Drug Safety

, Volume 32, Issue 8, pp 649–661 | Cite as

Amyotrophic Lateral Sclerosis-Like Conditions in Possible Association with Cholesterol-Lowering Drugs

An Analysis of Patient Reports to the University of California, San Diego (UCSD) Statin Effects Study
  • Beatrice A. Golomb
  • Edwin K. Kwon
  • Sabrina Koperski
  • Marcella A. Evans
Short Communication


Background: While cases of amyotrophic lateral sclerosis (ALS) or ALS-like conditions have arisen in apparent association with HMG-CoA reductase inhibitors (‘statins’) and/or other lipid-lowering drugs (collectively termed ‘statins’ in this paper for brevity), additional information is needed to understand whether the connection may be causal. The University of California, San Diego (UCSD) Statin Effects Study is a patient-targeted adverse event surveillance project focused on lipid-lowering agents, whose aim is to capitalize on patient reporting to further define characteristics and natural history of statin adverse effects (AEs), and to ascertain whether a patient-targeted surveillance system might lead to presumptive identification of previously unrecognized AEs. ALS was a candidate ‘new’ AE identified through this process. The aim of the analysis presented here was to examine characteristics and natural history of reported statin-associated ALS-like conditions with attention to factors that may bear on the issue of causality.

Methods: For the present analysis, we focused on cases of statin-associated ALS that were reported to our study group prior to publication of a possible statin-ALS association. Of 35 identified subjects who had contacted the UCSD Statin Effects Study group to report ALS or an ALS-like condition, 18 could not be reached (e.g. contact information was no longer valid). Six were unable to participate (e.g. due to progression of their disease). Of the 11 who could be contacted and were able to participate, one declined to give informed consent. The remaining ten, with either a formal or probable diagnosis of ALS in the context of progressive muscle wasting/weakness arising in association with lipid-lowering drug therapy, completed a mail or phone survey eliciting information about ALS symptom onset and change in association with drug use/modification and development of statin-associated AEs. We reviewed findings in the context of literature on statin antioxidant/pro-oxidant balance, as well as ALS mechanisms involving oxidative stress and mitochondrial dysfunction.

Results: All ten subjects reported amelioration of symptoms with drug discontinuation and/or onset or exacerbation of symptoms with drug change, rechallenge or dose increase. Three subjects initiated coenzyme Q10 supplementation; all reported initial benefit. All subjects reportedly developed statin AEs (not indicative of ALS) prior to ALS symptom onset, strongly disproportionate to expectation (p< 0.001). Since this reflects induction of pro-oxidant effects from statins, these findings lend weight to a literature-supported mechanism by which induction by statins of oxidative stress with amplification of mitochondrial dysfunction, arising in a vulnerable subgroup, may propel mechanisms underlying both AEs and, more rarely, ALS.

Conclusion: A theoretical foundation and preliminary clinical observations suggest that statins (and other lipid-lowering drugs) may rarely be associated with ALS in vulnerable individuals in whom pro-oxidant effects of statins predominate. Our observations have explanatory relevance extending to ALS causes that are not statin associated and to statin-associated neurodegenerative conditions that are not ALS. They suggest means for identification of a possible vulnerable subgroup. Indeed whether statins may, in contrast, confer ALS protection when antioxidant effects predominate merits examination.


Amyotrophic Lateral Sclerosis Statin Amyotrophic Lateral Sclerosis Patient Statin User Amyotrophic Lateral Sclerosis Case 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank all who have assisted with the Statin Effects Study. The authors especially thank the patients who took the effort and energy, not insubstantial in this setting, to share their information with them. Dr Beatrice Golomb had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors are grateful for support from a Robert Wood Johnson Generalist Physician Faculty Scholar Award to Dr Golomb, and to kind donations from subjects and others, which helped fund this effort. Contributing parties had no role in the design and conduct of this study; collection, management, analysis and interpretation of data; and preparation, review or approval of this manuscript. The authors have no conflicts of interest that are directly relevant to content of this study.

Supplementary material

40264_2012_32080649_MOESM1_ESM.pdf (149 kb)
Supplementary material, approximately 153 KB.


  1. 1.
    Strong M, Rosenfeld J. Amyotrophic lateral sclerosis: a review of current concepts. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4(3): 136–43PubMedGoogle Scholar
  2. 2.
    Golomb BA. Patient targeted adverse event surveillance: use for hypothesis generation. Robert Wood Johnson Generalist Physician Faculty Scholar meeting. 2005 Nov 10; Ft Lauderdale (FL) [online]. Available from URL: [Accessed 2009 Jan 27]
  3. 3.
    Golomb BA. Enhancing post-marketing drug surveillance: a response to expressed needs of patients. Robert Wood Johnson Generalist Physician Faculty Scholar meeting. 2006 Dec 1; San Antonio (TX) [online]. Available from URL: [Accessed 2009 Jan 27]
  4. 4.
    Edwards IR, Star K, Kiuru A. Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from vigibase. Drug Saf 2007; 30(6): 515–25PubMedGoogle Scholar
  5. 5.
    Buajordet I, Madsen S, Olsen H. Statins: the pattern of adverse effects with emphasis on mental reactions: data from a national and an international database [in Norwegian]. Tidsskrift for den Norske Laegeforening 1997; 117(22): 3210–3PubMedGoogle Scholar
  6. 6.
    Halkin A, Lossos IS, Mevorach D. HMG-CoA reductase inhibitor-induced impotence [letter]. Ann Pharmacother 1996; 30(2): 190Google Scholar
  7. 7.
    Boyd IW. Comment: HMG-CoA reductase inhibitor-induced impotence [letter; comment]. Ann Pharmacother 1996; 30(10): 1199PubMedGoogle Scholar
  8. 8.
    Jackson G. Simvastatin and impotence [editorial]. BMJ 1997; 315: 31Google Scholar
  9. 9.
    Bruckert E, Giral P, Heshmati HM, et al. Men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. J Clin Pharm Ther 1996; 21: 89–94PubMedGoogle Scholar
  10. 10.
    Adverse Drug Reactions Advisory Committee. Simvastatin and adverse endocrine effects in men. Aust Adv Drug React Bull 1995; 14(3): 10Google Scholar
  11. 11.
    Halkin A, Lossos IS, Mevorach D. HMG-CoA reductase inhibitor-induced impotence [letter]. Ann Pharmacother 1996; 30(2): 192PubMedGoogle Scholar
  12. 12.
    Rizvi K, Hampson JP, Harvey JN. Do lipid-lowering drugs cause erectile dysfunction? A systematic review. Fam Pract 2002; 19(1): 95–8PubMedGoogle Scholar
  13. 13.
    Pia Iglesias G, Fernandez Fernandez FJ, Ameneiros Lago E, et al. HMG-CoA reductase inhibitors and sexual dysfunction [letter; in Spanish]. Ann Med Interna 2001; 18(3): 171Google Scholar
  14. 14.
    Carvajal A, Macias D, Sainz M, et al. HMG CoA Reductase inhibitors and impotence: two case series from the Spanish and French drug monitoring systems. Drug Saf 2006; 29(2): 143–9PubMedGoogle Scholar
  15. 15.
    Boyd IW. Comment: HMG-CoA reductase inhibitor-induced impotence [letter]. Ann Pharmacother 1996; 30(10): 1199PubMedGoogle Scholar
  16. 16.
    Halkin A, Lossos IS, Mevorach D. HMG-CoA reductase inhibitor-induced impotence [letter]. Ann Pharmacother 1996; 30(2): 192PubMedGoogle Scholar
  17. 17.
    Solomon H, Samarasinghe YP, Feher MD, et al. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract 2006; 60(2): 141–5PubMedGoogle Scholar
  18. 18.
    Blanker MH, Verhagen AP. Lipid-lowering drugs and erectile dysfunction [letter]. Fam Pract 2002; 19(5): 567PubMedGoogle Scholar
  19. 19.
    de Graaf L, Brouwers AH, Diemont WL. Is decreased libido associated with the use of HMG-CoA-reductase inhibitors? Br J Clin Pharmacol 2004; 58(3): 326–8PubMedGoogle Scholar
  20. 20.
    Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002; 137(7): 581–5PubMedGoogle Scholar
  21. 21.
    Evans MA, Golomb BA. Statin associated cognitive problems reported by 171 subjects. Pharmacotherapy. In pressGoogle Scholar
  22. 22.
    Muldoon MF, Ryan CM, Sereika SM, et al. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med 2004; 117(11): 823–9PubMedGoogle Scholar
  23. 23.
    Wagstaff LR, Mitton MW, Arvik BM, et al. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 2003; 23(7): 871–80PubMedGoogle Scholar
  24. 24.
    Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med 2000; 108(7): 538–46PubMedGoogle Scholar
  25. 25.
    Jeppesen U, Gaist D, Smith T, et al. Statins and peripheral neuropathy. Eur J Clin Pharmacol 1999; 54(11): 835–8PubMedGoogle Scholar
  26. 26.
    Adverse Drug Reactions Advisory Committee (ADRAC). Statins and peripheral neuropathy. Aust Adverse Drug Reactions Bull 2005; 24(2): 6Google Scholar
  27. 27.
    Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology 2002; 58(9): 1333–7PubMedGoogle Scholar
  28. 28.
    Rundek T, Naini A, Sacco R, et al. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol 2004; 61(6): 889–92PubMedGoogle Scholar
  29. 29.
    Mortensen SA, Leth A, Agner E, et al. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 1997; 18 Suppl.: S137–44PubMedGoogle Scholar
  30. 30.
    Di Giovanni S, Mirabella M, Spinazzola A, et al. Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology 2001; 57(3): 515–8PubMedGoogle Scholar
  31. 31.
    Beal MF. Coenzyme Q10 as a possible treatment for neurodegenerative diseases. Free Radic Res 2002; 36(4): 455–60PubMedGoogle Scholar
  32. 32.
    Levy G, Kaufmann P, Buchsbaum R, et al. A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS. Neurology 2006; 66(5): 660–3PubMedGoogle Scholar
  33. 33.
    Praline J, Guennoc AM, Limousin N, et al. ALS and mercury intoxication: a relationship? Clin Neurol Neurosurg 2007; 109(10): 880–3PubMedGoogle Scholar
  34. 34.
    Morahan JM, Yu B, Trent RJ, et al. Genetic susceptibility to environmental toxicants in ALS. Am J Med Genet B Neuropsychiatr Genet 2007; 144(7): 885–90Google Scholar
  35. 35.
    O’Neill MJ, Murray TK, Lakics V, et al. The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration. Curr Drug Targets CNS Neurol Disord 2002; 1(4): 399–411PubMedGoogle Scholar
  36. 36.
    Abel EL. Football increases the risk for Lou Gehrig’s disease, amyotrophic lateral sclerosis. Percept Mot Skills 2007; 104 (3 Pt 2): 1251–4PubMedGoogle Scholar
  37. 37.
    Chio A, Benzi G, Dossena M, et al. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 2005; 128 (Pt 3): 472–6PubMedGoogle Scholar
  38. 38.
    Wicks P, Ganesalingham J, Collin C, et al. Three soccer playing friends with simultaneous amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2007; 8(3): 177–9PubMedGoogle Scholar
  39. 39.
    Vanacore N, Binazzi A, Bottazzi M, et al. Amyotrophic lateral sclerosis in an Italian professional soccer player. Parkinsonism Relat Disord 2006; 12(5): 327–9PubMedGoogle Scholar
  40. 40.
    Belli S, Vanacore N. Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease? Eur J Epidemiol 2005; 20(3): 237–42PubMedGoogle Scholar
  41. 41.
    Taioli E. All causes mortality in male professional soccer players. Eur J Public Health 2007; 17(6): 600–4PubMedGoogle Scholar
  42. 42.
    Konagaya M, Kato T, Sakai M, et al. A clinical and pathological study of a Japanese case of amyotrophic lateral sclerosis/parkinsonism-dementia complex with family history. J Neurol 2003; 250(2): 164–70PubMedGoogle Scholar
  43. 43.
    Plato CC, Garruto RM, Galasko D, et al. Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol 2003; 157(2): 149–57PubMedGoogle Scholar
  44. 44.
    Plato CC, Galasko D, Garruto RM, et al. ALS and PDC of Guam: forty-year follow-up. Neurology 2002; 58(5): 765–73PubMedGoogle Scholar
  45. 45.
    Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients: the PRIMO study. Cardiovasc Drugs Ther 2005; 19(6): 403–14PubMedGoogle Scholar
  46. 46.
    Scott RS, Lintott CJ, Wilson MJ. Simvastatin and side effects. N Z Med J 1991; 104(924): 493–5PubMedGoogle Scholar
  47. 47.
    Colman E, Szarfman A, Wyeth J, et al. An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA’s spontaneous adverse event reporting system. Pharmacoepidemiol Drug Saf 2008; 17(11): 1068–76PubMedGoogle Scholar
  48. 48.
    Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008; 8(6): 373–418PubMedGoogle Scholar
  49. 49.
    McClure DL, Valuck RJ, Glanz M, et al. Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiol Drug Saf 2007; 16(2): 132–43PubMedGoogle Scholar
  50. 50.
    Karlsson J, Diamant B, Edlund PO, et al. Plasma ubiquinone, alpha-tocopherol and cholesterol in man. Int J Vitam Nutr Res 1992; 62(2): 160–4PubMedGoogle Scholar
  51. 51.
    Neuhouser ML, Rock CL, Eldridge AL, et al. Serum concentrations of retinol, alpha-tocopherol and the carotenoids are influenced by diet, race and obesity in a sample of healthy adolescents. J Nutr 2001; 131(8): 2184–91PubMedGoogle Scholar
  52. 52.
    Karlsson J, Diamant B, Theorell H, et al. Ubiquinone and alpha-tocopherol in plasma; means of translocation or depot. Clin Investig 1993; 71 (8 Suppl.): S84–91PubMedGoogle Scholar
  53. 53.
    Oranje WA, Sels JP, Rondas-Colbers GJ, et al. Effect of atorvastatin on LDL oxidation and antioxidants in normocholesterolemic type 2 diabetic patients. Clin Chim Acta 2001; 311(2): 91–4PubMedGoogle Scholar
  54. 54.
    Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 2004; 3(3): 205–14PubMedGoogle Scholar
  55. 55.
    Huang X, Chen H, Miller WC, et al. Lower low-density lipoprotein cholesterol levels are associated with Parkinson’s disease. Mov Disord 2006; 22(3): 377–81Google Scholar
  56. 56.
    de Lau LM, Koudstaal PJ, Hofman A, et al. Serum cholesterol levels and the risk of Parkinson’s disease. Am J Epidemiol 2006; 164(10): 998–1002PubMedGoogle Scholar
  57. 57.
    Dupuis L, Corcia P, Fergani A, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008; 70(13): 1004–9PubMedGoogle Scholar
  58. 58.
    Zager RA, Johnson AC, Hanson SY. Proximal tubular cholesterol loading after mitochondrial, but not glycolytic, blockade. Am J Physiol Renal Physiol 2003; 285(6): F1092–9PubMedGoogle Scholar
  59. 59.
    Berthold HK, Naini A, Di Mauro S, et al. Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial. Drug Saf 2006; 29(8): 703–12PubMedGoogle Scholar
  60. 60.
    Albano CB, Muralikrishnan D, Ebadi M. Distribution of coenzyme Q homologues in brain. Neurochem Res 2002; 27(5): 359–68PubMedGoogle Scholar
  61. 61.
    Lenaz G, D’Aurelio M, Merlo Pich M, et al. Mitochondrial bioenergetics in aging. Biochim Biophys Acta 2000; 1459(2–3): 397–404PubMedGoogle Scholar
  62. 62.
    Sastre J, Pallardo FV, Vina J. The role of mitochondrial oxidative stress in aging. Free Radic Biol Med 2003; 35(1): 1–8PubMedGoogle Scholar
  63. 63.
    Linnane AW, Zhang C, Yarovaya N, et al. Human aging and global function of coenzyme Q 10. Ann N Y Acad Sci 2002; 959: 396–411PubMedGoogle Scholar
  64. 64.
    Whitman GJ, Niibori K, Yokoyama H, et al. The mechanisms of coenzyme Q10 as therapy for myocardial ischemia reperfusion injury. Mol Aspects Med 1997; 18 Suppl.: S195–203PubMedGoogle Scholar
  65. 65.
    Fernandez-Ayala DJ, Martin SF, Barroso MP, et al. Coenzyme Q protects cells against serum withdrawal-induced apoptosis by inhibition of ceramide release and caspase-3 activation. Antioxid Redox Signal 2000; 2(2): 263–75PubMedGoogle Scholar
  66. 66.
    Kagan T, Davis C, Lin L, et al. Coenzyme Q10 can in some circumstances block apoptosis, and this effect is mediated through mitochondria. AnnN Y Acad Sci 1999; 887: 31–47Google Scholar
  67. 67.
    Lopez-Lluch G, Barroso MP, Martin SF, et al. Role of plasma membrane coenzyme Q on the regulation of apoptosis. Biofactors 1999; 9(2–4): 171–7PubMedGoogle Scholar
  68. 68.
    Papucci L, Schiavone N, Witort E, et al. Coenzyme q10 prevents apoptosis by inhibiting mitochondrial depolarization independently of its free radical scavenging property. J Biol Chem 2003; 278(30): 28220–8PubMedGoogle Scholar
  69. 69.
    Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59(10): 1541–50PubMedGoogle Scholar
  70. 70.
    Barbiroli B, Frassineti C, Martinelli P, et al. Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies: an in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy. Cell Mol Biol (Noisy-le-grand) 1997; 43(5): 741–9Google Scholar
  71. 71.
    Mahoney DJ, Parise G, Tarnopolsky MA. Nutritional and exercise-based therapies in the treatment of mitochondrial disease. Curr Opin Clin Nutr Metab Care 2002; 5(6): 619–29PubMedGoogle Scholar
  72. 72.
    Rosenfeldt FL, Pepe S, Linnane A, et al. Coenzyme Q10 protects the aging heart against stress: studies in rats, human tissues, and patients. Ann N Y Acad Sci 2002; 959: 355–9PubMedGoogle Scholar
  73. 73.
    Mandavilli BS, Santos JH, Van Houten B. Mitochondrial DNA: repair and aging. Mutat Res 2002; 509(1–2): 127–51PubMedGoogle Scholar
  74. 74.
    Lee HC, Wei YH. Mutation and oxidative damage of mitochondrial DNA and defective turnover of mitochondria in human aging. J Formos Med Assoc 1997; 96(10): 770–8PubMedGoogle Scholar
  75. 75.
    Genova ML, Pich MM, Bernacchia A, et al. The mitochondrial production of reactive oxygen species in relation to aging and pathology. Ann N Y Acad Sci 2004; 1011: 86–100PubMedGoogle Scholar
  76. 76.
    Lestienne P. Do mitochondria play a role in aging? C R Seances Soc Biol Fil 1997; 191(4): 579–92PubMedGoogle Scholar
  77. 77.
    Vladutiu G. Statin-induced adverse effects and malignant hyperthermia susceptibility: comment on the article by Guis et al. Arthritis Rheum 2007; 57(1): 186–17PubMedGoogle Scholar
  78. 78.
    Oh J, Ban MR, Miskie BA, et al. Genetic determinants of statin intolerance. Lipids Health Dis 2007; 6: 7PubMedGoogle Scholar
  79. 79.
    Sinzinger H, Lupattelli G, Chehne F. Increased lipid peroxidation in a patient with CK-elevation and muscle pain during statin therapy. Atherosclerosis 2000; 153(1): 255–6PubMedGoogle Scholar
  80. 80.
    Sinzinger H, Lupattelli G, Chehne F, et al. Isoprostane 8-epi-PGF2alpha is frequently increased in patients with muscle pain and/or CK-elevation after HMG-Coenzyme-A-reductase inhibitor therapy. J Clin Pharm Ther 2001; 26(4): 303–10PubMedGoogle Scholar
  81. 81.
    Vladutiu GD, Simmons Z, Isackson PJ, et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 2006; 34(2): 153–62PubMedGoogle Scholar
  82. 82.
    Gambelli S, Dotti MT, Malandrini A, et al. Mitochondrial alterations in muscle biopsies of patients on statin therapy. J Submicrosc Cytol Pathol 2004; 36(1): 85–9PubMedGoogle Scholar
  83. 83.
    Meyer RA, Slade JM, Towse TF, et al. Elevated muscle phosphodiesterase in 31P-NMR spectra of patients on statins [abstract]. Proc Intl Soc Mag Reson Med 2005; 13: 2036Google Scholar
  84. 84.
    Schick BA, Laaksonen R, Frohlich JJ, et al. Decreased skeletal muscle mitochondrial DNA in patients treated with high-dose simvastatin. Clin Pharmacol Ther 2007; 81(5): 650–3PubMedGoogle Scholar
  85. 85.
    Guis S, Figarella-Branger D, Mattei JP, et al. In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects. Arthritis Rheum 2006; 55(4): 551–7PubMedGoogle Scholar
  86. 86.
    Phillips PS, Phillips CT, Sullivan MJ, et al. Statin myotoxicity is associated with changes in the cardiopulmonary function. Atherosclerosis 2004; 177(1): 183–8PubMedGoogle Scholar
  87. 87.
    Paiva H, Thelen KM, Van Coster R, et al. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther 2005; 78(1): 60–8PubMedGoogle Scholar
  88. 88.
    De Pinieux G, Chariot P, Ammi-Said M, et al. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol 1996; 42(3): 333–7PubMedGoogle Scholar
  89. 89.
    Chariot P, Abadia R, Agnus D, et al. Simvastatin-induced rhabdomyolysis followed by a MELAS syndrome. Am J Med 1993; 94(1): 109–10PubMedGoogle Scholar
  90. 90.
    Thomas JE, Lee N, Thompson PD. Statins provoking MELAS syndrome: a case report. Eur Neurol 2007; 57(4): 232–5PubMedGoogle Scholar
  91. 91.
    Neale R, Reynolds TM, Saweirs W. Statin precipitated lactic acidosis? J Clin Pathol 2004; 57(9): 989–90PubMedGoogle Scholar
  92. 92.
    Goli AK, Goli SA, Byrd Jr RP, et al. Simvastatin-induced lactic acidosis: a rare adverse reaction? Clin Pharmacol Ther 2002; 72(4): 461–4PubMedGoogle Scholar
  93. 93.
    England JD, Walsh JC, Stewart P, et al. Mitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors: simvastatin and pravastatin [letter]. Aust N Z J Med 1995; 25(4): 374–5PubMedGoogle Scholar
  94. 94.
    Diaczok BJ, Shali R. Statins unmasking a mitochondrial myopathy: a case report and proposed mechanism of disease. South Med J 2003; 96(3): 318–20PubMedGoogle Scholar
  95. 95.
    Troseid M, Henriksen OA, Lindal S. Statin-associated myopathy with normal creatine kinase levels: case report from a Norwegian family. APMIS 2005; 113(9): 635–7PubMedGoogle Scholar
  96. 96.
    Fukada K, Zhang F, Vien A, et al. Mitochondrial proteomic analysis of a cell line model of familial amyotrophic lateral sclerosis. Mol Cell Proteomics 2004; 3(12): 1211–23PubMedGoogle Scholar
  97. 97.
    Mancuso M, Conforti FL, Rocchi A, et al. Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis? Neurosci Lett 2004; 371(2–3): 158–62PubMedGoogle Scholar
  98. 98.
    Xu Z, Jung C, Higgins C, et al. Mitochondrial degeneration in amyotrophic lateral sclerosis. J Bioenerg Biomembr 2004; 36(4): 395–9PubMedGoogle Scholar
  99. 99.
    Dupuis L, Di Scala F, Rene F, et al. Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. Faseb J 2003; 17(14): 2091–3PubMedGoogle Scholar
  100. 100.
    Dupuis L, Gonzalez de Aguilar JL, Oudart H, et al. Mitochondria in amyotrophic lateral sclerosis: a trigger and a target. Neurodegener Dis 2004; 1(6): 245–54PubMedGoogle Scholar
  101. 101.
    Wallace DC. A mitochondrial paradigm for degenerative diseases and ageing. Novartis Found Symp 2001; 235: 247–63; discussion 263–6PubMedGoogle Scholar
  102. 102.
    Corral-Debrinski M, Horton T, Lott MT, et al. Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics 1994; 23(2): 471–6PubMedGoogle Scholar
  103. 103.
    Wallace DC. Mitochondrial defects in neurodegenerative disease. Ment Retard Dev Disabil Res Rev 2001; 7(3): 158–66PubMedGoogle Scholar
  104. 104.
    Borthwick GM, Johnson MA, Ince PG, et al. Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol 1999; 46(5): 787–90PubMedGoogle Scholar
  105. 105.
    Dupuis L, Gonzalez de Aguilar JL, Echaniz-Laguna A, et al. Mitochondrial dysfunction in amyotrophic lateral sclerosis also affects skeletal muscle. Muscle Nerve 2006; 34(2): 253–4PubMedGoogle Scholar
  106. 106.
    Kew JJ, Leigh PN, Playford ED, et al. Cortical function in amyotrophic lateral sclerosis: a positron emission tomography study. Brain 1993; 116 (Pt 3): 655–80PubMedGoogle Scholar
  107. 107.
    Sinzinger H, Chehne F, Lupattelli G. Oxidation injury in patients receiving HMG-CoA reductase inhibitors: occurrence in patients without enzyme elevation or myopathy. Drug Saf 2002; 25(12): 877–83PubMedGoogle Scholar
  108. 108.
    Food and Drug Administration. FDA Public Health Advisory on Crestor (rosuvastatin) [online]. Available from URL: [Accessed 2005 Mar 2]
  109. 109.
    McDermott MM, Guralnik JM, Greenland P, et al. Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease. Circulation 2003; 107(5): 757–61PubMedGoogle Scholar
  110. 110.
    Fisher S, Bryant SG. Postmarketing surveillance: accuracy of patient drug attribution judgments. Clin Pharmacol Ther 1990; 48(1): 102–7PubMedGoogle Scholar
  111. 111.
    Fisher S, Bryant SG, Kent TA, et al. Patient drug attributions and postmarketing surveillance. Pharmacotherapy 1994; 14(2): 202–9PubMedGoogle Scholar
  112. 112.
    Fisher S, Bryant SG, Kluge RM. New approaches to postmarketing surveillance. Psychopharmacology (Berl) 1986; 90(3): 347–50Google Scholar
  113. 113.
    Fisher S, Bryant SG. Postmarketing surveillance of adverse drug reactions: patient self-monitoring. J Am Board Fam Pract 1992; 5(1): 17–25PubMedGoogle Scholar
  114. 114.
    Jarernsiripornkul N, Krska J, Richards RM, et al. Patient reporting of adverse drug reactions: useful information for pain management? Eur J Pain 2003; 7(3): 219–24PubMedGoogle Scholar
  115. 115.
    Gray GC, Reed RJ, Kaiser KS, et al. Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: the Seabee Health Study. Am J Epidemiol 2002; 155(11): 1033–44PubMedGoogle Scholar
  116. 116.
    Kural BV, Orem C, Uydu HA, et al. The effects of lipid-lowering therapy on paraoxonase activities and their relationships with the oxidant-antioxidant system in patients with dyslipidemia. Coron Artery Dis 2004; 15(5): 277–83PubMedGoogle Scholar
  117. 117.
    Harangi M, Seres I, Varga Z, et al. Atorvastatin effect on high-density lipoprotein-associated paraoxonase activity and oxidative DNA damage. Eur J Clin Pharmacol 2004; 60(10): 685–91PubMedGoogle Scholar
  118. 118.
    Tomas M, Senti M, Garcia-Faria F, et al. Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2000; 20(9): 2113–9PubMedGoogle Scholar
  119. 119.
    Deakin S, Guernier S, James RW. Pharmacogenetic interaction between paraoxonase-1 gene promoter polymorphism C-107T and statin. Pharmacogenet Genomics 2007; 17(6): 451–7PubMedGoogle Scholar
  120. 120.
    Beltowski J, Wojcicka G, Jamroz A. Differential effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on plasma paraoxonase 1 activity in the rat. Pol J Pharmacol 2002; 54(6): 661–71PubMedGoogle Scholar
  121. 121.
    Gouedard C, Koum-Besson N, Barouki R, et al. Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins. Mol Pharmacol 2003; 63(4): 945–56PubMedGoogle Scholar
  122. 122.
    Muller T, Kuhn W, Pohlau D, et al. Parkinsonism unmasked by lovastatin. Ann Neurol 1995; 37(5): 685–6PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Beatrice A. Golomb
    • 1
    • 2
  • Edwin K. Kwon
    • 1
    • 3
  • Sabrina Koperski
    • 1
  • Marcella A. Evans
    • 1
    • 3
  1. 1.Department of MedicineUniversity of CaliforniaSan DiegoUSA
  2. 2.Department of Family & Preventive MedicineUniversity of CaliforniaSan DiegoUSA
  3. 3.Irvine School of MedicineUniversity of CaliforniaIrvineUSA

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