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.
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.
