PMID- 19591530
OWN - NLM
STAT- MEDLINE
DCOM- 20091109
LR  - 20211020
IS  - 1179-1942 (Electronic)
IS  - 0114-5916 (Linking)
VI  - 32
IP  - 8
DP  - 2009
TI  - 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.
PG  - 649-61
LID - 10.2165/00002018-200932080-00004 [doi]
AB  - 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      could not be reached (e.g. contact information was no longer valid).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.
FAU - Golomb, Beatrice A
AU  - Golomb BA
AD  - Department of Medicine, University of California, San Diego, California 
      92093-0995, USA. bgolomb@ucsd.edu
FAU - Kwon, Edwin K
AU  - Kwon EK
FAU - Koperski, Sabrina
AU  - Koperski S
FAU - Evans, Marcella A
AU  - Evans MA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - New Zealand
TA  - Drug Saf
JT  - Drug safety
JID - 9002928
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Vitamins)
RN  - 1339-63-5 (Ubiquinone)
RN  - EJ27X76M46 (coenzyme Q10)
SB  - IM
MH  - Aged
MH  - Amyotrophic Lateral Sclerosis/*chemically induced/diagnosis
MH  - Anticholesteremic Agents/administration & dosage/*adverse effects
MH  - Data Collection
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage/*adverse 
      effects
MH  - Male
MH  - Middle Aged
MH  - Mitochondria/metabolism
MH  - Oxidative Stress/*drug effects
MH  - Risk Factors
MH  - Ubiquinone/analogs & derivatives/therapeutic use
MH  - Vitamins/therapeutic use
EDAT- 2009/07/14 09:00
MHDA- 2009/11/10 06:00
CRDT- 2009/07/14 09:00
PHST- 2009/07/14 09:00 [entrez]
PHST- 2009/07/14 09:00 [pubmed]
PHST- 2009/11/10 06:00 [medline]
AID - 4 [pii]
AID - 10.2165/00002018-200932080-00004 [doi]
PST - ppublish
SO  - Drug Saf. 2009;32(8):649-61. doi: 10.2165/00002018-200932080-00004.