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Rhabdomyolysis due to interaction of simvastatin with mibefradil
RESEARCH LETTERS
EEGs of patients A: Depressed ST and inverted T caused by sodium stibogluconate in patient who developed cardiac arrest during amphotericin administration and could not be revived. B: Raised ST segment and inverted T (V2) caused by sodium stibogluconate in another patient who could not be revived from cardiac arrest during amphotericin administration.
schedule of treatment of group A and treat the remaining 18 patients in group A after a rest period of 10 days. The difference in the results of treatment of two groups A and B even at that stage was significant (p<0·05) (2 with Yate’s correction). The remaining 18 patients in group A and the patients of group B and C did not develop any cardiac problems. Arrhythmias could not have been due to myocarditis2 as it occurred on the first day of treatment, nor due to idiosyncracy,3 as there was no reaction during administration of the test dose nor due to electrolyte imbalance4,5 as electrolytes were corrected. We conclude that amphotericin treatment should be started only after the rest period of at least 10 days if a patient had electrocardiographic evidence of myocardial damage to avoid ventricular arrhythmia and cardiac arrest. 1
2
3 4
5
Thakur CP, Sinha GP, Pandey AK. Comparison of regimens of amphotericin B deoxycholate in kala-azar. Ind J Med Res 1996; 103: 29–263. Jha TK, Giri YN, Singh TK, Jha S. Use of amphotericin B in drug resistant cases of visceral leishmaniasis in North Bihar, India. Am J Trop Med Hyg 1995; 52: 536–38. Utz JP. Amphotericin B toxicity: general side effect. Ann Intern Med 1994; 61: 335–40. Thakur CP. Correction of serum electrolytes imbalance prevents cardiac arrhythmia during amphotericin B administration. Natl Med J Ind 1995; 8: 13–14. De Monaco HJ, Govern B. Transient asystole associated with amphotericin B infusion. Drug Intell Pharm 1983; 17: 547–48.
“Uma Complex”, Patna 800 001, Bihar, India (C Thakur)
Rhabdomyolysis due to interaction of simvastatin with mibefradil
suppressed deep-tendon reflexes and a substantial functional disability of the proximal lower limbs which prevented her from standing upright. Her blood pressure was 150/80 mm Hg and her body temperature was normal (36·6ºC). The laboratory workup on admission showed striking rhabdomyolysis (alanine aminotransferase 1179 U/L, aspartate aminotransferase 998 UL, phosphorus 2·45 mmol/L, creatine kinase 50125 U/L) with hyperkalaemia (potassium 7·2 mmol/L), myoglobinuria, and secondary severe renal failure (serum creatinine 814 mol/L, urea 46·1 mmol/L). Concentrations of sodium (137 mmol/L), calcium (2·27 mmol/L), and ␥-glutamyl transpeptidase (21 U/L) were normal and blood cultures and viral serology for HIV1, hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis C virus were negative. Simvastatin and -hydroxy-simvastatin acid concentrations in a serum sample drawn 24 h after the last dose were determined by high-performance liquid chromatography and mass spectrometry (HPLC-MS) and were 4·95 ng/mL and 1·02 ng/mL, respectively. Since there was no history of traumatic events, infectious diseases, excessive physical effort, or alcohol consumption, simvastatin-induced rhabdomyolysis was assumed to be the cause of her symptoms and all medication was stopped. During the next 3 weeks of her hospital stay the patient underwent seven sessions of haemodialysis and received intensive physiotherapy. Within 10 days, muscle pain disappeared and she regained the functional ability of her legs. Concentrations of creatine kinase and transaminases gradually returned to normal, diuresis occurred, and she was finally discharged after 4 weeks in good physical and mental condition with slightly impaired renal function (creatinine 207 mol/L). Simvastatin-induced rhabdomyolysis is a well known dose-dependent adverse effect which usually occurs 4–6 weeks after start of therapy, or after increases in the maintenance dose, that may be precipitated by coadministration of drugs known to interact with the simvastatin—metabolising cytochrome P450 isozyme CYP3A4.1,2 Mibefradil may have led to rhabdomyolysis in our patient. Because lovastatin and simvastatin, but not fluvastatin (mainly metabolised by CYP2C) and pravastatin (not metabolised by cytochromes and mostly excreted unchanged by the kidney), are substrates of this pathway, it was assumed that not all compounds would have such an interaction. To confirm this hypothesis we did in-vitro interaction experiments in human liver microsomes to study the effect of mibefradil and its main plasma metabolite
Diana Schmassmann-Suhijar, Roy Bullingham, Rodolfo Gasser, Jörg Schmutz, Walter E Haefeli
An 83-year old woman was admitted to hospital with progressive immobilising myopathy that had started 1 week before admission and was associated with low-back pain and oliguria. She gave a history of hypercholesterolaemia, which had been treated with simvastatin (20 mg once daily) for 1 year, and hypertension, which was initially treated with amlodipine (5 mg four times daily for 10 months), and later combined with torasemide (5 mg once daily for 6 months) because of ankle oedema. Since her blood pressure remained high (180/90 mm Hg), amlodipine and torasemide were replaced by the calcium-channel antagonist mibefradil (50 mg once daily) 4 weeks before admission, and the dose of simvastatin remained unchanged. 3 weeks after the introduction of mibefradil the woman experienced muscle pain and gait disturbances unresponsive to acemetacin and diclofenac. Eventually she required admission to hospital. On admission, she was oliguric (200–300 mL/day) and had a diffuse myopathy with
THE LANCET • Vol 351 • June 27, 1998
Effect of mibefradil and Ro 40-5966 on oxidative metabolism of simvastatin and lovastatin in human liver microsomes Data are expressed as mean (SE) of duplicate determinations.
1929
RESEARCH LETTERS
Ro 40-5966 on the metabolism of simvastatin and other commonly prescribed hydroxymethylglutaryl (HMG)-CoA reductase inhibitors. Human liver microsomes pooled from ten livers were prepared3,4 and incubated with simvastatin (10 mol), lovastatin (5 mol), pravastatin (10 mol), or fluvastatin (10 mol) with concentrations of mibefradil (0–2 mol) or its metabolite Ro-5966 (0–20 mol). Statin metabolite formation was assessed.5 Simvastatin and lovastatin metabolism were inhibited by mibefradil and Ro 40-5966 at low concentrations (figure), whereas the metabolism of pravastatin was unaffected. The respective IC50 values were with simvastatin 3 mol (SE 1) and 8·0 mol (2·5), with lovastatin 2·0 mol (0·2) and 11 mol (1), and with pravastatin >1000 and >1000. Fluvastatin showed a small effect. Preliminary results of a clinical interaction study between mibefradil and simvastatin revealed that 24 h after coadministration, simvastatin concentrations are similar to the values measured in our patient whereas they are expected to be below the detection limit of 1 ng/ml unless there is concurrent administration of an inhibitor (data on file). Until March 25, 1998, 19 cases of simvastatin-associated rhabdomyolysis in patients receiving mibefradil have been reported to F Hoffmann-La Roche. Of these 19 patients, nine also received cyclosporin which is known to increase circulating statin concentrations. In addition, one case of lovastatin-associated rhabdomyolysis in a patient receiving mibefradil has been reported. The use of simvastatin should be avoided or no more than 5 mg used with mibefradil. Lovastatin had similar metabolism and inhibition in vitro, and, therefore, coadministration of lovastatin with mibefradil should be avoided, or no more than 10 mg given. No case of rhabdomyolysis has been reported in association with atorvastatin, cerivastatin, fluvastatin, and pravastatin with mibefradil. 1
2
3
4
5
an attractive hypothesis involves gut-derived endotoxin translocation with subsequent Kuppfer-cell activation, PMN recruitment and activation, a cytokine cascade, and liver injury. The role of apoptosis in alcoholic liver diseases is poorly understood. However, hepatocyte apoptosis occurs in the normal liver and is involved in liver damage associated with hepatitis B and C, as shown by increased expression of Fas and Fas-ligand in liver tissue.1,2 In particular, in hepatitis B hepatocyte apoptosis is induced by Fas-ligand expressed on T lymphocytes, as in alcoholic cirrhosis, death of Fas and Fas-ligand-bearing hepatocytes might occur by paracrine or autocrine mechanisms.1 Fas and Fas-ligand can occur as membrane-bound and soluble proteins. Soluble Fas is generated by alternative mRNA splicing and seems to protect cells from apoptosis, whereas soluble Fas-ligand is generated by proteolytic cleavage of the membrane-bound form, and may be proapoptotic. To date, high concentrations of soluble Fas and soluble Fas-ligand have been described in lymphocytic disorders and viral hepatitis with cirrhosis.3,4 We measured the soluble forms of these two molecules in the plasma of patients with alcoholic liver disease. We studied 23 patients with severe (Maddrey score >32) biopsyproven AAH (without sepsis, renal failure, haemorrhage, or previous steroid therapy) and 18 patients with severe alcoholic cirrhosis. We included ten patients with chronic hepatitis C without cirrhosis and 20 healthy volunteers as controls. We obtained informed consent from all participants. We collected 5 mL blood in sterile vacuum tubes containing edetic acid and immediately centrifuged at
Jacobson RH, Wang P, Glueck CJ, Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. JAMA 1997; 277: 296. Horn M. Coadministration of itraconazole with hyperlipidemic agents may induce rhabdomyolysis in healthy individuals. Arch Dermatol 1996; 132: 1254. Van der Hoeven TA, Coon M. Preparation and properties of partial purified cytochrome P-450 and reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase from rabbit liver microsomes. J Biol Chem 1974; 249: 6302–10. Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996; 50: 209–15. Wang RW, Kari PH, Lu AY, Thomas PE, Guengerich FP, Vyas KP. Biotransformation of lovastatin IV. Identification of cytochrome P450 3A proteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes. Arch Biochem Biophys 1991; 290: 355–61.
Division of Clinical Pharmacology, University Hospital, Petersgraben 4, CH-4031, Basel, Switzerland (W E Haefeli); Department of Internal Medicine, University Hospital, Basel; CS Associates, Palo Alto, California, USA; F Hoffman-La Roche, Basel; General Practice, Basel
Raised plasma soluble Fas and Fasligand in alcoholic liver disease Julien Taïeb, Philippe Mathurin, Thierry Poynard, Marie Anne Gougerot-Pocidalo, Sylvie Chollet-Martin
Severe acute alcoholic hepatitis (AAH) is characterised by polymorphonuclear neutrophil (PMN) infiltration around degenerated hepatocytes on liver biopsy. The pathogenesis of AAH and alcoholic cirrhosis is not fully understood, but
1930
Soluble Fas and Fas-ligand plasma concentrations *p<0·001 compared with hepatitis C without cirrhosis and with healthy controls; †p<0·05 compared with alcoholic cirrhosis.
THE LANCET • Vol 351 • June 27, 1998
EEGs of patients A: Depressed ST and inverted T caused by sodium stibogluconate in patient who developed cardiac arrest during amphotericin administration and could not be revived. B: Raised ST segment and inverted T (V2) caused by sodium stibogluconate in another patient who could not be revived from cardiac arrest during amphotericin administration.
schedule of treatment of group A and treat the remaining 18 patients in group A after a rest period of 10 days. The difference in the results of treatment of two groups A and B even at that stage was significant (p<0·05) (2 with Yate’s correction). The remaining 18 patients in group A and the patients of group B and C did not develop any cardiac problems. Arrhythmias could not have been due to myocarditis2 as it occurred on the first day of treatment, nor due to idiosyncracy,3 as there was no reaction during administration of the test dose nor due to electrolyte imbalance4,5 as electrolytes were corrected. We conclude that amphotericin treatment should be started only after the rest period of at least 10 days if a patient had electrocardiographic evidence of myocardial damage to avoid ventricular arrhythmia and cardiac arrest. 1
2
3 4
5
Thakur CP, Sinha GP, Pandey AK. Comparison of regimens of amphotericin B deoxycholate in kala-azar. Ind J Med Res 1996; 103: 29–263. Jha TK, Giri YN, Singh TK, Jha S. Use of amphotericin B in drug resistant cases of visceral leishmaniasis in North Bihar, India. Am J Trop Med Hyg 1995; 52: 536–38. Utz JP. Amphotericin B toxicity: general side effect. Ann Intern Med 1994; 61: 335–40. Thakur CP. Correction of serum electrolytes imbalance prevents cardiac arrhythmia during amphotericin B administration. Natl Med J Ind 1995; 8: 13–14. De Monaco HJ, Govern B. Transient asystole associated with amphotericin B infusion. Drug Intell Pharm 1983; 17: 547–48.
“Uma Complex”, Patna 800 001, Bihar, India (C Thakur)
Rhabdomyolysis due to interaction of simvastatin with mibefradil
suppressed deep-tendon reflexes and a substantial functional disability of the proximal lower limbs which prevented her from standing upright. Her blood pressure was 150/80 mm Hg and her body temperature was normal (36·6ºC). The laboratory workup on admission showed striking rhabdomyolysis (alanine aminotransferase 1179 U/L, aspartate aminotransferase 998 UL, phosphorus 2·45 mmol/L, creatine kinase 50125 U/L) with hyperkalaemia (potassium 7·2 mmol/L), myoglobinuria, and secondary severe renal failure (serum creatinine 814 mol/L, urea 46·1 mmol/L). Concentrations of sodium (137 mmol/L), calcium (2·27 mmol/L), and ␥-glutamyl transpeptidase (21 U/L) were normal and blood cultures and viral serology for HIV1, hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis C virus were negative. Simvastatin and -hydroxy-simvastatin acid concentrations in a serum sample drawn 24 h after the last dose were determined by high-performance liquid chromatography and mass spectrometry (HPLC-MS) and were 4·95 ng/mL and 1·02 ng/mL, respectively. Since there was no history of traumatic events, infectious diseases, excessive physical effort, or alcohol consumption, simvastatin-induced rhabdomyolysis was assumed to be the cause of her symptoms and all medication was stopped. During the next 3 weeks of her hospital stay the patient underwent seven sessions of haemodialysis and received intensive physiotherapy. Within 10 days, muscle pain disappeared and she regained the functional ability of her legs. Concentrations of creatine kinase and transaminases gradually returned to normal, diuresis occurred, and she was finally discharged after 4 weeks in good physical and mental condition with slightly impaired renal function (creatinine 207 mol/L). Simvastatin-induced rhabdomyolysis is a well known dose-dependent adverse effect which usually occurs 4–6 weeks after start of therapy, or after increases in the maintenance dose, that may be precipitated by coadministration of drugs known to interact with the simvastatin—metabolising cytochrome P450 isozyme CYP3A4.1,2 Mibefradil may have led to rhabdomyolysis in our patient. Because lovastatin and simvastatin, but not fluvastatin (mainly metabolised by CYP2C) and pravastatin (not metabolised by cytochromes and mostly excreted unchanged by the kidney), are substrates of this pathway, it was assumed that not all compounds would have such an interaction. To confirm this hypothesis we did in-vitro interaction experiments in human liver microsomes to study the effect of mibefradil and its main plasma metabolite
Diana Schmassmann-Suhijar, Roy Bullingham, Rodolfo Gasser, Jörg Schmutz, Walter E Haefeli
An 83-year old woman was admitted to hospital with progressive immobilising myopathy that had started 1 week before admission and was associated with low-back pain and oliguria. She gave a history of hypercholesterolaemia, which had been treated with simvastatin (20 mg once daily) for 1 year, and hypertension, which was initially treated with amlodipine (5 mg four times daily for 10 months), and later combined with torasemide (5 mg once daily for 6 months) because of ankle oedema. Since her blood pressure remained high (180/90 mm Hg), amlodipine and torasemide were replaced by the calcium-channel antagonist mibefradil (50 mg once daily) 4 weeks before admission, and the dose of simvastatin remained unchanged. 3 weeks after the introduction of mibefradil the woman experienced muscle pain and gait disturbances unresponsive to acemetacin and diclofenac. Eventually she required admission to hospital. On admission, she was oliguric (200–300 mL/day) and had a diffuse myopathy with
THE LANCET • Vol 351 • June 27, 1998
Effect of mibefradil and Ro 40-5966 on oxidative metabolism of simvastatin and lovastatin in human liver microsomes Data are expressed as mean (SE) of duplicate determinations.
1929
RESEARCH LETTERS
Ro 40-5966 on the metabolism of simvastatin and other commonly prescribed hydroxymethylglutaryl (HMG)-CoA reductase inhibitors. Human liver microsomes pooled from ten livers were prepared3,4 and incubated with simvastatin (10 mol), lovastatin (5 mol), pravastatin (10 mol), or fluvastatin (10 mol) with concentrations of mibefradil (0–2 mol) or its metabolite Ro-5966 (0–20 mol). Statin metabolite formation was assessed.5 Simvastatin and lovastatin metabolism were inhibited by mibefradil and Ro 40-5966 at low concentrations (figure), whereas the metabolism of pravastatin was unaffected. The respective IC50 values were with simvastatin 3 mol (SE 1) and 8·0 mol (2·5), with lovastatin 2·0 mol (0·2) and 11 mol (1), and with pravastatin >1000 and >1000. Fluvastatin showed a small effect. Preliminary results of a clinical interaction study between mibefradil and simvastatin revealed that 24 h after coadministration, simvastatin concentrations are similar to the values measured in our patient whereas they are expected to be below the detection limit of 1 ng/ml unless there is concurrent administration of an inhibitor (data on file). Until March 25, 1998, 19 cases of simvastatin-associated rhabdomyolysis in patients receiving mibefradil have been reported to F Hoffmann-La Roche. Of these 19 patients, nine also received cyclosporin which is known to increase circulating statin concentrations. In addition, one case of lovastatin-associated rhabdomyolysis in a patient receiving mibefradil has been reported. The use of simvastatin should be avoided or no more than 5 mg used with mibefradil. Lovastatin had similar metabolism and inhibition in vitro, and, therefore, coadministration of lovastatin with mibefradil should be avoided, or no more than 10 mg given. No case of rhabdomyolysis has been reported in association with atorvastatin, cerivastatin, fluvastatin, and pravastatin with mibefradil. 1
2
3
4
5
an attractive hypothesis involves gut-derived endotoxin translocation with subsequent Kuppfer-cell activation, PMN recruitment and activation, a cytokine cascade, and liver injury. The role of apoptosis in alcoholic liver diseases is poorly understood. However, hepatocyte apoptosis occurs in the normal liver and is involved in liver damage associated with hepatitis B and C, as shown by increased expression of Fas and Fas-ligand in liver tissue.1,2 In particular, in hepatitis B hepatocyte apoptosis is induced by Fas-ligand expressed on T lymphocytes, as in alcoholic cirrhosis, death of Fas and Fas-ligand-bearing hepatocytes might occur by paracrine or autocrine mechanisms.1 Fas and Fas-ligand can occur as membrane-bound and soluble proteins. Soluble Fas is generated by alternative mRNA splicing and seems to protect cells from apoptosis, whereas soluble Fas-ligand is generated by proteolytic cleavage of the membrane-bound form, and may be proapoptotic. To date, high concentrations of soluble Fas and soluble Fas-ligand have been described in lymphocytic disorders and viral hepatitis with cirrhosis.3,4 We measured the soluble forms of these two molecules in the plasma of patients with alcoholic liver disease. We studied 23 patients with severe (Maddrey score >32) biopsyproven AAH (without sepsis, renal failure, haemorrhage, or previous steroid therapy) and 18 patients with severe alcoholic cirrhosis. We included ten patients with chronic hepatitis C without cirrhosis and 20 healthy volunteers as controls. We obtained informed consent from all participants. We collected 5 mL blood in sterile vacuum tubes containing edetic acid and immediately centrifuged at
Jacobson RH, Wang P, Glueck CJ, Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. JAMA 1997; 277: 296. Horn M. Coadministration of itraconazole with hyperlipidemic agents may induce rhabdomyolysis in healthy individuals. Arch Dermatol 1996; 132: 1254. Van der Hoeven TA, Coon M. Preparation and properties of partial purified cytochrome P-450 and reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase from rabbit liver microsomes. J Biol Chem 1974; 249: 6302–10. Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996; 50: 209–15. Wang RW, Kari PH, Lu AY, Thomas PE, Guengerich FP, Vyas KP. Biotransformation of lovastatin IV. Identification of cytochrome P450 3A proteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes. Arch Biochem Biophys 1991; 290: 355–61.
Division of Clinical Pharmacology, University Hospital, Petersgraben 4, CH-4031, Basel, Switzerland (W E Haefeli); Department of Internal Medicine, University Hospital, Basel; CS Associates, Palo Alto, California, USA; F Hoffman-La Roche, Basel; General Practice, Basel
Raised plasma soluble Fas and Fasligand in alcoholic liver disease Julien Taïeb, Philippe Mathurin, Thierry Poynard, Marie Anne Gougerot-Pocidalo, Sylvie Chollet-Martin
Severe acute alcoholic hepatitis (AAH) is characterised by polymorphonuclear neutrophil (PMN) infiltration around degenerated hepatocytes on liver biopsy. The pathogenesis of AAH and alcoholic cirrhosis is not fully understood, but
1930
Soluble Fas and Fas-ligand plasma concentrations *p<0·001 compared with hepatitis C without cirrhosis and with healthy controls; †p<0·05 compared with alcoholic cirrhosis.
THE LANCET • Vol 351 • June 27, 1998