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Nicotinic acid-associated myopathy: A report of three cases
Nicotinic Acid-Associated Myopathy: A Report of Three Cases SCOTT C. LITIN, M.D., CARL F. ANDERSON, M.D. Rochester, Minnesota
urrently, the lay public and most physicians are very concerned about achieving-,lower serum choC lesterol levels. This concern is a result of several studies showing that reducing total cholesterol with drug treatment could decrease the morbidity and mortality of coronary heart disease [1-3]. Since then, reviewers [4] and expert panels [5] have advocated nicotinic acid as the drug of choice for those hypercholesterolemic patients whose condition has not responded to dietary therapy. These recommendations are based on studies demonstrating that nicotinic acid is effective in lowering cholesterol levels [2,3,6,7] with acceptable side effects and cost. The most common adverse effects of nicotinic acid have been flushing, pruritus, gastrointestinal intolerance, skin hyperpigmentation, and occasional hypotension [6-10]. Other more rare adverse effects include acanthosis nigricans, toxic amblyopia, atrial arrhythmias, and panic attacks [6,9-12]. Laboratory abnormalities have also been reported including elevation of plasma glucose, uric acid, aspartate transaminase (AST), alkaline phosphatase, and serum bilirubin [8-10]. Occasionally, jaundice and fulminant hepatitis have been reported secondary to nicotinic acid [13-16]. We report three cases of nicotinic acid-associated myopathy. We are unaware of previous reports of this adverse effect.
CASE REPORTS Patient 1 A 61-year-old white man was noted to have an elevated total cholesterol level of 366 mg/dl. His highdensity lipoprotein (HDL) cholesterol level was 21 mg/dl, and his triglyceride level was 228 mg/dl. He had a family history of coronary artery disease and was a cigarette smoker. Since dietary therapy was not satisfactory in lowering his serum cholesterol, nicotinic acid was prescribed in a dose of 500 mg three times daily. The AST pretreatment level was mildly elevated at 39 U/liter (normal: 12 to 31 U/liter). This was believed to be related to chronic alcohol abuse. Four months later, the patient was reevaluated. He was complaining of severe nocturnal leg aching and cramping. The physical examination revealed mild tenderness of his calf and thigh muscles bilaterally. His total cholesterol level was 285 mg/dl. His triglyceride level was 163 mg/dl. Laboratory values were as follows: AST had risen to 267 U/liter, alanine aminotransferase (ALT) was elevated at 147 U/liter (normal: 10 to 32 U/liter), and creatine kinase was elevated at 1,205 U/liter (normal: 23 to 99 U/liter). Nicotinic acid was immediately discontinued, and From the Departmentof Internal Medicine, MayoGraduateSchoolof Medicine, Rochester,Minnesota.Requestsfor reprints should be addressedto Scott C. Litin, M.D., Area Medicine, Mayo Clinic, 200 First Street, Southwest, Rochester, Minnesota 55905. Manuscript submitted November 1, 1988, and acceptedin revisedform January 16, 1989.
the patient felt better within two or three days. One month later, AST was 43 U/liter (similar to pretreatment levels), and creatine kinase was normal at 28 U/ liter. The serum cholesterol level once again had risen to 364 mg/dl. Another lipid-lowering medication was begun.
Patient 2 A 63-year-old white woman was noted to have hypercholesterolemia during an evaluation for angina pectoris. At that time, her cholesterol level was 343 mg/dl, her HDL cholesterol level was 65 mg/dl, and her triglyceride level was 64 mg/dl. Creatine kinase at that time was 21 U/liter (normal: 18 to 57 U/liter). She had a family history of coronary heart disease. Her angina progressed despite medical therapy, and four months later she had coronary artery bypass surgery. Postoperatively, her cholesterol level was 313 mg/dl. She was treated with nicotinic acid at 500 mg twice daily combined with colestipol 15 g three times daily. This regimen initially lowered her lipid values, but two years later, her cholesterol level had risen to 280 mg/dl with an HDL level of 75 mg/dl and a triglyceride level of 72 mg/dl. At that time, her nicotinic acid dosage was increased to 500 mg three times daily and later to 1,000 mg twice daily. Four months later, cholesterol had fallen to 223 mg/dl, and AST was 22 U/liter (normal: 12 to 31 U/liter). Five months after she began nicotinic acid in a dosage of 1,000 mg twice daily, the patient was evaluated for nausea, vomiting, abdominal discomfort, and severe leg myalgias. AST had increased to 85 U/liter, and creatine kinase was 144 U/liter (normal: 18 to 57 U/liter). ALT was 53 U/liter (normal: 9 to 24 U/liter). The nicotinic acid and cholestipol were stopped. An ultrasound of the liver and gallbladder as well as an upper gastrointestinal radiograph yielded negative results. Hepatitis B surface antigen, antibody to hepatitis B core antigen, and antibody to hepatitis A virus were negative. The patient felt much better after the medications were discontinued. Three weeks later, the ALT and creatine kinase levels were normal, but the cholesterol level had risen to 324 mg/dl. Another lipid-lowering agent was started. Patient 3 A 64-year-old white woman was diagnosed as having angina pectoris. Her serum cholesterol level was 313 mg/dl; serum triglyceride level, 154 mg/dl; and AST level, 21 U/liter (normal: 12 to 31 U/liter). She was treated with gemfibrozil 600 mg twice daily and nicotinic acid 1,000 mg twice daily. Six weeks after starting these medications, she came to our institution complaining of nausea, vomiting, weight loss, and leg cramps. Her physical examination was unremarkable. Laboratory results were significant for an elevated AST level of 215 U/liter. Gemfibrozil and nicotinic acid April 1989 The American Journal of Medicine
Volume 86
481
NICOTINICACID-ASSOCIATEDMYOPATHY/ LITINANDANDERSON
were stopped. She returned to the clinic one week later feeling much better. At that time, AST had fallen to 66 U/liter. At that visit, creatine kinase was checked for the first time and was 108 U/liter (normal: 18 to 57 U/ liter), and ALT was 44 U/liter (normal: 9 to 29 U/liter). Her nausea and leg cramps were gone. COMMENTS
Although nicotinic acid is a safe and effective hypolipidemic agent, a number of adverse effects have been described. Most adverse effects are not serious, but they can interfere with compliance unless patients are properly instructed in the drug's use. The most common adverse effect is cutaneous flushing that results from dilation of skin capillaries. This usually occurs one to two hours after ingestion and is most common at the onset of treatment or when the dosage is increased. This dilation is mediated by prostaglandins, and thus can be retarded by aspirin administration prior to nicotinic acid use [9,11,12]. Gastrointestinal intolerance is also frequently observed. This can be diminished by the ingestion of nicotinic acid with meals and by the use of antacids [11,12].
Laboratory abnormalities have been reported with nicotinic acid use, including reversible elevations of glucose, uric acid, and hepatic enzymes. Currently, it is recommended that hepatic enzyme tests be monitored regularly in all patients during sustained treatment, because rare cases of serious hepatitis and jaundice have been reported associated with nicotinic acid use [13-16].
An increased creatine kinase level was observed in patients receiving nicotinic acid in the Coronary Drug Project Research Group [17]. In that study, 695 patients taking nicotinic acid had a mean creatine kinase level of 93.6 U/liter compared with a mean creatine kinase level of 80.0 U/liter in 757 patients taking placebo. The nicotinic acid group had been taking 3,000 mg of drug daily for more than four years. No patients with markedly elevated creatine kinase levels or symptomatic myopathies were reported. Our three reported cases illustrate the infrequent, potentially serious adverse effect of nicotinic acid myopathy. A variety of other drugs have been reported to be associated with myopathy, including chloroquine, penicillin, phenytoin, procainamide, clofibrate, and corticosteroids. Though there are many different mechanisms of drug-associated muscle damage, all of these disorders are reversible when the offending agent is withdrawn [18]. Our first case is especially noteworthy in implicating nicotinic acid as a cause of myopathy since the patient was not taking any other lipid-lowering drugs. Also, the vast majority of this patient's elevated AST was of muscle origin since the creatine kinase elevation was markedly greater than the elevation of the hepatic enzyme ALT. All of our patients immediately felt better with the cessation of nicotinic acid. Importantly, the leg aching and cramping resolved rapidly with the cessation of the drug, as did the enzyme abnormalities. To increase our certainty that nicotinic acid was the responsible agent, these patients would have to be rechallenged with the drug. We believed rechallenge was potentially dangerous based on other case reports in which patients with niacin hepatitis had severe reactions in
482
April 1989
The American Journal of Medicine
Volume 86
response to a rechallenge with nicotinic acid [14]; thus, our patients were not rechallenged. Another lipid-lowering drug, lovastatin, has been implicated in causing painful myopathy with elevated creatine kinase levels. This is most frequently reported to occur with concurrent use of immunosuppressive drugs (30 percent) or with gemfibrozil (5 percent). The chance of lovastatin alone causing myopathy is rare and has been estimated at 0.2 percent [19]. Rhabdomyolysis has been reported in cardiac transplant recipients receiving immunosuppressive drugs and lovastatin [20,21]. In one case [20], the patient was receiving lovastatin and nicotinic acid at the time of his myolysis with resultant acute renal failure. The authors speculated about a potential interaction between lovastatin and nicotinic acid in addition to the previously described interaction between lovastatin and cyclosporin as causing myopathy. Clinicians should be aware of this additional rare adverse effect of nicotinic acid. We believe myopathy has not been previously reported because creatine kinase is not routinely tested in most screening chemistry panels, and historically not all laboratories had the ability to test for this enzyme. In addition, physicians may have concluded that in patients feeling "poorly" while taking nicotinic acid, any AST elevation is simply a reflection of hepatitis. This could have easily occurred in our three cases. We suggest that patients treated with nicotinic acid be informed of the possible adverse effect of myopathy manifesting as leg cramps and painful muscles. Patients who experience these symptoms should be instructed to discontinue nicotinic acid and contact their physician. We agree with others [11] who suggest periodic testing of AST level in all patients taking nicotinic acid. If AST is elevated, we suggest also checking creatine kinase and ALT levels to differentiate if the AST elevation is secondary to myopathy, hepatitis, or macroenzyme [22]. Early recognition of nicotinic acid-associated myopathy will hopefully avoid unnecessary morbidity. REFERENCES 1. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. JAMA 1984; 251: 351-364. 2. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, CashinHemphill L: Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypassgrafts. JAMA 1987; 257: 3233-3240. 3. Canner PL, Berge KG, Wenger NK, et al: Fifteen year mortality in coronary drug project patients: tong-term benefit with niacin. J Am Coil Cardio11986; 8: 12451255. 4. Hoeg JM, Gregg RE, Brewer HB: An approach to the management of hyperlipoproteinemia. JAMA 1986; 255: 512-521. 5. The Expert Panel: Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988; 148: 36-69. 6. ParsonsWB Jr, Flinn JH: Reduction of serum cholesterol levelsand beta-lipoprotein cholesterol levels by nicotinic acid. Arch Intern Med 1959; 103: 783-790. 7. Belle M, Halbern MM: Oral nicotinic acid for hyperlipemia. Am J Cardio11958; 2: 449-452. 8. Berge KG: Side effects of nicotinic acid in treatment of hypercholesteremia. Geriatrics 1961; 16: 416-422. 9. Anderson CF: Hyperlipoproteinemia: diagnosis and treatment. Clinical medicine. Philadelphia: Harper & Row, 1985; 9: 1-15. 10. Mosher LR: Nicotinic acid side effects and toxicity: a review. Am J Psychiatry 1970; 126: 124-130. 11. Kane JP, Malloy MJ: Treatment of hypercholesterolemia. Med Clin North Am 1982; 66: 542-543. 12. Malinow MR: Adverse effects of the treatment for hyperlipidemia. Cardiol Clin 1986; 4: 95-103. 13. Patterson DJ, Dew EW, Gyorkey F, Graham DY: Niacin hepatitis. South Med J
NICOTINIC ACID-ASSOCIATEDMYOPATHY / LITIN AND ANDERSON 1983; 76: 239-241. 14. Clementz GL, Holmes AW: Nicotinic acid-induced fulminant hepatic failure. J Clin Gastroenterol 1987; 9: 582-584. 15. Rivin AU: Jaundice occurring during nicotinic acid therapy for hypercholesteremia. JAMA 1959; 170: 2088-2089. 16. Christiansen NA, Achor RWP,BergeKG, MasonHL: Nicotinic acid treatment of hypercholesteremia. JAMA 1961; 177: 76-80. 17. Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease. JAMA 1975; 231: 360-381. 18. Mastaglia FL: Adverseeffects of drugs on muscle. Drugs 1982; 24: 304-321.
19. Tobert JA: Rhabdomyolysisin patients receiving Iovastatinafter cardiac transplantation (letter). N Engl J Med 1988; 318: 48. 20. Norman DJ, Illingworth DR, Munson J, Hosenpud J: Myolysis and acute renal failure in a heart-transplant recipient receiving Iovastatin (letter). N Engl J Med 1988; 318: 46-47. 21. East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA: Rhabdomyolysis in patients receiving Iovastatin after cardiac transplantation (letter). N Engl J Med 1988; 318: 47-48. 22. Litin SC, O'Brien JF, Pruett S, etal: Macroenzyme as a cause of unexplained elevation of aspartate aminotransferase. Mayo Clin Proc 1987; 62: 681-687.
April 1989
The American Journal of Medicine
Volume 86
483
urrently, the lay public and most physicians are very concerned about achieving-,lower serum choC lesterol levels. This concern is a result of several studies showing that reducing total cholesterol with drug treatment could decrease the morbidity and mortality of coronary heart disease [1-3]. Since then, reviewers [4] and expert panels [5] have advocated nicotinic acid as the drug of choice for those hypercholesterolemic patients whose condition has not responded to dietary therapy. These recommendations are based on studies demonstrating that nicotinic acid is effective in lowering cholesterol levels [2,3,6,7] with acceptable side effects and cost. The most common adverse effects of nicotinic acid have been flushing, pruritus, gastrointestinal intolerance, skin hyperpigmentation, and occasional hypotension [6-10]. Other more rare adverse effects include acanthosis nigricans, toxic amblyopia, atrial arrhythmias, and panic attacks [6,9-12]. Laboratory abnormalities have also been reported including elevation of plasma glucose, uric acid, aspartate transaminase (AST), alkaline phosphatase, and serum bilirubin [8-10]. Occasionally, jaundice and fulminant hepatitis have been reported secondary to nicotinic acid [13-16]. We report three cases of nicotinic acid-associated myopathy. We are unaware of previous reports of this adverse effect.
CASE REPORTS Patient 1 A 61-year-old white man was noted to have an elevated total cholesterol level of 366 mg/dl. His highdensity lipoprotein (HDL) cholesterol level was 21 mg/dl, and his triglyceride level was 228 mg/dl. He had a family history of coronary artery disease and was a cigarette smoker. Since dietary therapy was not satisfactory in lowering his serum cholesterol, nicotinic acid was prescribed in a dose of 500 mg three times daily. The AST pretreatment level was mildly elevated at 39 U/liter (normal: 12 to 31 U/liter). This was believed to be related to chronic alcohol abuse. Four months later, the patient was reevaluated. He was complaining of severe nocturnal leg aching and cramping. The physical examination revealed mild tenderness of his calf and thigh muscles bilaterally. His total cholesterol level was 285 mg/dl. His triglyceride level was 163 mg/dl. Laboratory values were as follows: AST had risen to 267 U/liter, alanine aminotransferase (ALT) was elevated at 147 U/liter (normal: 10 to 32 U/liter), and creatine kinase was elevated at 1,205 U/liter (normal: 23 to 99 U/liter). Nicotinic acid was immediately discontinued, and From the Departmentof Internal Medicine, MayoGraduateSchoolof Medicine, Rochester,Minnesota.Requestsfor reprints should be addressedto Scott C. Litin, M.D., Area Medicine, Mayo Clinic, 200 First Street, Southwest, Rochester, Minnesota 55905. Manuscript submitted November 1, 1988, and acceptedin revisedform January 16, 1989.
the patient felt better within two or three days. One month later, AST was 43 U/liter (similar to pretreatment levels), and creatine kinase was normal at 28 U/ liter. The serum cholesterol level once again had risen to 364 mg/dl. Another lipid-lowering medication was begun.
Patient 2 A 63-year-old white woman was noted to have hypercholesterolemia during an evaluation for angina pectoris. At that time, her cholesterol level was 343 mg/dl, her HDL cholesterol level was 65 mg/dl, and her triglyceride level was 64 mg/dl. Creatine kinase at that time was 21 U/liter (normal: 18 to 57 U/liter). She had a family history of coronary heart disease. Her angina progressed despite medical therapy, and four months later she had coronary artery bypass surgery. Postoperatively, her cholesterol level was 313 mg/dl. She was treated with nicotinic acid at 500 mg twice daily combined with colestipol 15 g three times daily. This regimen initially lowered her lipid values, but two years later, her cholesterol level had risen to 280 mg/dl with an HDL level of 75 mg/dl and a triglyceride level of 72 mg/dl. At that time, her nicotinic acid dosage was increased to 500 mg three times daily and later to 1,000 mg twice daily. Four months later, cholesterol had fallen to 223 mg/dl, and AST was 22 U/liter (normal: 12 to 31 U/liter). Five months after she began nicotinic acid in a dosage of 1,000 mg twice daily, the patient was evaluated for nausea, vomiting, abdominal discomfort, and severe leg myalgias. AST had increased to 85 U/liter, and creatine kinase was 144 U/liter (normal: 18 to 57 U/liter). ALT was 53 U/liter (normal: 9 to 24 U/liter). The nicotinic acid and cholestipol were stopped. An ultrasound of the liver and gallbladder as well as an upper gastrointestinal radiograph yielded negative results. Hepatitis B surface antigen, antibody to hepatitis B core antigen, and antibody to hepatitis A virus were negative. The patient felt much better after the medications were discontinued. Three weeks later, the ALT and creatine kinase levels were normal, but the cholesterol level had risen to 324 mg/dl. Another lipid-lowering agent was started. Patient 3 A 64-year-old white woman was diagnosed as having angina pectoris. Her serum cholesterol level was 313 mg/dl; serum triglyceride level, 154 mg/dl; and AST level, 21 U/liter (normal: 12 to 31 U/liter). She was treated with gemfibrozil 600 mg twice daily and nicotinic acid 1,000 mg twice daily. Six weeks after starting these medications, she came to our institution complaining of nausea, vomiting, weight loss, and leg cramps. Her physical examination was unremarkable. Laboratory results were significant for an elevated AST level of 215 U/liter. Gemfibrozil and nicotinic acid April 1989 The American Journal of Medicine
Volume 86
481
NICOTINICACID-ASSOCIATEDMYOPATHY/ LITINANDANDERSON
were stopped. She returned to the clinic one week later feeling much better. At that time, AST had fallen to 66 U/liter. At that visit, creatine kinase was checked for the first time and was 108 U/liter (normal: 18 to 57 U/ liter), and ALT was 44 U/liter (normal: 9 to 29 U/liter). Her nausea and leg cramps were gone. COMMENTS
Although nicotinic acid is a safe and effective hypolipidemic agent, a number of adverse effects have been described. Most adverse effects are not serious, but they can interfere with compliance unless patients are properly instructed in the drug's use. The most common adverse effect is cutaneous flushing that results from dilation of skin capillaries. This usually occurs one to two hours after ingestion and is most common at the onset of treatment or when the dosage is increased. This dilation is mediated by prostaglandins, and thus can be retarded by aspirin administration prior to nicotinic acid use [9,11,12]. Gastrointestinal intolerance is also frequently observed. This can be diminished by the ingestion of nicotinic acid with meals and by the use of antacids [11,12].
Laboratory abnormalities have been reported with nicotinic acid use, including reversible elevations of glucose, uric acid, and hepatic enzymes. Currently, it is recommended that hepatic enzyme tests be monitored regularly in all patients during sustained treatment, because rare cases of serious hepatitis and jaundice have been reported associated with nicotinic acid use [13-16].
An increased creatine kinase level was observed in patients receiving nicotinic acid in the Coronary Drug Project Research Group [17]. In that study, 695 patients taking nicotinic acid had a mean creatine kinase level of 93.6 U/liter compared with a mean creatine kinase level of 80.0 U/liter in 757 patients taking placebo. The nicotinic acid group had been taking 3,000 mg of drug daily for more than four years. No patients with markedly elevated creatine kinase levels or symptomatic myopathies were reported. Our three reported cases illustrate the infrequent, potentially serious adverse effect of nicotinic acid myopathy. A variety of other drugs have been reported to be associated with myopathy, including chloroquine, penicillin, phenytoin, procainamide, clofibrate, and corticosteroids. Though there are many different mechanisms of drug-associated muscle damage, all of these disorders are reversible when the offending agent is withdrawn [18]. Our first case is especially noteworthy in implicating nicotinic acid as a cause of myopathy since the patient was not taking any other lipid-lowering drugs. Also, the vast majority of this patient's elevated AST was of muscle origin since the creatine kinase elevation was markedly greater than the elevation of the hepatic enzyme ALT. All of our patients immediately felt better with the cessation of nicotinic acid. Importantly, the leg aching and cramping resolved rapidly with the cessation of the drug, as did the enzyme abnormalities. To increase our certainty that nicotinic acid was the responsible agent, these patients would have to be rechallenged with the drug. We believed rechallenge was potentially dangerous based on other case reports in which patients with niacin hepatitis had severe reactions in
482
April 1989
The American Journal of Medicine
Volume 86
response to a rechallenge with nicotinic acid [14]; thus, our patients were not rechallenged. Another lipid-lowering drug, lovastatin, has been implicated in causing painful myopathy with elevated creatine kinase levels. This is most frequently reported to occur with concurrent use of immunosuppressive drugs (30 percent) or with gemfibrozil (5 percent). The chance of lovastatin alone causing myopathy is rare and has been estimated at 0.2 percent [19]. Rhabdomyolysis has been reported in cardiac transplant recipients receiving immunosuppressive drugs and lovastatin [20,21]. In one case [20], the patient was receiving lovastatin and nicotinic acid at the time of his myolysis with resultant acute renal failure. The authors speculated about a potential interaction between lovastatin and nicotinic acid in addition to the previously described interaction between lovastatin and cyclosporin as causing myopathy. Clinicians should be aware of this additional rare adverse effect of nicotinic acid. We believe myopathy has not been previously reported because creatine kinase is not routinely tested in most screening chemistry panels, and historically not all laboratories had the ability to test for this enzyme. In addition, physicians may have concluded that in patients feeling "poorly" while taking nicotinic acid, any AST elevation is simply a reflection of hepatitis. This could have easily occurred in our three cases. We suggest that patients treated with nicotinic acid be informed of the possible adverse effect of myopathy manifesting as leg cramps and painful muscles. Patients who experience these symptoms should be instructed to discontinue nicotinic acid and contact their physician. We agree with others [11] who suggest periodic testing of AST level in all patients taking nicotinic acid. If AST is elevated, we suggest also checking creatine kinase and ALT levels to differentiate if the AST elevation is secondary to myopathy, hepatitis, or macroenzyme [22]. Early recognition of nicotinic acid-associated myopathy will hopefully avoid unnecessary morbidity. REFERENCES 1. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. JAMA 1984; 251: 351-364. 2. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, CashinHemphill L: Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypassgrafts. JAMA 1987; 257: 3233-3240. 3. Canner PL, Berge KG, Wenger NK, et al: Fifteen year mortality in coronary drug project patients: tong-term benefit with niacin. J Am Coil Cardio11986; 8: 12451255. 4. Hoeg JM, Gregg RE, Brewer HB: An approach to the management of hyperlipoproteinemia. JAMA 1986; 255: 512-521. 5. The Expert Panel: Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988; 148: 36-69. 6. ParsonsWB Jr, Flinn JH: Reduction of serum cholesterol levelsand beta-lipoprotein cholesterol levels by nicotinic acid. Arch Intern Med 1959; 103: 783-790. 7. Belle M, Halbern MM: Oral nicotinic acid for hyperlipemia. Am J Cardio11958; 2: 449-452. 8. Berge KG: Side effects of nicotinic acid in treatment of hypercholesteremia. Geriatrics 1961; 16: 416-422. 9. Anderson CF: Hyperlipoproteinemia: diagnosis and treatment. Clinical medicine. Philadelphia: Harper & Row, 1985; 9: 1-15. 10. Mosher LR: Nicotinic acid side effects and toxicity: a review. Am J Psychiatry 1970; 126: 124-130. 11. Kane JP, Malloy MJ: Treatment of hypercholesterolemia. Med Clin North Am 1982; 66: 542-543. 12. Malinow MR: Adverse effects of the treatment for hyperlipidemia. Cardiol Clin 1986; 4: 95-103. 13. Patterson DJ, Dew EW, Gyorkey F, Graham DY: Niacin hepatitis. South Med J
NICOTINIC ACID-ASSOCIATEDMYOPATHY / LITIN AND ANDERSON 1983; 76: 239-241. 14. Clementz GL, Holmes AW: Nicotinic acid-induced fulminant hepatic failure. J Clin Gastroenterol 1987; 9: 582-584. 15. Rivin AU: Jaundice occurring during nicotinic acid therapy for hypercholesteremia. JAMA 1959; 170: 2088-2089. 16. Christiansen NA, Achor RWP,BergeKG, MasonHL: Nicotinic acid treatment of hypercholesteremia. JAMA 1961; 177: 76-80. 17. Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease. JAMA 1975; 231: 360-381. 18. Mastaglia FL: Adverseeffects of drugs on muscle. Drugs 1982; 24: 304-321.
19. Tobert JA: Rhabdomyolysisin patients receiving Iovastatinafter cardiac transplantation (letter). N Engl J Med 1988; 318: 48. 20. Norman DJ, Illingworth DR, Munson J, Hosenpud J: Myolysis and acute renal failure in a heart-transplant recipient receiving Iovastatin (letter). N Engl J Med 1988; 318: 46-47. 21. East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA: Rhabdomyolysis in patients receiving Iovastatin after cardiac transplantation (letter). N Engl J Med 1988; 318: 47-48. 22. Litin SC, O'Brien JF, Pruett S, etal: Macroenzyme as a cause of unexplained elevation of aspartate aminotransferase. Mayo Clin Proc 1987; 62: 681-687.
April 1989
The American Journal of Medicine
Volume 86
483