858
algorithm used in France for adverse drug monitoring’ were: probably excluded relation for ofloxacin; doubtful for clindamycin, pyrimethamine, itraconazole, valproic acid, and pentamidine; and probable relation for didanosine. After discontinuation of this therapy, his temperature and cutaneous lesions improved rapidly and the patient was discharged on July 30. In three phase I trials,2-4 the major toxic effects related to didanosine were pancreatitis and peripheral neuropathy. Both seemed to be dose-related and resolved or improved3,4 after discontinuation of therapy. Other toxic effects included hyperuricaemia related to high dose/-4 elevated liver enzymes/,3 and abnormalities in cardiac conduction.2 Adverse cutaneous drug reactions were uncommon. In these trials, 4 patients had a rash: 1/34/ 2/37,3and 1/37. The rash was morbilliform’ and maculopapular.3 In 1 case,2 the rash recurred with more intensity on rechallenge. In 2 other cases,3 didanosine was not discontinued and the rash resolved spontaneously. The manufacturer (Bristol) had similar case. Patients with AIDS have an increased risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis when treated with antibacterial sulphonamides and other drugs.s Our case suggests that didanosine might be another not heard of any
cause.
Department of Dermatology and Immunopathology, Hôpital Henri-Mondor, Université Paris XII, 94010 Créteil, France
A. PARNEIX-SPAKE S. BASTUJI-GARIN Y. LEVY M-L. DUBREUIL-LEMAIRE
J-C. ROUJEAU
1. Moore N, Paux G, Begaud B, et al. Adverse drug reaction monitoring: doing it the French way. Lancet 1985; ii: 1056-58. 2 Cooley TP, Kunches LM, Saunders CA, et al. Once-daily administration of 2’,3’
didanosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990; 322: 1340-45. 3. Lambert J S, Seidlin M, Reichman RC, et al. 2’,3’-didanosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990; 322: 1333-40. 4. Yarchoan R, Mitsuya H, Pluda JM, et al. The national cancer institute phase I study of 2’,3’-didanosine administration in adults with AIDS and AIDS-related complex: analysis of activity and toxicity profiles. Rev Infect Dis 1990; 12: 522-23. 5. Coopman SA, Stem RS. Cutaneous drug reactions in human immunodeficency virus infection. Arch Dermatol 1991; 127: 714-17.
Bradycardia due to anthracyclines SIR,-Dr Walker and colleagues describe (Aug 8, p 380) bradycardia following administration of amphotericin after cancer chemotherapy. We report a further three patients with bradycardia after treatment with cytotoxic drugs, including anthracyclines. Patient 1-A 48-year-old man had lobar pneumonia as the first manifestation of acute myeloblastic leukaemia. He was given antibiotics and started on daunorubicin, cytarabine, and thioguanine. The total dose of daunorubicin was less than 150 mg/m2. Amphotericin was added afr t-n days because pneumonia had not resolved. A month after treatment finished he developed symptomatic bradycardia. Electrocardiography (ECG) before chemotherapy had been normal. ECG now showed Mobitz type I
second-degree atrioventricular block, and substantial pauses with periods of rapid atrial flutter on ambulatory electrocardiography. A permanent pacemaker was inserted and he was given digoxin. Patient 2-A 56-year-old woman presented with renal failure. ECG was normal. Renal biopsy showed a plasma-cell infiltrate and positive amyloid staining. Myeloma was diagnosed and she was given vincristine, dexamethasone, and doxorubicin. The cumulative dose of doxorubicin was less than 36 mg/m2. Four days after the last drug administration she was syncopal. A rhythm strip showed atrial fibrillation with a ventricular rate of 60 per min and pauses of more than 2 s; a few hours later she developed a junctional rhythm. After a further 6 h ECG showed complete heart block, and a permanent pacemaker was inserted. Two days later ventricular fibrillation was followed by unsuccessful resuscitation. Necropsy showed no myocardial amyloid. Patient 3-A 47-year-old man with Wegener’s granulomatosis received 7 years treatment with cyclophosphamide and developed erythroleukaemia, which was treated with cytarabine, etoposide, and daunorubicin. He was also given antibiotics, including
amphotericin for otitis interna. Two months later he was given a second course of chemotherapy. The total dose of daunorubicin was 300 mg/m2. He received further amphotericin for a second infection, to which he responded, but three weeks later he became syncopal. The ECG now showed complete heart block, and a permanent pacemaker was inserted; ECG was normal before chemotherapy. These three patients were younger than most who develop bradyarrhythmias requiring pacemakers, and none had a history of cardiac disease. All developed symptomatic bradycardia after chemotherapy. Each of the patients received intravenous anthracyclines but the dose given was below that (> 550 mg/m2) usually associated with cardiotoxicity. Two patients also received amphotericin, which may have precipitated the clinical presentation. Unlike Walker and colleagues’ patient, there was no evidence of bradycardia during the administration of amphotericin, with the last dose being given at least one month before presentation. Rhythm disturbances during anthracycline treatment have been reported in conjunction with left ventricular dysfunction,l of which there was no clinical evidence in our patients. Arrhythmias, such as atrial flutter, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation,2,3may also arise after acute exposure to the drug, but the development of symptomatic bradycardia has not been reported after anthracyclines alone. Wegener’s granulomatosis and amyloidosis seem unlikely causes of the bradyarrhythmias. The most probable trigger in our patients is an adverse effect due to anthracyclines with a further possible contribution in two patients from co-administered amphotericin. Patients presenting with syncopal spells should be investigated at an early stage to identify arrhythmias so that appropriate management can be provided. H. BETHELL Papworth Hospital, Cambridge CB3 8RE, UK
A. A. GRACE
M.C.PETCH P. M. SCHOFIELD
J. A. HALL
Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukaemia in childhood. N Engl J Med 1991; 324: 808-14. 2. Bristow MR, Billingham ME, Mason JW, Daniels JR. Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat Rep 1978; 62: 873-79. 3. Bristow M, Thompson P, Martin R, Mason J, Billingham M, Harrison D Early anthracycline toxicity Am J Med 1978; 65: 823-32. 1.
Susceptibility of low-density lipoproteins to oxidation in coronary bypass patients SIR,-Dr Regnstrom and colleagues (May 16, p 1183) report that the susceptibility of low-density lipoprotein (LDL) to oxidation is associated with the severity of atherosclerosis in male survivors of myocardial infarction. Their finding supports the hypothesis on the pathological importance of oxidised LDL as an atherogenic particle.’ We attempted to relate the severity of atherosclerosis in coronary arteries and grafts to the susceptiblity of LDL to oxidative modification in vitro. 1766 patients underwent aortocoronary bypass surgery with insertion of 1-6 grafts. 158 were selected randomly and blindly for recatheterisation. This study was approved by the ethics committee of the Academic Hospital, University of Leiden, and patients gave written informed consent before angiography was done. The mean interval between surgery and angiographic reexamination was 72 years. Randomly, 28 of these 158 patients were divided into two groups (group A with progression; group B without progression). Progression was defined as: occurrence of a new lesion leading to 50% or more stenosis, increment of an existing lesion by 30% or more, or progression to occlusion. After isolation from plasma by density-gradient ultracentrifugation, LDL was used within 2 h to determine the susceptibility to in-vitro oxidation.2 The table shows patients’ details and laboratory findings. LDL isolated from group A patients was less resistant to oxidation than was LDL from group B patients, as shown by a shorter lag time (table). The reduced lag time could not be attributed to a lower a-tocopherol content in LDL. The protective effect of &agr;-tocopherol against oxidative modification of lipids can be prolonged by ascorbate. However, blood ascorbate
algorithm used in France for adverse drug monitoring’ were: probably excluded relation for ofloxacin; doubtful for clindamycin, pyrimethamine, itraconazole, valproic acid, and pentamidine; and probable relation for didanosine. After discontinuation of this therapy, his temperature and cutaneous lesions improved rapidly and the patient was discharged on July 30. In three phase I trials,2-4 the major toxic effects related to didanosine were pancreatitis and peripheral neuropathy. Both seemed to be dose-related and resolved or improved3,4 after discontinuation of therapy. Other toxic effects included hyperuricaemia related to high dose/-4 elevated liver enzymes/,3 and abnormalities in cardiac conduction.2 Adverse cutaneous drug reactions were uncommon. In these trials, 4 patients had a rash: 1/34/ 2/37,3and 1/37. The rash was morbilliform’ and maculopapular.3 In 1 case,2 the rash recurred with more intensity on rechallenge. In 2 other cases,3 didanosine was not discontinued and the rash resolved spontaneously. The manufacturer (Bristol) had similar case. Patients with AIDS have an increased risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis when treated with antibacterial sulphonamides and other drugs.s Our case suggests that didanosine might be another not heard of any
cause.
Department of Dermatology and Immunopathology, Hôpital Henri-Mondor, Université Paris XII, 94010 Créteil, France
A. PARNEIX-SPAKE S. BASTUJI-GARIN Y. LEVY M-L. DUBREUIL-LEMAIRE
J-C. ROUJEAU
1. Moore N, Paux G, Begaud B, et al. Adverse drug reaction monitoring: doing it the French way. Lancet 1985; ii: 1056-58. 2 Cooley TP, Kunches LM, Saunders CA, et al. Once-daily administration of 2’,3’
didanosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990; 322: 1340-45. 3. Lambert J S, Seidlin M, Reichman RC, et al. 2’,3’-didanosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990; 322: 1333-40. 4. Yarchoan R, Mitsuya H, Pluda JM, et al. The national cancer institute phase I study of 2’,3’-didanosine administration in adults with AIDS and AIDS-related complex: analysis of activity and toxicity profiles. Rev Infect Dis 1990; 12: 522-23. 5. Coopman SA, Stem RS. Cutaneous drug reactions in human immunodeficency virus infection. Arch Dermatol 1991; 127: 714-17.
Bradycardia due to anthracyclines SIR,-Dr Walker and colleagues describe (Aug 8, p 380) bradycardia following administration of amphotericin after cancer chemotherapy. We report a further three patients with bradycardia after treatment with cytotoxic drugs, including anthracyclines. Patient 1-A 48-year-old man had lobar pneumonia as the first manifestation of acute myeloblastic leukaemia. He was given antibiotics and started on daunorubicin, cytarabine, and thioguanine. The total dose of daunorubicin was less than 150 mg/m2. Amphotericin was added afr t-n days because pneumonia had not resolved. A month after treatment finished he developed symptomatic bradycardia. Electrocardiography (ECG) before chemotherapy had been normal. ECG now showed Mobitz type I
second-degree atrioventricular block, and substantial pauses with periods of rapid atrial flutter on ambulatory electrocardiography. A permanent pacemaker was inserted and he was given digoxin. Patient 2-A 56-year-old woman presented with renal failure. ECG was normal. Renal biopsy showed a plasma-cell infiltrate and positive amyloid staining. Myeloma was diagnosed and she was given vincristine, dexamethasone, and doxorubicin. The cumulative dose of doxorubicin was less than 36 mg/m2. Four days after the last drug administration she was syncopal. A rhythm strip showed atrial fibrillation with a ventricular rate of 60 per min and pauses of more than 2 s; a few hours later she developed a junctional rhythm. After a further 6 h ECG showed complete heart block, and a permanent pacemaker was inserted. Two days later ventricular fibrillation was followed by unsuccessful resuscitation. Necropsy showed no myocardial amyloid. Patient 3-A 47-year-old man with Wegener’s granulomatosis received 7 years treatment with cyclophosphamide and developed erythroleukaemia, which was treated with cytarabine, etoposide, and daunorubicin. He was also given antibiotics, including
amphotericin for otitis interna. Two months later he was given a second course of chemotherapy. The total dose of daunorubicin was 300 mg/m2. He received further amphotericin for a second infection, to which he responded, but three weeks later he became syncopal. The ECG now showed complete heart block, and a permanent pacemaker was inserted; ECG was normal before chemotherapy. These three patients were younger than most who develop bradyarrhythmias requiring pacemakers, and none had a history of cardiac disease. All developed symptomatic bradycardia after chemotherapy. Each of the patients received intravenous anthracyclines but the dose given was below that (> 550 mg/m2) usually associated with cardiotoxicity. Two patients also received amphotericin, which may have precipitated the clinical presentation. Unlike Walker and colleagues’ patient, there was no evidence of bradycardia during the administration of amphotericin, with the last dose being given at least one month before presentation. Rhythm disturbances during anthracycline treatment have been reported in conjunction with left ventricular dysfunction,l of which there was no clinical evidence in our patients. Arrhythmias, such as atrial flutter, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation,2,3may also arise after acute exposure to the drug, but the development of symptomatic bradycardia has not been reported after anthracyclines alone. Wegener’s granulomatosis and amyloidosis seem unlikely causes of the bradyarrhythmias. The most probable trigger in our patients is an adverse effect due to anthracyclines with a further possible contribution in two patients from co-administered amphotericin. Patients presenting with syncopal spells should be investigated at an early stage to identify arrhythmias so that appropriate management can be provided. H. BETHELL Papworth Hospital, Cambridge CB3 8RE, UK
A. A. GRACE
M.C.PETCH P. M. SCHOFIELD
J. A. HALL
Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukaemia in childhood. N Engl J Med 1991; 324: 808-14. 2. Bristow MR, Billingham ME, Mason JW, Daniels JR. Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat Rep 1978; 62: 873-79. 3. Bristow M, Thompson P, Martin R, Mason J, Billingham M, Harrison D Early anthracycline toxicity Am J Med 1978; 65: 823-32. 1.
Susceptibility of low-density lipoproteins to oxidation in coronary bypass patients SIR,-Dr Regnstrom and colleagues (May 16, p 1183) report that the susceptibility of low-density lipoprotein (LDL) to oxidation is associated with the severity of atherosclerosis in male survivors of myocardial infarction. Their finding supports the hypothesis on the pathological importance of oxidised LDL as an atherogenic particle.’ We attempted to relate the severity of atherosclerosis in coronary arteries and grafts to the susceptiblity of LDL to oxidative modification in vitro. 1766 patients underwent aortocoronary bypass surgery with insertion of 1-6 grafts. 158 were selected randomly and blindly for recatheterisation. This study was approved by the ethics committee of the Academic Hospital, University of Leiden, and patients gave written informed consent before angiography was done. The mean interval between surgery and angiographic reexamination was 72 years. Randomly, 28 of these 158 patients were divided into two groups (group A with progression; group B without progression). Progression was defined as: occurrence of a new lesion leading to 50% or more stenosis, increment of an existing lesion by 30% or more, or progression to occlusion. After isolation from plasma by density-gradient ultracentrifugation, LDL was used within 2 h to determine the susceptibility to in-vitro oxidation.2 The table shows patients’ details and laboratory findings. LDL isolated from group A patients was less resistant to oxidation than was LDL from group B patients, as shown by a shorter lag time (table). The reduced lag time could not be attributed to a lower a-tocopherol content in LDL. The protective effect of &agr;-tocopherol against oxidative modification of lipids can be prolonged by ascorbate. However, blood ascorbate
