914
rhesus incompatibility was established. Serum bilirubin concentrations were monitored at 6 h intervals. Exchange transfusions were undertaken if serum bilirubin concentrations exceeded the modified curves of Polacek2 by more than 2 mgjdJ. The two groups were not significantly different with respect to birth weight, age, haemoglobin, and bilirubin concentrations on admission. Two patients, one in the control and one in the treatment group, were excluded from the final evaluation because of protocol violations. Results from 32 children were analysed. Of 16 children who received HDivGG, only 2 (12-5%) required exchange transfusion, while 11of 16 (69%) required transfusion in the control group (xl-test with Yates’ correction; p < 0-005). No side-effects were observed. The two treatment failures may be attributable to suboptimum management. In one, phototherapy was discontinued on day 2 without closely monitoring further bilirubin concentrations. This child required exchange transfusion on day 4. In the other child, HDivGG was given at 12 h when the bilirubin concentration was already 2 mg/dl below the exchange curve defmed by the protocol. The time available for HDivGG to act was probably too short because exchange transfusion was begun 2 h after administration of HDivGG. These preliminary data indicate that the frequency of exchange transfusion can be significantly reduced by combining conventional phototherapy with HDivGG. However, HDivGG is only effective if given early after a positive direct Coombs’ test result is obtained. HDivGG will not influence the elimination of bilirubin, but probably prevents its production by interaction with the reticuloendothelial system Fc receptors. A similar process may take place in patients with immune thrombocytopenia who are also treated with HDivGG.3,4 Since rhesus antibodies do not fix complement, antibody-coated red blood cells are probably eliminated via antibody dependent cellular cytotoxicity. The optimum dose of HDivGG, the number of infusions, and the best preparation remain to be determined. soon as
mild to moderate reversible airways obstruction. Exacerbations in the salmeterol patients were grouped according to the 3-monthly visit structure (although during the first 3 months visits also took place at 2, 4, and 8 weeks). The frequency of patients having 0, 1, 2, 3, or 4 exacerbations during each 3 month period were tabulated and the time in days for the first exacerbation to occur was analysed with an actuarial life-table method (table, figure). The total number of patients decreased during the study since not all completed 12 months. Patients who withdrew as a result of asthma exacerbation are included at the relevant time points. Those withdrawn for reasons other than asthma exacerbation are included until the time of the withdrawal. If long-term treatment with salmeterol leads to a deterioration in asthma and its control, we would expect to see an increase in the frequency of exacerbations during the study and an increase in the change, between time points, in the cumulative percentage of patients having their first exacerbation. The frequency of exacerbations in patients taking salmeterol was clearly higher in the first 3 month period but this almost certainly reflects the frequency of study visits during that time. The number of patients reporting several exacerbations in a 3 month period, during the last 9 months of the study, remained constant. The rate at which first exacerbations occurred did not increase during the trial, with changes in the cumulative percentage of patients with an exacerbation of 66%, 81%, and 7-8% between months 3 and 6,6 and 9, and 9 and 12, respectively. Improvements in lung function, as monitored during the first 3 months by increase in morning and evening peak expiratory flow rates, reduction in diurnal variation, and reduction in noctural symptoms, were maintained throughout the 12 month treatment
period. This study, of over 350 patients, is therefore at variance with Sears and colleagues’ suggestion. Similar analyses are under way for other studies. M. M.
JENKINS
C. J. HILTON J. C. DE KOCK J. B. D. PALMER
Glaxo Group Research Ltd, Greenford UB6 0HE, UK; and Glaxo Research Institute
German Rhesus Alloimmunisation Department of Paediatrics, University of Dusseldorf, D-4000 Dusseldorf, Germany
Study Group,
JOCHEN RUBO VOLKER WAHN
1 Rubo J, Wahn V. Versuch einer hochdosierten Gammaglobulm-therapie bei drei Kindern mit Hyperbilirubinamie bei Rhesusin-kompatibilitat Monatsschr Kinderheilkd 1990; 138: 216-20 2. Polacek K. Das universale Diagram zur Behandlung der Hyperbilirubinamie der Neugeborenen. Padiatr Prax 1984; 29: 1-3. 3. Derycke M, Dreyfus M, Robert JC, Tschernia G. Intravenous immunoglobulin for neonatal isoimmune thrombocytopenia. Arch Dis Child 1985; 60: 667-69. 4. Massey G, McWilliams N, Mueller D, Napolitano A, Maurer H. Intravenous immunoglobulin in treatment of neonatal isoimmune thrombocytopenia J Pediatr 1987; 111: 133-35
Warfarin
antagonism by avocado
SIR,-Warfarin antagonises vitamin-K-dependent coagulation factors, and resistance to its hypoprothrombinaemic effect caused by vitamin-K-rich vegetables has been reported.1-3 We present the warfarin-antagonising effect of avocado, which is low in vitamin K. A 15-year-old girl with antiphospholipid syndrome was being treated with warfarin for
1. Sears MR, Taylor DR, Print CG, et al. Regular inhaled bronchial asthma. Lancet 1990; 336: 1391-96.
beta-agonist
treatment m
High-dose intravenous gammaglobulin rhesus-haemolytic disease SIR,-We have completed
a
multicentre controlled trial
in to test
previously reported hypothesis1 that high-dose intravenous gammaglobulin (HDivGG) can reduce the frequency of exchange transfusions in newborn infants with Rhesus-haemolytic disease. After both ethical committee approval of our protocol and informed consent by parents, 34 children with a positive direct Coombs’test were randomly assigned to receive either conventional phototherapy alone or phototherapy with intravenous HDivGG (’Polyglobin N’, Cutter, Cologne, Germany) 500 mg/kg over 2 h, as our
a parieto-occipital brain infarct. She was adequately anticoagulated (international normalised ratio [INR] 2-5) for the first 6 weeks. Thereafter, while she was on the same dose of warfarin, the INR fell to 1 ’7. No other medications and no intercurrent illness were documented. At the time the patient was eating at least 100 g avocado every day. Once avocado was
eliminated from her diet, the INR returned to 2-5. 3 months later, despite advice, she started to eat avocado again and the INR fell to 17. A return to an avocado-free diet resulted in effective
anticoagulation once more. A 30-year-old woman in the 22nd gestational week of her sixth pregnancy was treated with heparin followed by warfarin because of pulmonary embolism. She was well anticoagulated, maintaining an average INR of 2-7. 2 months later she consumed 200 g avocado on two consecutive evenings, and her INR fell to 1-6. Elimination of
avodaco from her diet restored adequate anticoagulation. Avocado is low in vitamin K at 8 u.g per 100 g,4 compared
with
915
broccoli (200), beetroot (650), lettuce (129), and cabbage (125 f!gper 100 g),s but it is high in lipids (17-5%). Oils extracted from intact avocado cause changes in liver metabolism of growing ratsIn the two patients reported here avocado intake interfered with warfarin therapy and, though the precise mechanism is obscure, it may be that avocado affects microsomal liver enzymes, leading to increased degradation of warfarin, rather as barbiturates8 and rifampicin9 do. Avocado may also interfere with intestinal warfarin absorption, as cholestyramine does." Avocado intake should be thought of as a possible cause of reduction of warfarin effect in patients previously
adequately anticoagulated. Division of Haematology, Beilinson Medical Centre,
DORIT BLICKSTEIN MATI SHAKLAI AIDA INBAL
Petah Tiqva, 49100, Israel, and Tel Aviv University, Sackler Faculty of Medicine
1. Kempin SJ. Warfarin resistance caused by broccoli. N Engl JMed 1983; 308: 1229. 2 Karlson B. Leijd B, Hellstrom K. On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment. Acta Med Scand 1986; 220: 347-50. 3 Oren B, Shvartzman P. Unsuspected source of vitamin K in patients treated with anticoagulants: a case report. Family Practice 1989; 6: 151-52. 4. Souci SW, Fachmann W, Kraut H. Food composition and nutrition tables 1986/87, 3rd ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1986: 830. 5. Olson RE. Vit K. In: Goodhart RS, Shils ME, eds. Modem nutrition in health and disease, 6th ed. Philadelphia: Lea & Febiger, 1980: 170-180. 6. Guggenheim YK Human nutrition: physiology, public health, pathology. 4th ed. Jerusalem: Magnes Press, Hebrew University, 1981: table 1, p 6-7 (appendix). 7. Werman MJ, Mokady S, Neeman I, Auslaender L, Zeidler A. The effect of avocado oils on some liver characteristics in growing rats. Food Chem Toxicol 1989; 27: 279-82. 8 McDonald MG, Robinson DS, Sylvester D, Jaffee JJ. The effects of phenobarbital, chloral betaine, and glutethimide administration on warfarin plasma levels and hypoprothrombinemic responses in man. Clin Pharmacol Ther 1969; 10: 80. 9. O’Reilly RA Interaction of chronic daily warfarin therapy and rifampin Ann Intern Med 1975; 83: 506. 10. Robinson D, Benjamin D, McCormick J. Interaction of warfarin and non-systemic
gastrointestinal drugs. Clin Pharmacol Ther 1971; 12: 491.
Muscular disorders associated with
cyclosporin SIR,-It has lately been reported that cyclosporin (’Sandimmum’) may affect skeletal muscle.1,2 The Drug Monitoring Centre of Sandoz Pharma is aware of 29 cases of skeletal muscle disorder in association with this drug (up to Dec 31,1990). These were published single case-reports, spontaneous reports to the Centre, or observations during a post-marketing surveillance study of cyclosporin in bone marrow and organ transplant recipientReports of isolated cramps, a frequent side-effect, are not included. 5 spontaneously reported cases were too poorly documented to be evaluated and have not been included. These cases suggest two patterns of cyclosporin-associated muscular disorder. The first is myopathy without evidence of rhabdomyolysis developing in transplant patients. These 6 patients were receiving cyclosporin at conventional doses when myalgia and muscular weakness developed 5-25 months after the start of therapy (table). Concomitant medications have not been reported to cause this type of effect. Electromyograms were normal or showed changes compatible with myopathy or mild sensory motor neuropathy. Biopsy, when done, revealed toxic or non-specific myopathy; muscle enzymes were normal. These changes appear to be dose-dependent since clincial and, sometimes, pathological signs
seemed to abate with dose reduction or upon withdrawal of the drug. Cases 1-31 and 42 have been published; the other 2 were spontaneous reports. In the post-marketing surveillance, 5 cases of muscular disorder were reported which showed a similar pattern; they were observed among the 3017 patients followed up for a year, yielding an incidence rate of 0-17%. It is not possible to assess a causal relation between drug and event in post-marketing surveillance. The second pattern consists of rhabdomyolysis. This type of muscular disorder seems to result primarily from interactions with other drugs. Rhabdomyolysis was described in 7 patients treated concomitantly with cyclosporin and lovastatin. 4-6 The pathophysiology of this interaction has not been established, but cyclosporin may interfere with the metabolism of lovastatin. Rhabdomyolysis may also result from concomitant intake of cyclosporin and colchicine, which is known to cause such a side-effectA case suggestive of such an interaction has been published,8 and Sandoz has received a well-documented spontaneous report of a further case of possible interaction between cyclosporin and colchicine. However, rhabdomyolysis caused by cyclosporin alone cannot be excluded.9 An additional case of rhabdomyolysis has been reported during post-marketing surveillance, giving an incidence of less than 0-05%. Rhabdomyolysis may occur in association with grand mal seizures that can develop in cyclosporin-treated patients; this has been reported in one case.1o Clinically relevant muscular disorders associated with cyclosporin are rare. Most have been mild and have abated with dose reduction. However, the possibility of myopathy associated with the drug should be considered if muscle pain and/or weakness develop during cyclosporin treatment, especially if these symptoms occur after 6 months of therapy. Myopathic symptoms can be expected to improve upon dose reduction. If not, withdrawal of the drug has to be considered-but before such action a risk-benefit evaluation should be made. Concomitant use of cyclosporin and lovastatin or colchicine should be carefully judged, and the treatment changed if signs and symptoms of myolysis develop. Drug Monitoring Centre,
F. ARELLANO P. KRUPP
Sandoz Pharma Ltd, 4002 Basel, Switzerland
Goy JJ, Stauffer SC, Deruaz JP, et al. Myopathy as a possible side-effect of cyclosporin. Lancet 1989; i: 1446-47. 2. Fernandez-Sola J, Campistol J, Casademont J, Grau JM, Urbano-Marquez A. Reversible cyclosporin myopathy. Lancet 1990; 335: 362-63. 3. Cockburn I, Götz E, Gulich A, Krupp A. An interim analysis of the on-going long-term safety study of cyclosporin in renal transplantation. Transplant Proc 1988; suppl 3: 519-29. 4. Norman D, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal failure in a heart transplant recipient receiving lovastatin. N Engl J Med 1988; 318: 46-47. 5. East C, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in patient receiving lovastatin after cardiac transplantation. N Engl J Med 1988; 318: 47-48. 6. Corpier CL, Jones PH, Suki WN, et al. Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients. JAMA 1988; 1.
260: 239-41.
Rieger EH, Halasz NA, Wahlstrom HE. Colchicine neuromyopathy after renal transplantation. Transplantation 1990; 49: 1196-98 8. Noppen M, Velkeniers B, Dierckx R, et al. Cyclosporin and myopathy. Ann Intern Med 1987; 107: 945-46. 9. Grezard O, Lebranchu Y, Birmele B, Sharobeem R, Nivet H, Bagros PH. Cyclosporin-induced muscular toxicity. Lancet 1990; 335: 177. 10. Volin L, Jarventie G, Ruut U. Fatal rhabdomyolysis as a complication of bone marrow transplantation. Bone Marrow Transplant 1990; 6: 59-60. 7.
PATIENTS REPORTED WITH MYOPATHY I
’Heart (nos 1-3, and ND not done
5)
or
kidney (4 and 6) transplant recipients.
ATG =antithymocyte globulin.
I
I
rhesus incompatibility was established. Serum bilirubin concentrations were monitored at 6 h intervals. Exchange transfusions were undertaken if serum bilirubin concentrations exceeded the modified curves of Polacek2 by more than 2 mgjdJ. The two groups were not significantly different with respect to birth weight, age, haemoglobin, and bilirubin concentrations on admission. Two patients, one in the control and one in the treatment group, were excluded from the final evaluation because of protocol violations. Results from 32 children were analysed. Of 16 children who received HDivGG, only 2 (12-5%) required exchange transfusion, while 11of 16 (69%) required transfusion in the control group (xl-test with Yates’ correction; p < 0-005). No side-effects were observed. The two treatment failures may be attributable to suboptimum management. In one, phototherapy was discontinued on day 2 without closely monitoring further bilirubin concentrations. This child required exchange transfusion on day 4. In the other child, HDivGG was given at 12 h when the bilirubin concentration was already 2 mg/dl below the exchange curve defmed by the protocol. The time available for HDivGG to act was probably too short because exchange transfusion was begun 2 h after administration of HDivGG. These preliminary data indicate that the frequency of exchange transfusion can be significantly reduced by combining conventional phototherapy with HDivGG. However, HDivGG is only effective if given early after a positive direct Coombs’ test result is obtained. HDivGG will not influence the elimination of bilirubin, but probably prevents its production by interaction with the reticuloendothelial system Fc receptors. A similar process may take place in patients with immune thrombocytopenia who are also treated with HDivGG.3,4 Since rhesus antibodies do not fix complement, antibody-coated red blood cells are probably eliminated via antibody dependent cellular cytotoxicity. The optimum dose of HDivGG, the number of infusions, and the best preparation remain to be determined. soon as
mild to moderate reversible airways obstruction. Exacerbations in the salmeterol patients were grouped according to the 3-monthly visit structure (although during the first 3 months visits also took place at 2, 4, and 8 weeks). The frequency of patients having 0, 1, 2, 3, or 4 exacerbations during each 3 month period were tabulated and the time in days for the first exacerbation to occur was analysed with an actuarial life-table method (table, figure). The total number of patients decreased during the study since not all completed 12 months. Patients who withdrew as a result of asthma exacerbation are included at the relevant time points. Those withdrawn for reasons other than asthma exacerbation are included until the time of the withdrawal. If long-term treatment with salmeterol leads to a deterioration in asthma and its control, we would expect to see an increase in the frequency of exacerbations during the study and an increase in the change, between time points, in the cumulative percentage of patients having their first exacerbation. The frequency of exacerbations in patients taking salmeterol was clearly higher in the first 3 month period but this almost certainly reflects the frequency of study visits during that time. The number of patients reporting several exacerbations in a 3 month period, during the last 9 months of the study, remained constant. The rate at which first exacerbations occurred did not increase during the trial, with changes in the cumulative percentage of patients with an exacerbation of 66%, 81%, and 7-8% between months 3 and 6,6 and 9, and 9 and 12, respectively. Improvements in lung function, as monitored during the first 3 months by increase in morning and evening peak expiratory flow rates, reduction in diurnal variation, and reduction in noctural symptoms, were maintained throughout the 12 month treatment
period. This study, of over 350 patients, is therefore at variance with Sears and colleagues’ suggestion. Similar analyses are under way for other studies. M. M.
JENKINS
C. J. HILTON J. C. DE KOCK J. B. D. PALMER
Glaxo Group Research Ltd, Greenford UB6 0HE, UK; and Glaxo Research Institute
German Rhesus Alloimmunisation Department of Paediatrics, University of Dusseldorf, D-4000 Dusseldorf, Germany
Study Group,
JOCHEN RUBO VOLKER WAHN
1 Rubo J, Wahn V. Versuch einer hochdosierten Gammaglobulm-therapie bei drei Kindern mit Hyperbilirubinamie bei Rhesusin-kompatibilitat Monatsschr Kinderheilkd 1990; 138: 216-20 2. Polacek K. Das universale Diagram zur Behandlung der Hyperbilirubinamie der Neugeborenen. Padiatr Prax 1984; 29: 1-3. 3. Derycke M, Dreyfus M, Robert JC, Tschernia G. Intravenous immunoglobulin for neonatal isoimmune thrombocytopenia. Arch Dis Child 1985; 60: 667-69. 4. Massey G, McWilliams N, Mueller D, Napolitano A, Maurer H. Intravenous immunoglobulin in treatment of neonatal isoimmune thrombocytopenia J Pediatr 1987; 111: 133-35
Warfarin
antagonism by avocado
SIR,-Warfarin antagonises vitamin-K-dependent coagulation factors, and resistance to its hypoprothrombinaemic effect caused by vitamin-K-rich vegetables has been reported.1-3 We present the warfarin-antagonising effect of avocado, which is low in vitamin K. A 15-year-old girl with antiphospholipid syndrome was being treated with warfarin for
1. Sears MR, Taylor DR, Print CG, et al. Regular inhaled bronchial asthma. Lancet 1990; 336: 1391-96.
beta-agonist
treatment m
High-dose intravenous gammaglobulin rhesus-haemolytic disease SIR,-We have completed
a
multicentre controlled trial
in to test
previously reported hypothesis1 that high-dose intravenous gammaglobulin (HDivGG) can reduce the frequency of exchange transfusions in newborn infants with Rhesus-haemolytic disease. After both ethical committee approval of our protocol and informed consent by parents, 34 children with a positive direct Coombs’test were randomly assigned to receive either conventional phototherapy alone or phototherapy with intravenous HDivGG (’Polyglobin N’, Cutter, Cologne, Germany) 500 mg/kg over 2 h, as our
a parieto-occipital brain infarct. She was adequately anticoagulated (international normalised ratio [INR] 2-5) for the first 6 weeks. Thereafter, while she was on the same dose of warfarin, the INR fell to 1 ’7. No other medications and no intercurrent illness were documented. At the time the patient was eating at least 100 g avocado every day. Once avocado was
eliminated from her diet, the INR returned to 2-5. 3 months later, despite advice, she started to eat avocado again and the INR fell to 17. A return to an avocado-free diet resulted in effective
anticoagulation once more. A 30-year-old woman in the 22nd gestational week of her sixth pregnancy was treated with heparin followed by warfarin because of pulmonary embolism. She was well anticoagulated, maintaining an average INR of 2-7. 2 months later she consumed 200 g avocado on two consecutive evenings, and her INR fell to 1-6. Elimination of
avodaco from her diet restored adequate anticoagulation. Avocado is low in vitamin K at 8 u.g per 100 g,4 compared
with
915
broccoli (200), beetroot (650), lettuce (129), and cabbage (125 f!gper 100 g),s but it is high in lipids (17-5%). Oils extracted from intact avocado cause changes in liver metabolism of growing ratsIn the two patients reported here avocado intake interfered with warfarin therapy and, though the precise mechanism is obscure, it may be that avocado affects microsomal liver enzymes, leading to increased degradation of warfarin, rather as barbiturates8 and rifampicin9 do. Avocado may also interfere with intestinal warfarin absorption, as cholestyramine does." Avocado intake should be thought of as a possible cause of reduction of warfarin effect in patients previously
adequately anticoagulated. Division of Haematology, Beilinson Medical Centre,
DORIT BLICKSTEIN MATI SHAKLAI AIDA INBAL
Petah Tiqva, 49100, Israel, and Tel Aviv University, Sackler Faculty of Medicine
1. Kempin SJ. Warfarin resistance caused by broccoli. N Engl JMed 1983; 308: 1229. 2 Karlson B. Leijd B, Hellstrom K. On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment. Acta Med Scand 1986; 220: 347-50. 3 Oren B, Shvartzman P. Unsuspected source of vitamin K in patients treated with anticoagulants: a case report. Family Practice 1989; 6: 151-52. 4. Souci SW, Fachmann W, Kraut H. Food composition and nutrition tables 1986/87, 3rd ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1986: 830. 5. Olson RE. Vit K. In: Goodhart RS, Shils ME, eds. Modem nutrition in health and disease, 6th ed. Philadelphia: Lea & Febiger, 1980: 170-180. 6. Guggenheim YK Human nutrition: physiology, public health, pathology. 4th ed. Jerusalem: Magnes Press, Hebrew University, 1981: table 1, p 6-7 (appendix). 7. Werman MJ, Mokady S, Neeman I, Auslaender L, Zeidler A. The effect of avocado oils on some liver characteristics in growing rats. Food Chem Toxicol 1989; 27: 279-82. 8 McDonald MG, Robinson DS, Sylvester D, Jaffee JJ. The effects of phenobarbital, chloral betaine, and glutethimide administration on warfarin plasma levels and hypoprothrombinemic responses in man. Clin Pharmacol Ther 1969; 10: 80. 9. O’Reilly RA Interaction of chronic daily warfarin therapy and rifampin Ann Intern Med 1975; 83: 506. 10. Robinson D, Benjamin D, McCormick J. Interaction of warfarin and non-systemic
gastrointestinal drugs. Clin Pharmacol Ther 1971; 12: 491.
Muscular disorders associated with
cyclosporin SIR,-It has lately been reported that cyclosporin (’Sandimmum’) may affect skeletal muscle.1,2 The Drug Monitoring Centre of Sandoz Pharma is aware of 29 cases of skeletal muscle disorder in association with this drug (up to Dec 31,1990). These were published single case-reports, spontaneous reports to the Centre, or observations during a post-marketing surveillance study of cyclosporin in bone marrow and organ transplant recipientReports of isolated cramps, a frequent side-effect, are not included. 5 spontaneously reported cases were too poorly documented to be evaluated and have not been included. These cases suggest two patterns of cyclosporin-associated muscular disorder. The first is myopathy without evidence of rhabdomyolysis developing in transplant patients. These 6 patients were receiving cyclosporin at conventional doses when myalgia and muscular weakness developed 5-25 months after the start of therapy (table). Concomitant medications have not been reported to cause this type of effect. Electromyograms were normal or showed changes compatible with myopathy or mild sensory motor neuropathy. Biopsy, when done, revealed toxic or non-specific myopathy; muscle enzymes were normal. These changes appear to be dose-dependent since clincial and, sometimes, pathological signs
seemed to abate with dose reduction or upon withdrawal of the drug. Cases 1-31 and 42 have been published; the other 2 were spontaneous reports. In the post-marketing surveillance, 5 cases of muscular disorder were reported which showed a similar pattern; they were observed among the 3017 patients followed up for a year, yielding an incidence rate of 0-17%. It is not possible to assess a causal relation between drug and event in post-marketing surveillance. The second pattern consists of rhabdomyolysis. This type of muscular disorder seems to result primarily from interactions with other drugs. Rhabdomyolysis was described in 7 patients treated concomitantly with cyclosporin and lovastatin. 4-6 The pathophysiology of this interaction has not been established, but cyclosporin may interfere with the metabolism of lovastatin. Rhabdomyolysis may also result from concomitant intake of cyclosporin and colchicine, which is known to cause such a side-effectA case suggestive of such an interaction has been published,8 and Sandoz has received a well-documented spontaneous report of a further case of possible interaction between cyclosporin and colchicine. However, rhabdomyolysis caused by cyclosporin alone cannot be excluded.9 An additional case of rhabdomyolysis has been reported during post-marketing surveillance, giving an incidence of less than 0-05%. Rhabdomyolysis may occur in association with grand mal seizures that can develop in cyclosporin-treated patients; this has been reported in one case.1o Clinically relevant muscular disorders associated with cyclosporin are rare. Most have been mild and have abated with dose reduction. However, the possibility of myopathy associated with the drug should be considered if muscle pain and/or weakness develop during cyclosporin treatment, especially if these symptoms occur after 6 months of therapy. Myopathic symptoms can be expected to improve upon dose reduction. If not, withdrawal of the drug has to be considered-but before such action a risk-benefit evaluation should be made. Concomitant use of cyclosporin and lovastatin or colchicine should be carefully judged, and the treatment changed if signs and symptoms of myolysis develop. Drug Monitoring Centre,
F. ARELLANO P. KRUPP
Sandoz Pharma Ltd, 4002 Basel, Switzerland
Goy JJ, Stauffer SC, Deruaz JP, et al. Myopathy as a possible side-effect of cyclosporin. Lancet 1989; i: 1446-47. 2. Fernandez-Sola J, Campistol J, Casademont J, Grau JM, Urbano-Marquez A. Reversible cyclosporin myopathy. Lancet 1990; 335: 362-63. 3. Cockburn I, Götz E, Gulich A, Krupp A. An interim analysis of the on-going long-term safety study of cyclosporin in renal transplantation. Transplant Proc 1988; suppl 3: 519-29. 4. Norman D, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal failure in a heart transplant recipient receiving lovastatin. N Engl J Med 1988; 318: 46-47. 5. East C, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in patient receiving lovastatin after cardiac transplantation. N Engl J Med 1988; 318: 47-48. 6. Corpier CL, Jones PH, Suki WN, et al. Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients. JAMA 1988; 1.
260: 239-41.
Rieger EH, Halasz NA, Wahlstrom HE. Colchicine neuromyopathy after renal transplantation. Transplantation 1990; 49: 1196-98 8. Noppen M, Velkeniers B, Dierckx R, et al. Cyclosporin and myopathy. Ann Intern Med 1987; 107: 945-46. 9. Grezard O, Lebranchu Y, Birmele B, Sharobeem R, Nivet H, Bagros PH. Cyclosporin-induced muscular toxicity. Lancet 1990; 335: 177. 10. Volin L, Jarventie G, Ruut U. Fatal rhabdomyolysis as a complication of bone marrow transplantation. Bone Marrow Transplant 1990; 6: 59-60. 7.
PATIENTS REPORTED WITH MYOPATHY I
’Heart (nos 1-3, and ND not done
5)
or
kidney (4 and 6) transplant recipients.
ATG =antithymocyte globulin.
I
I
