13. 4. Gibson PH, Tomlinson BE. Numbers of Hirano bodies in the hippocampus of normal and demented people with Alzheimer’s disease. J Neurol Sci 1977; 27: 199-206.
**Thisletter has been shown - ED.L.
to
Dr
Lewin, whose reply follows.
SIR,-We agree that artifactual changes can be seen in mitochondria, even in rapidly fixed biopsy material, and that these changes have sometimes been implicated as the underlying causal factors in some disease processes. However, artifactual changes in mitochondria are often accompanied by many other intracellular changes1 that were not noted in our case. Nuclear membranes were intact, and neighbouring mitochondria with their cristae looked normal. The mitochondrial crystalloid arrays that we observed were well organised and exhibited a repetitive pattern. Further, the mitochondria containing crystalloid inclusions had intact membranes and cristae, and did not show swelling, variation in matrix density, or disruption of membranes. We feel that the inclusions noted are not artifacts and are related to the underlying spongiform encephalopathy. However, definitive characterisation will only be possible after further histochemical, biochemical, and immunological analyses. Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
PETER LEWIN VERN EDWARDS
BF, Ericsson JLE. The effect of the fixative solution on the ultrastructure of cells and tissue. Lab Invest 1965; 14: 1245-323.
1. Trump
Psychiatry 1988; 153: 752-57. 7. Hickie
I, Hickie C, Silove D, Wakefield D, Lloyd A. Is there significant immune dysfunction in depressive disorders? Psychol Med 1990; 20: 755-61 8. Schleifer SJ, Keller SE, Bond R, Cohen J, Stein M. Major depressive disorder and immunity. Arch Gen Psychiatry 1989; 46: 81-87 9 Lloyd A, Wakefield D, Boughton C, Dwyer J. Immunological abnormalities in the chronic fatigue syndrome. Med J Aust 1989; 151: 122-24. 10. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990; 28: 1403-10. 11 Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J. High dose intravenous immunoglobulin therapy in the chronic fatigue syndrome: a double-blind, placebo-controlled trial. Am J Med 190; 89: 561-68. 12 Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988; 109: 554-56.
Mutations in
amyloid precursor protein gene and disease SIR,-Dr Nieto et al (March 9, p 622) note similarities in the molecular genetics of familial amyloidotic polyneuropathy and familial prion disease. In both these conditions one of several mutations in the relevant precursor protein leads to the deposition of &bgr;-pleated sheets of amyloid fibrils. Dutch-type amyloid angiopathy has a similar molecular pathology except that only one mutation in the amyloid precursor protein has been described.’ In
924
these three disorders the deposition of amyloid is presumably central to the disease process. New findings have suggested that a point mutation in the amyloid precursor protein gene is associated Z with familial Alzheimer’s disease in two unrelated families If this mutation in the familial Alzheimer’s pedigrees proves causative then all four diseases show striking similarities in their molecular aetiology. Alzheimer’s Disease Research Group,
Departments of Biochemistry and Neurology, St Mary’s Hospital Medical School, London W2 1 PG, UK 1.
JEREMY BROWN
Levy E, Carman M, Fernandez-Madrid I, et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral haemorrhage, Dutch type Science 1990; 248:
1124-26. 2. Goate A, Chartier-Harlin M, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991; 349: 704-06.
Rarity of systemic lupus erythematosus after oral iron chelator L1 SIR,-Dr Mehta and colleagues report (Feb 2, p 298) fatal systemic lupus erythematosus in a patient taking oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (Ll). We are presently continuing a prospective evaluation of the safety and efficacy of the oral iron chelator Ll in iron-loaded patients who are not achieving net negative iron balance with nightly subcutaneous desferrioxamine.1 It is noteworthy that arthropathy, associated with both positive and negative tests for antinuclear antibodies (ANA), has been reported in a total of 15 of 36 patients receiving Ll in the Bombay studyZ but, in striking contrast, none of the 12 patients receiving a similar regimen of Ll therapy in Toronto for up to one year have had similar complaints. A more important observation may be that laboratory testing in all our patients, before initiation of L1 therapy, has revealed several abnormalities. Of the 12 patients, all of whom had erratically received desferrioxamine as the only chelating agent, 5 had high titres for ANA-2 of these had a positive test for rheumatoid factor (RF)—and 3 were positive for RF and negative for ANA. Neither antidouble stranded DNA antibodies nor antibodies to nuclear histones were detected in any of the 12 patients. No patient had a history or symptoms of arthralgias or arthritis, or any other clinical manifestations of drug-related lupus.3 Taken together these results provide no clinical or serological evidence for drug-induced lupus erythematosus in our patients treated with L 1. Although our findings do not rule out the possibility of Ll-induced lupus, they do confirm that antibodies to nuclear antigens, as well as RF, are not an infrequent finding in patients with thalassaemia major, in both those who are unchelated or those treated with desferrioxamine only, and cannot be attributed to L 1. Divisions of Haematology/Oncology, Clinical Pharmacology, and Immunology, Hospital for Sick Children, Toronto, Canada M5G IX8
NANCY F. OLIVIERI GIDEON KOREN MELVIN H. FREEDMAN CHAIM ROIFMAN
1. Olivieri NF, Koren G, Hermann C, et al Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. Lancet 1990; 336: 1275-79. 2. Agarwal MB. Second international meeting on oral iron chelation, Bombay, India, November, 1990. 3. Solinger AM Drug-related lupus: clinical and etiologic considerations Rheum Dis Clin N Am 1988; 14: 187-202.
Calcium
antagonists and hypercalcaemia
SIR,-Dr Samani (Feb 9, p 372) reports on the worsening of hypercalcaemia in a patient with primary hyperparathyroidism who was given nifedipine. He claimed that the underlying mechanism is unclear. We have seen, in three patients with breast cancer taking calcium antagonists (two diltiazem, one nifedipine), hypercalcaemia that improved when the drug was stopped. Serum calcium fell from 3-1to 2-7, from 3-4 to 28, and from 32 to 2-5 mmol/1. These results indicate at least a contributory role of calcium antagonists.
Two of five patients with malignant disease without bone metastasis (scintigraphy) who were given calcium antagonists showed an apparent increase in serum calcium within 3 weeks when the drug was started (2-4 to 2-7 mmol/1 [verapamil]; 24 to 29
mmol/1 [nifedipine]). Calcium antagonists stimulate prostacyclin generation1 which, like prostaglandin E2,may increase circulatory calcium’ by mobilising it in a parathyroid-hormone-like effect from the bonesS.4 Hypercalcaemia as a paraneoplastic syndrome in malignant disease, especially breast cancer, can be successfully treated by aspirin or indomethacin5,6-ie, by blocking prostaglandin synthesis via cyclooxygenase inhibition. This evidence, together with Samani’s fmdings, indicates that although rare and usually mild in form, hypercalcaemia may be induced or promoted by agents that stimulate prostaglandin
synthesis. Wilhelm Auerswald Atherosclerosis Research Group (ASF), A-1090 Vienna, Austria
H. SINZINGER
Department of Cardiology, University of Vienna
F. RAUSCHA
2nd Department of Internal Medicine, Policlinic, Vienna
P. FITSCHA
Department of Pharmacology, University of Bochum, Bochum, Germany
B. A. PESKAR
1. Weiss
K, Fitscha P, O’Grady, Sinzinger H. Israpidine: a potent calcium blocker with beneficial effects on platelet function and vascular prostacyclin production. Thromb Res 1989; 54: 311-17. 2. Raisz LG, Dietrich JW, Simmons HA, Seyberth HW, Hubbard W, Oates JA Effect of prostaglandin endoperoxides and metabolites on bone resorption in vitro Nature 1977; 267: 532-34. 3. Robin JC, Brown MJ, Weinfeld M, Dziek R. Prostacyclin. effect on cAMP in bone cells Res Commun Chem Pathol Pharmacol 1982, 35: 43-46. 4. Seyberth HW, Segre GV, Morgan JL, Sweetman BJ, Potts JT, Oates JA. Prostaglandins as mediators of hypercalcemia associated with certain types of
5
6.
cancer. N Engl J Med 1975; 293: 1278-83 Seyberth HW. Prostaglandin-mediated hypercalcemia
a
Klin Wschr 1978; 56: 373-87 Tashijan AH, Voelkel EF, Goldhaber P, Levine L. metabolism and cancer Fed Proc 1974; 33: 81.
paraneoplastic syndrome. Prostaglandins,
calcium
Agents for diarrhoea in children SIR,- The World Health Organisation’s booklet on drugs in the management of acute diarrhoea in children’ (summarised in your issue of Jan 19, p 169) would, it seems, have recommended a drug, in addition to oral rehydration solution, if it proved safe and effective. WHO is also concerned about the cost of drugs for people attending primary health care centres. Safety, efficacy, and cost are major concerns of all responsible doctors. Nevertheless, WHO concludes that a drug that is safe and reduces the duration of diarrhoea, but not the volume of diarrhoeal stools, should not be recommended. We question this conclusion. The drug in question is smectite, tested in a double-blind study by Madkour et a1,2from EI-Shatby Hospital, Alexandria, Egypt, a centre designated by WHO for clinical trials in acute diarrhoea. "... the duration of diarrhoea was significantly reduced in children given Smectite (53 hrs compared with 73 hrs in the placebo; p < 0’00 1)", though smectite had little effect on stool output during the early phase of treatment. Why should a drug with such an effect not be recommended, provided it is safe? The answer may be either that 20 h extra duration of diarrhoea is negligible in the life of a child attending a primary health care centre, or that the cost of the drug for poor people is not worth the effect. Neither answer, however, takes into account the value of time, and both may prove expensive and possibly unethical, for the following reasons. The time for which a child has diarrhoea is not negligible in the light of the WHO estimate of 1000 million episodes of diarrhoea in children less than 5 years of age.’ The time of the mother who cares for her sick child is usually forgotten.3 We did a pilot study in 14 Algerian families last summer, to evaluate, by the budget-time method,4 how long the mothers spent treating their children with oral rehydration solution to relieve acute diarrhoea.
