184
2,8-dihydroxyadenine crystalluria
vs
urolithiasis SIR,-Dr Ceballos-Picot and colleagues’ statement (April 25, 1050) that 2,8-dihydroxyadenine urolithiasis is an underdiagnosed disease has received worthy attention (May 23, p 1295). Since Iceland has contributed 8 of the 62 adenine phosphoribosyltransferase (APRT) deficient type-I homozygotes diagnosed so far, I would like to record the fact that the diagnosis frequently starts with a skilled, experienced laboratory technician.
p
Our 8 cases, from 8 different families (however, 3 were related three to four, and 5 were related six to eight, generations back, leading us to search for a common ancestor 250-300 years ago) were all detected by the typical round red-brownish crystals in urine, which are seen on light microscopy. The diagnosis was then confirmed by spectrophotometry of the crystals and enzyme analysis of red blood cells. 4 of the 8 cases were adults. All had a history of repeated urolithiasis and recurrent urinary tract infections when the correct diagnosis was finally made on the basis of spherical urine crystals detected by microscopy (figure). The 4 children were all symptom-free, apart from recurrent urinary tract infections in 1. 2 had a history of brownish spots in their diapers and 2 were already diagnosed before age one, only because of the presence of urine crystals. All have been started on allopurinol, which has been well tolerated.
method, especially in patients in whom there is increased
ventilation-perfusion mismatch.5,6 Second, it is unlikely that patients achieved a steady state in metabolic gas exchange. If they were asked to start from rest to 15, 30, and 45 W, they will not have achieved a steady state until the last minute of each test. During the incremental exercise tests, twominute stages were used, again suggesting that a steady state was probably not achieved. Interpretation of the control of ventilation in non-steady state conditions is not reliable. Perhaps in these short-term, non-steady-state exercise stages, ventilation, rather than being driven by muscular carbon dioxide production, is driven by some other signal. Measured carbon dioxide excretion would then reflect ventilation in a passive manner. If this were so, Moore and colleagues’ findings can be explained by the proposal that the increased inspired oxygen reduced the chemoreflex-mediated ventilatory drive, and that the apparent carbon dioxide production fell because of the reduction in ventilation. Coupled to this, an increase in ventilation is known to follow immediately after an increment in load with an immediate passive "blowing off’ of carbon dioxide; carbon dioxide production would in these circumstances merely rise again when the circulating carbon dioxide pool rose sufficiently, and would only be noticeable once a steady state had been achieved. From these data it cannot be concluded that ventilation is reduced via some change in oxygen delivery. The mechanism by which oxygen exerts its effects could simply be that it increases exercise tolerance by suppressing the sensation of breathlessness in much the same way as inhaled diamorphine A possible effect on chemoreceptor sensitivity rather than any change in the intrinsic pathophysiology of heart failure seems the most likely explanation. A. L. CLARK National Heart and Lung Institute, A. J. S. COATS London SW3 6LY, UK LI, Wilson JR, Ferraro N. Exercise ventilation and pulmonary artery wedge m chronic stable congestive heart failure. AmJ Cardiol 1986; 57: 249-53. 2. Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite haemodynamic and pulmonary abnormalities Circulation 1988; 77: 552-59. 3. Buller NP, Poole-Wilson PA Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure. Br Heart J 1990; 63: 281-83. 4. Jones HA, Lakshminarayan S, Becket JM, Hughes JMB. Comparison of estimates of cardiac output by indicator dilution and freon 22 uptake during gas mixing in dogs 1. Fink
pressure
Light microscopy of 2,8-dihydroxyadenine urine crystals (x700). It is noteworthy that 5 of our 8 cases were detected in the same hospital in Reykjavik by the same laboratory technician and the other 3 from a second hospital, also in Reykjavik, after introducing a group of technicians to the rather unique appearance of the 2,8-dihydroxyadenine crystals. Thus, our 8 cases all come from the capital Reykjavik, with a population of 100 000. All were originally detected by alert laboratory technicians in two hospitals. The recognition of more cases of 2,8-dihydroxyadeninuria, especially before the development of urolithiasis, might therefore mainly depend on competent urine microscopists. Department of Paediatrics, University of Iceland, St Joseph’s Hospital, 121 Reykjavik, Iceland
Cardiovasc Res 1991, 25: 523-28. 5. Rubin SA, Brown HV. Ventilation and gas exchange during exercise in severe chronic heart failure. Am Rev Respir Dis 1984; 129 (suppl): S63-64.
6. Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite haemodynamic and pulmonary abnormalities. Circulation 1988; 77: 552-59. 7. Uren NG, Davies SW, Jordan SL, Lipkin DP Increased exercise tolerance after nebulised diamorphine in chronic heart failure. Br Heart J 1991; 66: 112.
*** This
letter has been shown to Dr Moore and
colleagues, whose
reply follows.-ED. L. THRÖSTUR LAXDAL
Increased oxygen and exercise performance in chronic heart failure SIR,-Dr Moore and colleagues (April 4, p 850) report the effects of increased inspired oxygen on exercise performance in chronic heart failure. As is well known in healthy individuals, increased inspired oxygen concentrations reduce ventilation and increase exercise capacity. In heart failure, the ventilation to carbon dioxide production ratio is increased,1,2 and this provides an index of severity of the disease. Any observations on the control of ventilation and the relation between ventilation and carbon dioxide production in chronic heart failure are therefore valuable. There are, however, two difficulties with Moore and colleagues’ methodology. First, the fact that cardiac output does not change across the range of exercise loads for a specific inspired oxygen value, even up to 45 W, calls into question the reliability of the single-breath inert gas method for measuring cardiac output. The method relies on complete gaseous mixing during rebreathing with no recirculation of the gas in lungs and with minimum ventilationperfusion n-lismatching.4 During exercise, when cardiac output is increased, there are thus likely to be considerable inaccuracies in this
SIR,-We agree with Dr Clark and Dr Coats that the differences in cardiac output between exercise at 15 and 45 W were small but, apart from those with 50% inspired oxygen, they were not negligible. Patients with heart failure have an impaired cardiac output response to exercise, so it is not surprising that the difference between these two workloads was small. Indeed, our data are similar to changes in cardiac output measured in other patients with heart failure during exercise with the thermodilution technique.1,2 Coats and Clark say that measuring cardiac output with the single breath technique is unreliable. We used a rebreathing, not single breath, method in our study, which has a long history and is well validated. We correct the soluble gas concentration (freon 22) breath-by-breath (1s per breath) by a sensitive technique with the inert gases helium and sulphur hexafluoride, interpolating from their mixing patterns to a nominal inert gas of the same molecular weight (88) as freon 22. The method has been validated in dogs against simultaneous measurements with indocyanin green’ and in man with thermodilution.1 In addition, there was very little maldistribution of ventilation in our patients whose helium mixing time durng the rebreathe manoeuvre at 15 and 45 W (6’4-11-9 s) was within the normal range. The forced expiratory volume in 1 s vital capacity ratio was greater than 70% in all the study patients. In those with chronic heart failure, multibreath inert gas washout
185
sensitive test for maldistribution) is normal at rests and on exercise.6 We therefore do not accept criticism of the technique on the grounds of maldistribution. We agree that exercise stages of two minutes duration will not aclueve a steady state. That is why we chose three minute periods of exercise for steady-state evaluation. The main reason for doing a progressive exercise test is not to achieve steady state but to stress the subject maximally; hence exercise stages less than three minutes are not only valid but desirable. Clark and Coats suggest that increasing the inspired concentration lowers ventilation by mechanisms other than by reducing the carbon dioxide drive. We know that measurement of carbon dioxide production during the progressive exercise test is not ideal ; however, measurements were continuous and identical for every oxygen concentration, and any cyclical variations in carbon dioxide excretion would not have affected the overall result. We clearly state that the reduction in ventilation may have been attributable to correction of the increased physiological dead space m patients with heart failure. We did not rule out an inhibitory effect on arterial chemoreceptors produced by a rise in arterial oxygen tension on 50% inspired oxygen. Indeed, exercise heart rate also fell at higher oxygen concentrations, suggesting that relief of hypoxaemia may have reduced sympathetic drive.7 Nor did we conclude that ventilation is reduced at these submaximum workloads via some change in oxygen delivery; in fact, total delivery was unchanged comparing air with 50% oxygen.
Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN, UK
D. P. MOORE A. R. WESTON J. M. B. HUGHES C. M. OAKLEY J. C. F. CLELAND
1 Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite haemodynamic and pulmonary abnormalities. Circulation 1988; 77: 552-59. 2 Franciosa JA, Ziesche RN, Wilen M. Functional capacity of patients with chronic left ventricular failure: relationship of bicycle exercise performance to clinical and hemodynamic characterisation. Ann JMed 1979; 67: 460-66. 3 Jones HA, Lakshminarayan S, Becket JM, Hughes JMB. Companson of estimates of cardiac output by indicator dilution and freon 22 uptake during gas mixing in dogs. Cardiovasc Res 1991; 25: 523-28. 4 Moore DP, Weston AR, Jones HA, Cleland JCF, Hughes JMB, Oakley CM. Non-invasive determination of exercise cardiac output: a rebreathing method developed for use in heart failure. Eur Heart J 1991; 12: S102. 5 Frank NR, Cugell DW, Gaensler EA, Ellis LB. Ventilation studies m mitral stenosis.
Am J Med 1953; 15: 60-76. 6 Jebavy P, Widimsky J, Hurych J, Stanek
V. Relationships between orthostatic changes pulmonary diffusing capacity and haemodynamics of lesser circulation Respiration 1971; 28: 101-13. Escourrou P, Johnson DG, Rowell LB. Hypoxaemia increases plasma catecholamine concentrations m exercising humans. J Appl Physiol 1984; 57: 1507-11. of
SIR,- There is no recognised therapy for vincristine overdose apart from symptomatic treatment possibly combined with folinic acid.’ Kosmidis et aP reported three cases treated by a
JEAN-YVES PIERGA PHILIPPE BEUZEBOC THIERRY DORVAL THAO PALANGIE PIERRE POUILLART
Medical Oncology Department, Institut Curie, 75 231 Paris Cedex 05, France 1. Grush OC, Morgan SK. Folinic add 14: 71-78.
rescue
for vincristine toxicity. Clin Toxicol 1979;
2. Kosmidis HV, Bouhoutsou DO, Varvoutsi MC, et al. Vincristine overdose: experience with 3 patients. Pediatr Hematol Oncol 1991; 8: 171-78. 3. Neslon RL, Dyke RW, Root MA. Comparative pharmacokinetics of vindesine, vincristine and vinblastine in patients with cancer. Cancer Treat Rev 1980; 7: 17-24.
Ondansetron in carcinoid syndrome SIR,-Dr Platt and colleagues (June 6, p 1416) report a beneficial effect of ondansetron in a patient with carcinoid syndrome. This finding accords with previous reports of symptomatic effect of serotonin antagonists in this disease.’ We have treated several patients with symptoms of carcinoid disease with ondansetronpreferably as an antiemetic in combination with a somatostatinanalogue after embolisation of liver metastases. 5-HT3-specific receptors are thought to be unable to induce extrapyramidal side-effects,2and as far as we are aware no stimulatory effect of ondansetron on this receptor has been reported. We have, however, seen severe dystonia, tremor, mouth dryness, gait disturbances, and impaired vision in a 73-year-old man with multiple liver metastases from a carcinoid pancreatic tumour. These symptoms developed one week after the initiation of 8 mg ondansetron orally per day, as sole therapy for nausea. Discontinuation of the therapy two months ago improved, but has not completely resolved, the symptoms. The possible induction of true extrapyramidal symptoms may indicate modulation by ondansetron of a receptor different from the 5-HT3 receptor. Previous experience with other serotonin antagonists (ketanserin, methysergide) in carcinoid disease has warned us about the possible enhancement of side-effects seen in these patients. A randomised, controlled trial of long-term treatment of carcinoid patients with ondansetron is therefore called for. Medical
Department A, Rikshospitalet,
MORTEN BJ.
JACOBSEN
1. Hodgson HJF. Controlling the carcinoid syndrome. BMJ 1988; 297: 1213-14. 2. Priestman TJ. Clinical studies with ondansetron in the control of radiation-induced emesis. Eur J Cancer Clin Oncol 1989; 25 (suppl 1): 29-33.
Idarubicin
cardiotoxicity in acute myeloid leukaemia
a
second phase of 1-2 h, and a third phase of about 85 h. Vincristine is predominantly excreted in the bile and is highly bound to plasma proteins (50-80%). The volume of distribution in the third phase is large, reflecting intense tissue uptake with a high tissue/blood ratio. In vincristine poisoning, plasmapheresis may be justified because of the mtense protein binding, especially since vincristine cannot be
dialysed. An 18-year-old patient treated for osteosarcoma received in error times the intended dose of vincristine by two 8 mg injections 12 h apart. Plasmapheresis of 1 ’5 times the plasma volume was done 6 h after the second injection. Vincristine sulphate was assayed by ELISA’LiUy) immediately before and after plasmapheresis, with concentrations of 7-1 and 5-5 ng/ml, respectively. Assay of pldsma-exchange fluid showed 11-6 ng/ml. The plasma concentrations were 2-3 and 2.11 ng/ml 24 and 48 h later. The clinical course was favourable with grade IV neutropenia for 4 days. Central nuerotoxicity was confined to drowsiness with a slowed ten
but without vinca alkaloids.
0027 Oslo, Norway
Favourable outcome after plasmapheresis for vincristine overdose
plasmapheresis. The pharmacokinetics of vincristineobey three-companment model with an exponential phase of 5 min,
electroencephalogram, and peripheral neurological involvement consisted of accentuation of the abolition of deep tendon reflexes without any occlusive syndrome or any motor or sensory deficits on clinical examination or electromyogram. However, antidiuretic hormone secretion was inappropriate with serum sodium of 119 mmol/1 on day 12, which was corrected by fluid restriction. The scheduled chemotherapy could be given 5 weeks after this episode,
SIR,-Your June 6 editorial on anthracycline-related cardiotoxicity suggests that the newer anthracycline analogues idarubicin and epirubicin retain their antitumour activity without cardiotoxicity. In the south-west England trial of cytotoxic chemotherapy of de novo AML, patients were given idarubicin 12 mg/m2 intravenously for 2 days and cytarabine 400 mg/m2 by continuous intravenous infusion for 5 daYS.1 Patients not achieving marrow clearance of leukaemic blasts by day 21 received a second identical course. Patients achieving complete remission of AML were given a further identical course as consolidation therapy, followed by a final course of cytarabine 1 g/m2 daily by continuous infusion for 5 daYS.1 All other recently reported trials of idarubicin in AML used at least 50% more drug in remission induction therapy but similar doses in consolidation therapy.2-s In twenty-four patients (mean age 62 years, range 27-75) receiving 1-2 courses, left ventricular ejection fractions (LVEF) were measured pre and post treatment by echocardiography or
2,8-dihydroxyadenine crystalluria
vs
urolithiasis SIR,-Dr Ceballos-Picot and colleagues’ statement (April 25, 1050) that 2,8-dihydroxyadenine urolithiasis is an underdiagnosed disease has received worthy attention (May 23, p 1295). Since Iceland has contributed 8 of the 62 adenine phosphoribosyltransferase (APRT) deficient type-I homozygotes diagnosed so far, I would like to record the fact that the diagnosis frequently starts with a skilled, experienced laboratory technician.
p
Our 8 cases, from 8 different families (however, 3 were related three to four, and 5 were related six to eight, generations back, leading us to search for a common ancestor 250-300 years ago) were all detected by the typical round red-brownish crystals in urine, which are seen on light microscopy. The diagnosis was then confirmed by spectrophotometry of the crystals and enzyme analysis of red blood cells. 4 of the 8 cases were adults. All had a history of repeated urolithiasis and recurrent urinary tract infections when the correct diagnosis was finally made on the basis of spherical urine crystals detected by microscopy (figure). The 4 children were all symptom-free, apart from recurrent urinary tract infections in 1. 2 had a history of brownish spots in their diapers and 2 were already diagnosed before age one, only because of the presence of urine crystals. All have been started on allopurinol, which has been well tolerated.
method, especially in patients in whom there is increased
ventilation-perfusion mismatch.5,6 Second, it is unlikely that patients achieved a steady state in metabolic gas exchange. If they were asked to start from rest to 15, 30, and 45 W, they will not have achieved a steady state until the last minute of each test. During the incremental exercise tests, twominute stages were used, again suggesting that a steady state was probably not achieved. Interpretation of the control of ventilation in non-steady state conditions is not reliable. Perhaps in these short-term, non-steady-state exercise stages, ventilation, rather than being driven by muscular carbon dioxide production, is driven by some other signal. Measured carbon dioxide excretion would then reflect ventilation in a passive manner. If this were so, Moore and colleagues’ findings can be explained by the proposal that the increased inspired oxygen reduced the chemoreflex-mediated ventilatory drive, and that the apparent carbon dioxide production fell because of the reduction in ventilation. Coupled to this, an increase in ventilation is known to follow immediately after an increment in load with an immediate passive "blowing off’ of carbon dioxide; carbon dioxide production would in these circumstances merely rise again when the circulating carbon dioxide pool rose sufficiently, and would only be noticeable once a steady state had been achieved. From these data it cannot be concluded that ventilation is reduced via some change in oxygen delivery. The mechanism by which oxygen exerts its effects could simply be that it increases exercise tolerance by suppressing the sensation of breathlessness in much the same way as inhaled diamorphine A possible effect on chemoreceptor sensitivity rather than any change in the intrinsic pathophysiology of heart failure seems the most likely explanation. A. L. CLARK National Heart and Lung Institute, A. J. S. COATS London SW3 6LY, UK LI, Wilson JR, Ferraro N. Exercise ventilation and pulmonary artery wedge m chronic stable congestive heart failure. AmJ Cardiol 1986; 57: 249-53. 2. Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite haemodynamic and pulmonary abnormalities Circulation 1988; 77: 552-59. 3. Buller NP, Poole-Wilson PA Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure. Br Heart J 1990; 63: 281-83. 4. Jones HA, Lakshminarayan S, Becket JM, Hughes JMB. Comparison of estimates of cardiac output by indicator dilution and freon 22 uptake during gas mixing in dogs 1. Fink
pressure
Light microscopy of 2,8-dihydroxyadenine urine crystals (x700). It is noteworthy that 5 of our 8 cases were detected in the same hospital in Reykjavik by the same laboratory technician and the other 3 from a second hospital, also in Reykjavik, after introducing a group of technicians to the rather unique appearance of the 2,8-dihydroxyadenine crystals. Thus, our 8 cases all come from the capital Reykjavik, with a population of 100 000. All were originally detected by alert laboratory technicians in two hospitals. The recognition of more cases of 2,8-dihydroxyadeninuria, especially before the development of urolithiasis, might therefore mainly depend on competent urine microscopists. Department of Paediatrics, University of Iceland, St Joseph’s Hospital, 121 Reykjavik, Iceland
Cardiovasc Res 1991, 25: 523-28. 5. Rubin SA, Brown HV. Ventilation and gas exchange during exercise in severe chronic heart failure. Am Rev Respir Dis 1984; 129 (suppl): S63-64.
6. Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite haemodynamic and pulmonary abnormalities. Circulation 1988; 77: 552-59. 7. Uren NG, Davies SW, Jordan SL, Lipkin DP Increased exercise tolerance after nebulised diamorphine in chronic heart failure. Br Heart J 1991; 66: 112.
*** This
letter has been shown to Dr Moore and
colleagues, whose
reply follows.-ED. L. THRÖSTUR LAXDAL
Increased oxygen and exercise performance in chronic heart failure SIR,-Dr Moore and colleagues (April 4, p 850) report the effects of increased inspired oxygen on exercise performance in chronic heart failure. As is well known in healthy individuals, increased inspired oxygen concentrations reduce ventilation and increase exercise capacity. In heart failure, the ventilation to carbon dioxide production ratio is increased,1,2 and this provides an index of severity of the disease. Any observations on the control of ventilation and the relation between ventilation and carbon dioxide production in chronic heart failure are therefore valuable. There are, however, two difficulties with Moore and colleagues’ methodology. First, the fact that cardiac output does not change across the range of exercise loads for a specific inspired oxygen value, even up to 45 W, calls into question the reliability of the single-breath inert gas method for measuring cardiac output. The method relies on complete gaseous mixing during rebreathing with no recirculation of the gas in lungs and with minimum ventilationperfusion n-lismatching.4 During exercise, when cardiac output is increased, there are thus likely to be considerable inaccuracies in this
SIR,-We agree with Dr Clark and Dr Coats that the differences in cardiac output between exercise at 15 and 45 W were small but, apart from those with 50% inspired oxygen, they were not negligible. Patients with heart failure have an impaired cardiac output response to exercise, so it is not surprising that the difference between these two workloads was small. Indeed, our data are similar to changes in cardiac output measured in other patients with heart failure during exercise with the thermodilution technique.1,2 Coats and Clark say that measuring cardiac output with the single breath technique is unreliable. We used a rebreathing, not single breath, method in our study, which has a long history and is well validated. We correct the soluble gas concentration (freon 22) breath-by-breath (1s per breath) by a sensitive technique with the inert gases helium and sulphur hexafluoride, interpolating from their mixing patterns to a nominal inert gas of the same molecular weight (88) as freon 22. The method has been validated in dogs against simultaneous measurements with indocyanin green’ and in man with thermodilution.1 In addition, there was very little maldistribution of ventilation in our patients whose helium mixing time durng the rebreathe manoeuvre at 15 and 45 W (6’4-11-9 s) was within the normal range. The forced expiratory volume in 1 s vital capacity ratio was greater than 70% in all the study patients. In those with chronic heart failure, multibreath inert gas washout
185
sensitive test for maldistribution) is normal at rests and on exercise.6 We therefore do not accept criticism of the technique on the grounds of maldistribution. We agree that exercise stages of two minutes duration will not aclueve a steady state. That is why we chose three minute periods of exercise for steady-state evaluation. The main reason for doing a progressive exercise test is not to achieve steady state but to stress the subject maximally; hence exercise stages less than three minutes are not only valid but desirable. Clark and Coats suggest that increasing the inspired concentration lowers ventilation by mechanisms other than by reducing the carbon dioxide drive. We know that measurement of carbon dioxide production during the progressive exercise test is not ideal ; however, measurements were continuous and identical for every oxygen concentration, and any cyclical variations in carbon dioxide excretion would not have affected the overall result. We clearly state that the reduction in ventilation may have been attributable to correction of the increased physiological dead space m patients with heart failure. We did not rule out an inhibitory effect on arterial chemoreceptors produced by a rise in arterial oxygen tension on 50% inspired oxygen. Indeed, exercise heart rate also fell at higher oxygen concentrations, suggesting that relief of hypoxaemia may have reduced sympathetic drive.7 Nor did we conclude that ventilation is reduced at these submaximum workloads via some change in oxygen delivery; in fact, total delivery was unchanged comparing air with 50% oxygen.
Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN, UK
D. P. MOORE A. R. WESTON J. M. B. HUGHES C. M. OAKLEY J. C. F. CLELAND
1 Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite haemodynamic and pulmonary abnormalities. Circulation 1988; 77: 552-59. 2 Franciosa JA, Ziesche RN, Wilen M. Functional capacity of patients with chronic left ventricular failure: relationship of bicycle exercise performance to clinical and hemodynamic characterisation. Ann JMed 1979; 67: 460-66. 3 Jones HA, Lakshminarayan S, Becket JM, Hughes JMB. Companson of estimates of cardiac output by indicator dilution and freon 22 uptake during gas mixing in dogs. Cardiovasc Res 1991; 25: 523-28. 4 Moore DP, Weston AR, Jones HA, Cleland JCF, Hughes JMB, Oakley CM. Non-invasive determination of exercise cardiac output: a rebreathing method developed for use in heart failure. Eur Heart J 1991; 12: S102. 5 Frank NR, Cugell DW, Gaensler EA, Ellis LB. Ventilation studies m mitral stenosis.
Am J Med 1953; 15: 60-76. 6 Jebavy P, Widimsky J, Hurych J, Stanek
V. Relationships between orthostatic changes pulmonary diffusing capacity and haemodynamics of lesser circulation Respiration 1971; 28: 101-13. Escourrou P, Johnson DG, Rowell LB. Hypoxaemia increases plasma catecholamine concentrations m exercising humans. J Appl Physiol 1984; 57: 1507-11. of
SIR,- There is no recognised therapy for vincristine overdose apart from symptomatic treatment possibly combined with folinic acid.’ Kosmidis et aP reported three cases treated by a
JEAN-YVES PIERGA PHILIPPE BEUZEBOC THIERRY DORVAL THAO PALANGIE PIERRE POUILLART
Medical Oncology Department, Institut Curie, 75 231 Paris Cedex 05, France 1. Grush OC, Morgan SK. Folinic add 14: 71-78.
rescue
for vincristine toxicity. Clin Toxicol 1979;
2. Kosmidis HV, Bouhoutsou DO, Varvoutsi MC, et al. Vincristine overdose: experience with 3 patients. Pediatr Hematol Oncol 1991; 8: 171-78. 3. Neslon RL, Dyke RW, Root MA. Comparative pharmacokinetics of vindesine, vincristine and vinblastine in patients with cancer. Cancer Treat Rev 1980; 7: 17-24.
Ondansetron in carcinoid syndrome SIR,-Dr Platt and colleagues (June 6, p 1416) report a beneficial effect of ondansetron in a patient with carcinoid syndrome. This finding accords with previous reports of symptomatic effect of serotonin antagonists in this disease.’ We have treated several patients with symptoms of carcinoid disease with ondansetronpreferably as an antiemetic in combination with a somatostatinanalogue after embolisation of liver metastases. 5-HT3-specific receptors are thought to be unable to induce extrapyramidal side-effects,2and as far as we are aware no stimulatory effect of ondansetron on this receptor has been reported. We have, however, seen severe dystonia, tremor, mouth dryness, gait disturbances, and impaired vision in a 73-year-old man with multiple liver metastases from a carcinoid pancreatic tumour. These symptoms developed one week after the initiation of 8 mg ondansetron orally per day, as sole therapy for nausea. Discontinuation of the therapy two months ago improved, but has not completely resolved, the symptoms. The possible induction of true extrapyramidal symptoms may indicate modulation by ondansetron of a receptor different from the 5-HT3 receptor. Previous experience with other serotonin antagonists (ketanserin, methysergide) in carcinoid disease has warned us about the possible enhancement of side-effects seen in these patients. A randomised, controlled trial of long-term treatment of carcinoid patients with ondansetron is therefore called for. Medical
Department A, Rikshospitalet,
MORTEN BJ.
JACOBSEN
1. Hodgson HJF. Controlling the carcinoid syndrome. BMJ 1988; 297: 1213-14. 2. Priestman TJ. Clinical studies with ondansetron in the control of radiation-induced emesis. Eur J Cancer Clin Oncol 1989; 25 (suppl 1): 29-33.
Idarubicin
cardiotoxicity in acute myeloid leukaemia
a
second phase of 1-2 h, and a third phase of about 85 h. Vincristine is predominantly excreted in the bile and is highly bound to plasma proteins (50-80%). The volume of distribution in the third phase is large, reflecting intense tissue uptake with a high tissue/blood ratio. In vincristine poisoning, plasmapheresis may be justified because of the mtense protein binding, especially since vincristine cannot be
dialysed. An 18-year-old patient treated for osteosarcoma received in error times the intended dose of vincristine by two 8 mg injections 12 h apart. Plasmapheresis of 1 ’5 times the plasma volume was done 6 h after the second injection. Vincristine sulphate was assayed by ELISA’LiUy) immediately before and after plasmapheresis, with concentrations of 7-1 and 5-5 ng/ml, respectively. Assay of pldsma-exchange fluid showed 11-6 ng/ml. The plasma concentrations were 2-3 and 2.11 ng/ml 24 and 48 h later. The clinical course was favourable with grade IV neutropenia for 4 days. Central nuerotoxicity was confined to drowsiness with a slowed ten
but without vinca alkaloids.
0027 Oslo, Norway
Favourable outcome after plasmapheresis for vincristine overdose
plasmapheresis. The pharmacokinetics of vincristineobey three-companment model with an exponential phase of 5 min,
electroencephalogram, and peripheral neurological involvement consisted of accentuation of the abolition of deep tendon reflexes without any occlusive syndrome or any motor or sensory deficits on clinical examination or electromyogram. However, antidiuretic hormone secretion was inappropriate with serum sodium of 119 mmol/1 on day 12, which was corrected by fluid restriction. The scheduled chemotherapy could be given 5 weeks after this episode,
SIR,-Your June 6 editorial on anthracycline-related cardiotoxicity suggests that the newer anthracycline analogues idarubicin and epirubicin retain their antitumour activity without cardiotoxicity. In the south-west England trial of cytotoxic chemotherapy of de novo AML, patients were given idarubicin 12 mg/m2 intravenously for 2 days and cytarabine 400 mg/m2 by continuous intravenous infusion for 5 daYS.1 Patients not achieving marrow clearance of leukaemic blasts by day 21 received a second identical course. Patients achieving complete remission of AML were given a further identical course as consolidation therapy, followed by a final course of cytarabine 1 g/m2 daily by continuous infusion for 5 daYS.1 All other recently reported trials of idarubicin in AML used at least 50% more drug in remission induction therapy but similar doses in consolidation therapy.2-s In twenty-four patients (mean age 62 years, range 27-75) receiving 1-2 courses, left ventricular ejection fractions (LVEF) were measured pre and post treatment by echocardiography or
