Original Paper Eur Neurol 1992;32:293-296
Antoine Chuerallaha Umberto De Girolami'dX Roy Freemanh Micheline Federmana Departments of
Pathology,
Lovastatin/ Gemfibrozil Myopathy: A Clinical, Histochemical, and Ultrastructural Study
Neurology and Internal Medicine, New England Deaconess Hospital, and Department of Pathology. Brigham and Women’s/Children’s Hospital, Boston. Mass.. USA
K e y w o rd s
A b stra ct
Toxic myopathy Lovastatin Muscle pathology
Lovastatin has been used with increasing frequency over the past few years to reduce serum cholesterol. The onset of muscle weakness, one of the most seri ous side effects of long-term treatment with the drug, constitutes a contraindi cation to the continuation of therapy and commonly occurs in patients who are also receiving gemfibrozil or cyclosporine. We report the clinical and pathologic findings in a patient treated for hypercholesterolemia with lovasta tin and gemfibrozil who developed a rapidly progressive necrotizing myopa thy. A 57-year-old woman with hyperlipidemia, treated with lovastatin and gemfibrozil, was admitted to the hospital forevaluation of muscular weakness in her legs and neck. Neurologic examination revealed severe proximal muscle weakness involving both upper and lower extremities as well as proximal mus cle tenderness and areflexia in the lower limbs. A biopsy of the quadriceps muscle showed multiple foci of mononuclear cell infiltration with myophagocytosis and slight variation in the size and shape of muscle fibers. Electron microscopy of the affected fibers showed accumulations of subsarcolemmal autophagic lysosomes. The patient’s condition dramatically improved after discontinuation of lovastatin-gemfibrozil therapy.
Lovastatin-treated patients have been found to run a risk of developing a drug-related myopathy [ 1]. Although infrequent, this complication requires prompt recogni tion and discontinuation of therapy since it could lead to potentially life-threatening renal failure from rhabdomyolysis [1-4]. We report the clinical and pathologic findings in a patient with lovastatin myopathy with light and elec tron microscopic documentation of accompanying
Received: August 27, 1991 Accepted: October 3. 1991
changes in a muscle biopsy. Dramatic improvement of the patient’s clinical condition followed discontinuation of drug therapy.
Case Report Clinical History
A 57-year-old right-handed woman with hyperlipidemia was admitted with a 4-dav history of pain and weakness in her legs and neck. Eight months previously she had begun taking lovastatin
Umberto De Girolami. MD Department of Pathology Brigham and Women's Hospital 75 Francis Street. Boston. MA 02115 (USA)
€> 1992 S. Kargcr AG. Basel 0 0 14-3022/92/0325-0293 $2.75/0
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 7:27:00 AM
Introduction
Pathology>
Biopsy of the right quadriceps was processed for light microscop ic. histochemical and ultrastructural examination as follows: (a) par affin sections - formalin-fixed and stained with HE. Masson’s tri chrome. PTAH: (b) frozen sections - HE, Gomori trichrome. ATPasc (pH 9.4. 4.3. 4.6). NADH. PAS ± diastase, and oil red O. and (c) plastic sections fixed in Karnovsky’s solution - 1-pm sections stained with toluidine blue and then processed for electron microsco py. Light microscopic examination of frozen sections, paraffin and plastic-embedded transverse and longitudinal sections of muscle showed multiple foci of necrosis of muscle fibers throughout the biopsy specimen. The affected fibers had lost the normal staining properties and cross striations (HE. PTAH). They were either sur rounded or invaded by clusters of macrophages or showed no inflam matory cell reaction (fig. 1). Several adjoining muscle fibers had large nuclei, prominent nucleoli and a basophilic cytoplasm (HE), indicat ing regeneration. There was also slight variation in the size and shape
294
Fig. 1. Light micrograph of abnormal muscle showing a cluster of macrophages surrounding and penetrating a neocrotic muscle fiber. Bar= l pm. HE. X 83.
of muscle fibers, with small and rounded orangulatcd fibers. Frozen sections processed with the Gomori trichrome stain, oil red O and PAS ± diastase failed to demonstrate alterations of the sarcoplasmic organelles or abnormal quantities of glycogen or lipid. Enzyme histo chemical reactions showed the normal checkerboard pattern of type I and II fibers. The necrotic fibers could not be typed so that it was not possible to determine if there was preferential involvement of type I or II fibers. Electron microscopic study of the affected fibers dis closed subsarcolentmal autophagic lysosomes (fig. 2). There was no evidence of mitochondrial abnormalities.
D iscu ssio n
Lovastatin is a 3-hydroxy-3-niethylglutaryl coenzyme A reductase inhibitor used for the treatment of hypercho lesterolemia. Since it first became available in the United States in September. 1987, there have been several clini cal studies indicating that the drug may cause a toxic myopathy [1. 4]. The incidence of this complication is estimated by the manufacturer of the drug to be approxi mately 0.5% of all treated patients. It may be as high as 30% in patients who have received organ transplants and have also been treated with cyclosporine and 5% in patients receiving gemfibrozil [5], Patients treated with erythromycin [6] or nicotinic acid [7], and individuals with severe hepatobiliary dysfunction and renal insuffi ciency [1,2] may also be at risk of developing a toxic myopathy when taking lovastatin. The clinical manifesta tions of this toxic myopathy are proximal muscle weak ness involving the lower more than the upper extremities
Chucrallah/De Girolami/Freeman/ Federman
Lovastatin/Gemfibrozil Myopathy
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 7:27:00 AM
(40 mg a day) for her hyperlipidemia. One month prior to admission she had begun therapy with gemfibrozil (1.2 g a day). The patient had a 27-year history of insulin-dependent diabetes mellitus. complicated by chronic renal insufficiency, diabetic retinopathy, and peripheral neuropathy. She had a previous right transmetatarsal amputation and a left great toe amputation as a result of peripheral vascular dis ease. She also had a history of congestive heart failure, gout, renal calculi, high blood pressure and esophagitis. Two weeks prior to admission she had an upper respiratory infection which resolved spontaneously without complication. Her medications on admission were lovastatin (40 mg a day), gemfibrozil (600 mg b.i.d.). cholestyr amine (4 g t.i.d.). isosorbidc dinitrate (40 mgt.i.d.). diltiazem (90 mgq.i.d.), furosemide (20 mgq.i.d.). digoxin (0.125 mg q.d.), metoclopramide (10 mgq.i.d.). captopril (50 mgq.i.d.), clorazepate (7.5 mgq.i.d.) and ranitidine (150 mg b.i.d.). The general physical examination was unremarkable. On neurologic examination she had a right exotropia; her pupils were minimally reactive to light. There was severe proximal weakness which involved the lower limbs more than the upper limbs. The patient was unable to stand and had mus cle tenderness, particularly in the proximal lower extremities. The deep tendon reflexes were depressed in the upper extremities and absent in the lower extremities. There was evidence of a distal sen sory neuropathy to thermal, nociceptive and proprioceptive modali ties. The serum electrolytes were normal: the urea nitrogen (BUN) was 90 mg/dl; the creatinine was 4.6 mg/dl; the sedimentation rate was 142 mm/hr: the creatine kinase (CK) was 11.722 U/l (100% MM): the aspartateaminotransfera.se (AST) was 825 U/l: the alanine amino transferase (ALT) was 177 U/l; the lactic dehydrogenase (LDH) was 1.425 U/l: and the aldolase was 96 U/l. The digoxin level was 1.2 mg/dl, the uric acid 11.5 mg/dl. and the cholesterol 380 mg/dl. The antinuclear antibody and rheumatoid factor were both negative. The precipitating antibody panel was negative. The urine had a specific gravity of 1.015 and pH of 5.0:2+ protein and myoglo bin were present. A muscle biopsy of the right quadriceps was per formed. Lovastatin and gemfibrozil were discontinued. The urine was alkalinized. The muscle enzyme levels declined and renal func tion gradually improved. On discharge. 3 weeks later, the BUN was 33 mg/dl and creatinine 1.9 mg/dl. the CK was 144 U/l. the AST was 17 U/l, the ALT was 37 U/l. and the LDH was 232 U/l. The lower extremity strength had improved and she was able to walk 150 feet without assistance. Oxandrelone was substituted for her prior lipid lowering agents.
Fig. 2. Electron micrograph of abnormal muscle fiber showing focal, subsarcolemmal accumulation of autophagic Ivsosomes. Bar = I pm. X 17.000.
was no evidence of vasculitis. The ultrastructural finding of subsarcolemmal autophagic Ivsosomes is also in keep ing with a toxic myopathy. Five previous case reports of affected individuals on lovastatin who underwent muscle biopsy at varying times after the onset of symptoms also recorded absence or paucity of inflammatory cells amidst variable numbers of necrotic muscle cells and variation in fiber size [3. 11-14], These observations seem to indicate that an immune-mediated pathogenetic mechanism is not likely to be an important cause of the myopathy. Focal muscle fiber necrosis might be caused by a toxic effect from FIGM-CoA reductase inhibitors on endogenous muscle cell membrane synthesis of cholesterol.
295
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 7:27:00 AM
and muscle tenderness. Serum CK levels are usually markedly elevated (>8,00 U/l). Patients often develop rhabdomyolysis which may lead to myoglobinuria and acute renal failure of a variable degree [ 1-4], Elevations of serum AST and ALT levels, as seen in this case, have been reported in 2 other cases of lovastatin myopathy [6.7]. Transient elevations of these serum enzyme levels have also been observed in the absence of myopathy, but ALT levels did not exceed 82 U/l [8]. The clinical manifesta tions and laboratory abnormalities are reversible with dis continuation of lovastatin therapy and clinical relapse has been reported in 1 patinet following reinstitution of treat ment [9], There are a few drugs known to cause an acute necro tizing toxic myopathy [10]. In the patient here described, histopathologic examination of the skeletal msucle 1 week into the course of the illness showed myopathic changes characterized by necrosis of muscle fibers, phagocytosis of destroyed tissue, and muscle fiber regeneration. There
R eferences
296
5 Mevacor (Lovastatin, MSD): United Stales Food and Drug Administration package insert. West Point, Merck. 1988. 6 Ayanian JZ, Fuchs CS, Stone RM: Lovastatin and rhabdomyolysis. Ann Intern Med 1988; 109:682-683.’ 7 Reaven P. Witztum JL: Lovastatin, nicotinic acid and rhabdomyolysis. Ann Intern Med 1988;109:597-598. ’ 8 The lovastatin Study Group 11: Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolemia: A multiccnter study. JAMA 1986:256:2829-2834. 9 Israeli A. Raveh D. Amon R. Eisenberg S. Stein Y: Lovastatin and elevated creatine ki nase: Results of rechallenge. Lancet I989:i: 725.
Chucrallah/De Girolami/Freeman/ Federman
10 Mastaglia FL: Adverse effects of drugs on mus cle. Drugs 1982;24:304-321. 11 East C. Alivizatos PA. Grundy SM. Jones PH. Farmer JA: Rhabdomyolysis in patients receiv ing lovastatin after cardiac transplantation. N Engl J Med 1988:318:47-48. 12 Norman DJ, 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. 13 Goldman JA, Fishman AB, Lee JE: Johnson RJ: The role of cholesterol-lowering agents in drug-induced rhabdomyolysis and polymyosi tis. Arthritis Rheum 1989;32:358-359." 14 London SF. Gross KF. Ringel SP: Cholesterollowering agent myopathy (CLAM). Neurology 1991:41:1159-1160.
Lovastatin/Gcmfibrozil Myopathy
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 7:27:00 AM
1 Tobert JA: Efficacy and long-term adverse ef fect pattern of lovastatin. Am J Cardiol 1988: 62:28J-34J. 2 Corpier CL. Jones PH, Suki WN. L.ederer ED. Quinones MA. Schmidt SW. Young JB: Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients. JAMA 1988:260:239-241. 3 Manoukian AA, Bhagavan NV. Hayashi T, Nestor TA. Rios C, Scottolini AG: Rhabdomyolvsis secondary' to lovastatin therapy. Clin Chem 1990;36:2145-2147. 4 Pierce LR: Wysowski DK. Gross TP: Myopa thy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990:264:71-75.
Antoine Chuerallaha Umberto De Girolami'dX Roy Freemanh Micheline Federmana Departments of
Pathology,
Lovastatin/ Gemfibrozil Myopathy: A Clinical, Histochemical, and Ultrastructural Study
Neurology and Internal Medicine, New England Deaconess Hospital, and Department of Pathology. Brigham and Women’s/Children’s Hospital, Boston. Mass.. USA
K e y w o rd s
A b stra ct
Toxic myopathy Lovastatin Muscle pathology
Lovastatin has been used with increasing frequency over the past few years to reduce serum cholesterol. The onset of muscle weakness, one of the most seri ous side effects of long-term treatment with the drug, constitutes a contraindi cation to the continuation of therapy and commonly occurs in patients who are also receiving gemfibrozil or cyclosporine. We report the clinical and pathologic findings in a patient treated for hypercholesterolemia with lovasta tin and gemfibrozil who developed a rapidly progressive necrotizing myopa thy. A 57-year-old woman with hyperlipidemia, treated with lovastatin and gemfibrozil, was admitted to the hospital forevaluation of muscular weakness in her legs and neck. Neurologic examination revealed severe proximal muscle weakness involving both upper and lower extremities as well as proximal mus cle tenderness and areflexia in the lower limbs. A biopsy of the quadriceps muscle showed multiple foci of mononuclear cell infiltration with myophagocytosis and slight variation in the size and shape of muscle fibers. Electron microscopy of the affected fibers showed accumulations of subsarcolemmal autophagic lysosomes. The patient’s condition dramatically improved after discontinuation of lovastatin-gemfibrozil therapy.
Lovastatin-treated patients have been found to run a risk of developing a drug-related myopathy [ 1]. Although infrequent, this complication requires prompt recogni tion and discontinuation of therapy since it could lead to potentially life-threatening renal failure from rhabdomyolysis [1-4]. We report the clinical and pathologic findings in a patient with lovastatin myopathy with light and elec tron microscopic documentation of accompanying
Received: August 27, 1991 Accepted: October 3. 1991
changes in a muscle biopsy. Dramatic improvement of the patient’s clinical condition followed discontinuation of drug therapy.
Case Report Clinical History
A 57-year-old right-handed woman with hyperlipidemia was admitted with a 4-dav history of pain and weakness in her legs and neck. Eight months previously she had begun taking lovastatin
Umberto De Girolami. MD Department of Pathology Brigham and Women's Hospital 75 Francis Street. Boston. MA 02115 (USA)
€> 1992 S. Kargcr AG. Basel 0 0 14-3022/92/0325-0293 $2.75/0
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 7:27:00 AM
Introduction
Pathology>
Biopsy of the right quadriceps was processed for light microscop ic. histochemical and ultrastructural examination as follows: (a) par affin sections - formalin-fixed and stained with HE. Masson’s tri chrome. PTAH: (b) frozen sections - HE, Gomori trichrome. ATPasc (pH 9.4. 4.3. 4.6). NADH. PAS ± diastase, and oil red O. and (c) plastic sections fixed in Karnovsky’s solution - 1-pm sections stained with toluidine blue and then processed for electron microsco py. Light microscopic examination of frozen sections, paraffin and plastic-embedded transverse and longitudinal sections of muscle showed multiple foci of necrosis of muscle fibers throughout the biopsy specimen. The affected fibers had lost the normal staining properties and cross striations (HE. PTAH). They were either sur rounded or invaded by clusters of macrophages or showed no inflam matory cell reaction (fig. 1). Several adjoining muscle fibers had large nuclei, prominent nucleoli and a basophilic cytoplasm (HE), indicat ing regeneration. There was also slight variation in the size and shape
294
Fig. 1. Light micrograph of abnormal muscle showing a cluster of macrophages surrounding and penetrating a neocrotic muscle fiber. Bar= l pm. HE. X 83.
of muscle fibers, with small and rounded orangulatcd fibers. Frozen sections processed with the Gomori trichrome stain, oil red O and PAS ± diastase failed to demonstrate alterations of the sarcoplasmic organelles or abnormal quantities of glycogen or lipid. Enzyme histo chemical reactions showed the normal checkerboard pattern of type I and II fibers. The necrotic fibers could not be typed so that it was not possible to determine if there was preferential involvement of type I or II fibers. Electron microscopic study of the affected fibers dis closed subsarcolentmal autophagic lysosomes (fig. 2). There was no evidence of mitochondrial abnormalities.
D iscu ssio n
Lovastatin is a 3-hydroxy-3-niethylglutaryl coenzyme A reductase inhibitor used for the treatment of hypercho lesterolemia. Since it first became available in the United States in September. 1987, there have been several clini cal studies indicating that the drug may cause a toxic myopathy [1. 4]. The incidence of this complication is estimated by the manufacturer of the drug to be approxi mately 0.5% of all treated patients. It may be as high as 30% in patients who have received organ transplants and have also been treated with cyclosporine and 5% in patients receiving gemfibrozil [5], Patients treated with erythromycin [6] or nicotinic acid [7], and individuals with severe hepatobiliary dysfunction and renal insuffi ciency [1,2] may also be at risk of developing a toxic myopathy when taking lovastatin. The clinical manifesta tions of this toxic myopathy are proximal muscle weak ness involving the lower more than the upper extremities
Chucrallah/De Girolami/Freeman/ Federman
Lovastatin/Gemfibrozil Myopathy
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 7:27:00 AM
(40 mg a day) for her hyperlipidemia. One month prior to admission she had begun therapy with gemfibrozil (1.2 g a day). The patient had a 27-year history of insulin-dependent diabetes mellitus. complicated by chronic renal insufficiency, diabetic retinopathy, and peripheral neuropathy. She had a previous right transmetatarsal amputation and a left great toe amputation as a result of peripheral vascular dis ease. She also had a history of congestive heart failure, gout, renal calculi, high blood pressure and esophagitis. Two weeks prior to admission she had an upper respiratory infection which resolved spontaneously without complication. Her medications on admission were lovastatin (40 mg a day), gemfibrozil (600 mg b.i.d.). cholestyr amine (4 g t.i.d.). isosorbidc dinitrate (40 mgt.i.d.). diltiazem (90 mgq.i.d.), furosemide (20 mgq.i.d.). digoxin (0.125 mg q.d.), metoclopramide (10 mgq.i.d.). captopril (50 mgq.i.d.), clorazepate (7.5 mgq.i.d.) and ranitidine (150 mg b.i.d.). The general physical examination was unremarkable. On neurologic examination she had a right exotropia; her pupils were minimally reactive to light. There was severe proximal weakness which involved the lower limbs more than the upper limbs. The patient was unable to stand and had mus cle tenderness, particularly in the proximal lower extremities. The deep tendon reflexes were depressed in the upper extremities and absent in the lower extremities. There was evidence of a distal sen sory neuropathy to thermal, nociceptive and proprioceptive modali ties. The serum electrolytes were normal: the urea nitrogen (BUN) was 90 mg/dl; the creatinine was 4.6 mg/dl; the sedimentation rate was 142 mm/hr: the creatine kinase (CK) was 11.722 U/l (100% MM): the aspartateaminotransfera.se (AST) was 825 U/l: the alanine amino transferase (ALT) was 177 U/l; the lactic dehydrogenase (LDH) was 1.425 U/l: and the aldolase was 96 U/l. The digoxin level was 1.2 mg/dl, the uric acid 11.5 mg/dl. and the cholesterol 380 mg/dl. The antinuclear antibody and rheumatoid factor were both negative. The precipitating antibody panel was negative. The urine had a specific gravity of 1.015 and pH of 5.0:2+ protein and myoglo bin were present. A muscle biopsy of the right quadriceps was per formed. Lovastatin and gemfibrozil were discontinued. The urine was alkalinized. The muscle enzyme levels declined and renal func tion gradually improved. On discharge. 3 weeks later, the BUN was 33 mg/dl and creatinine 1.9 mg/dl. the CK was 144 U/l. the AST was 17 U/l, the ALT was 37 U/l. and the LDH was 232 U/l. The lower extremity strength had improved and she was able to walk 150 feet without assistance. Oxandrelone was substituted for her prior lipid lowering agents.
Fig. 2. Electron micrograph of abnormal muscle fiber showing focal, subsarcolemmal accumulation of autophagic Ivsosomes. Bar = I pm. X 17.000.
was no evidence of vasculitis. The ultrastructural finding of subsarcolemmal autophagic Ivsosomes is also in keep ing with a toxic myopathy. Five previous case reports of affected individuals on lovastatin who underwent muscle biopsy at varying times after the onset of symptoms also recorded absence or paucity of inflammatory cells amidst variable numbers of necrotic muscle cells and variation in fiber size [3. 11-14], These observations seem to indicate that an immune-mediated pathogenetic mechanism is not likely to be an important cause of the myopathy. Focal muscle fiber necrosis might be caused by a toxic effect from FIGM-CoA reductase inhibitors on endogenous muscle cell membrane synthesis of cholesterol.
295
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 7:27:00 AM
and muscle tenderness. Serum CK levels are usually markedly elevated (>8,00 U/l). Patients often develop rhabdomyolysis which may lead to myoglobinuria and acute renal failure of a variable degree [ 1-4], Elevations of serum AST and ALT levels, as seen in this case, have been reported in 2 other cases of lovastatin myopathy [6.7]. Transient elevations of these serum enzyme levels have also been observed in the absence of myopathy, but ALT levels did not exceed 82 U/l [8]. The clinical manifesta tions and laboratory abnormalities are reversible with dis continuation of lovastatin therapy and clinical relapse has been reported in 1 patinet following reinstitution of treat ment [9], There are a few drugs known to cause an acute necro tizing toxic myopathy [10]. In the patient here described, histopathologic examination of the skeletal msucle 1 week into the course of the illness showed myopathic changes characterized by necrosis of muscle fibers, phagocytosis of destroyed tissue, and muscle fiber regeneration. There
R eferences
296
5 Mevacor (Lovastatin, MSD): United Stales Food and Drug Administration package insert. West Point, Merck. 1988. 6 Ayanian JZ, Fuchs CS, Stone RM: Lovastatin and rhabdomyolysis. Ann Intern Med 1988; 109:682-683.’ 7 Reaven P. Witztum JL: Lovastatin, nicotinic acid and rhabdomyolysis. Ann Intern Med 1988;109:597-598. ’ 8 The lovastatin Study Group 11: Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolemia: A multiccnter study. JAMA 1986:256:2829-2834. 9 Israeli A. Raveh D. Amon R. Eisenberg S. Stein Y: Lovastatin and elevated creatine ki nase: Results of rechallenge. Lancet I989:i: 725.
Chucrallah/De Girolami/Freeman/ Federman
10 Mastaglia FL: Adverse effects of drugs on mus cle. Drugs 1982;24:304-321. 11 East C. Alivizatos PA. Grundy SM. Jones PH. Farmer JA: Rhabdomyolysis in patients receiv ing lovastatin after cardiac transplantation. N Engl J Med 1988:318:47-48. 12 Norman DJ, 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. 13 Goldman JA, Fishman AB, Lee JE: Johnson RJ: The role of cholesterol-lowering agents in drug-induced rhabdomyolysis and polymyosi tis. Arthritis Rheum 1989;32:358-359." 14 London SF. Gross KF. Ringel SP: Cholesterollowering agent myopathy (CLAM). Neurology 1991:41:1159-1160.
Lovastatin/Gcmfibrozil Myopathy
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 7:27:00 AM
1 Tobert JA: Efficacy and long-term adverse ef fect pattern of lovastatin. Am J Cardiol 1988: 62:28J-34J. 2 Corpier CL. Jones PH, Suki WN. L.ederer ED. Quinones MA. Schmidt SW. Young JB: Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients. JAMA 1988:260:239-241. 3 Manoukian AA, Bhagavan NV. Hayashi T, Nestor TA. Rios C, Scottolini AG: Rhabdomyolvsis secondary' to lovastatin therapy. Clin Chem 1990;36:2145-2147. 4 Pierce LR: Wysowski DK. Gross TP: Myopa thy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990:264:71-75.
