MCQ Psychiatry 38

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Anonymous said...

3/08/2007 11:28 AM

One of the first questions to ask: "Is this man taking a cholesterol-lowering statin drug or statin combination drug?"

Amnesia and Transient Global Amnesia are well-documented adverse effects of the statin class of drugs, which are the most prescribed class of drugs in the world, and in the history of the world.

References include:

Two countries, Australia and Canada, have officially warned about statins causing memory loss as a serious adverse effect.

“DRUGS THAT MAKE YOU FORGET”
Australian Adverse Drug Reactions Bulletin (Australia’s equivalent to the FDA)
Volume 17, Number 3, August 1998, section 3, page 3
Simvastatn is listed under “DRUGS THAT MAKE YOU FORGET”
Recognizing the 14 reports of Amnesia under that drug, .8% of the total adverse effects for that drug.
www.health.gov.au/tga/docs/pdf/aadrbltn/aadr9808.pdf

See also: National Prescribing Service Limited
Australia’s peak, independent, education and information provider about medicines
Fact Sheet 18 November 2004
Statins and memory loss


Canadian Adverse Reaction Newsletter
Volume 15 • Issue 4 • October 2005
[carn-bcei_v15n4_e.pdf]
Pages: 6, Size: 705 K, Date: 2005-10-07

Statins and memory loss

The role of HMG–CoA reductase inhibitors, or statins, in cardiovascular protection is well established.However, evidence in the current literature is conflicting as to the effect of statins on cognitive function.1 It has been postulated that statins may prevent dementia of the Alzheimer’s type through inhibition of -amyloid formation and thus decreased production of neurofibrillary tangles and plaques.2 Other studies have suggested that statins can contribute to memory loss.1–4 The proposed mechanism relates to cholesterol’s essential role in myelin production. Statins, especially the more lipophilic ones (e.g., atorvastatin and simvastatin), may cross the blood– brain barrier and decrease the amount of central nervous system (CNS) cholesterol necessary for the formation of myelin.2,3 Inadequate myelin production may result in demyelination of nerve fibres in the CNS and thus lead to memory loss.2 Memory impairment is listed in the product monograph for Pravachol.5

From the date of marketing of statins in Canada to May 31, 2005,Health Canada received 19 reports of amnesia suspected of being associated with these drugs (Table 1). The onset was reported to occur within 1 month after starting statin therapy in 5 cases,within 1 year in 7 cases and after 1 year in 3 cases. Four cases did not report an onset date. Eleven reports described that the amnesia resolved or improved when the drug was discontinued or the dose reduced, and one of them also described a positive rechallenge. Other reports did not provide this information. Given these findings, changes in cognitive status temporally associated with statin therapy should be monitored.2 Michel Trottier, BScPhm, RPEBC, RPh, Health Canada

References
1. Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM. Statin-associated memory loss: analysis of 60 case reports and review of the literature.
Pharmacotherapy 2003;23(7):871-80.
2. King DS, Wilburn AJ, Wofford MR, Harrell TK, Lindley BJ, Jones DW. Cognitive impairment associated with atorvastatin and simvastatin.
Pharmacotherapy 2003;23(12):1663-7.
3. Orsi A, Sherman O, Woldeselassie Z. Simvastatinassociated memory loss. Pharmacotherapy 2001;21(6):767-9.
4. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in
hypercholesterolemic adults. Am J Med 2004;117(11):823-9.
5. Pravachol (pravastatin) [product monograph]. Montréal: Bristol-Myers Squibb Canada; 2005.


Medical Journals have published articles on Memory Loss from statin adverse effects:

Short-term memory loss associated with rosuvastatin.
Pharmacotherapy. 2006 Aug;26(8):1190-2
Galatti L, Polimeni G, Salvo F, Romani M, Sessa A, Spina E.
Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy. lgalatti@unime.it
Memory loss and cognitive impairment have been reported in the literature in association with several 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), but we found no published case reports associated with rosuvastatin. To our knowledge, this is the first reported case of rosuvastatin-related short-term memory loss. A 53-year-old Caucasian man with hypercholesterolemia experienced memory loss after being treated with rosuvastatin 10 mg/day. He had no other concomitant conditions or drug therapies. After discontinuation of rosuvastatin, the neuropsychiatric adverse reaction resolved gradually, suggesting a probable drug association. During the following year, the patient remained free from neuropsychiatric disturbances. Clinicians should be aware of possible adverse cognitive reactions during statin therapy, including rosuvastatin.
PMID: 16863497 [PubMed - indexed for MEDLINE]


Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults.
Am J Med. 2004 Dec 1;117(11):823-9.
Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB.
Center for Clinical Pharmacology, University of Pittsburgh, Pennsylvania 15260, USA. mfm10@pitt.edu
“This study provides partial support for minor decrements in cognitive functioning with statins. Whether such effects have any long-term sequelae or occur with other cholesterol-lowering interventions is not known.” This is the second of two studies by Muldoon, both showing measurable cognitive decline in statin groups after only 6 months, using Neuropsychological (NP) testing. Further, this study identifies the subset of NP tests that are “statin sensitive” in detecting the cognitive deficits. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15589485


Effects of lovastatin on cognitive function and psychological well-being.
Muldoon MF, Barger SD, Ryan CM, Flory JD, Lehoczky JP, Matthews KA, Manuck SB.
After 6 months, 100% of the patients on placeboes showed a measurable increase in cognitive function, while the statin patients showed a measurable decrease in cognitive function in some areas.
Am J Med. 2000 May;108(7):538-46.
PMID: 10806282 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10806282&dopt=Abstract


Cognitive impairment associated with atorvastatin and simvastatin.
King DS, Wilburn AJ, Wofford MR, Harrell TK, Lindley BJ, Jones DW.
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA. dking@pharmacy.umsmed.edu
Pharmacotherapy. 2003 Dec;23(12):1663-7.
“we report two women who experienced significant cognitive impairment temporally related to statin therapy. One woman took atorvastatin, and the other first took atorvastatin, then was rechallenged with simvastatin. Clinicians should be aware of cognitive impairment and dementia as potential adverse effects associated with statin therapy.” PMID: 14695047
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14695047


“DRUGS THAT MAKE YOU FORGET”
Australian Adverse Drug Reactions Bulletin (Australia’s equivalent to the FDA)
Volume 17, Number 3, August 1998, section 3, page 3
Simvastatn is listed under “DRUGS THAT MAKE YOU FORGET”
Recognizing the 14 reports of Amnesia under that drug, .8% of the total adverse effects for that drug.
www.health.gov.au/tga/docs/pdf/aadrbltn/aadr9808.pdf


Statin-associated memory loss: analysis of 60 case reports and review of the literature.
Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM.
Drug Information Service, Duke University Medical Center, Durham, North Carolina 27710, USA. Pharmacotherapy. 2003 Jul;23(7):871-80.
This study searched the MedWatch drug surveillance system of the Food and Drug Administration (FDA) from November 1997-February 2002 for reports of statin-associated memory loss. They also reviewed the published literature. References from the study are good for follow-up research.
Abstract: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12885101&dopt=Abstract
Full Study Text free on Medscape:
http://www.medscape.com/viewarticle/458867


The Role of Lipid-Lowering Drugs in Cognitive Function: A Meta-Analysis of Observational Studies
from Pharmacotherapy
Posted 06/30/2003
Mahyar Etminan, Pharm.D., Sudeep Gill, M.D., FRCPC, Ali Samii, M.D., FRCPC
Although this study does bring the cognitive issues to light, it is a very poor study. The authors left out the pivotal study by Dr. Muldoon, that showed 100% of statin users had a measurable loss of cognitive ability after 6 months, while 100% of the placebo group improved their scores.
Abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12820814&dopt=Abstract
Full Study Text free on Medscape:
http://www.medscape.com/viewarticle/456866


Simvastatin-Associated Memory Loss
Amanda Orsi, Pharm.D., Olga Sherman, Pharm.D., and Zegga Woldeselassie, Pharm.D.,
Abstract: The statins are widely used to treat dyslipidemias. They are generally associated with mild adverse effects, but rarely, more serious reactions may occur. A 51-year-old man experienced delayed-onset, progressive memory loss while receiving simvastatin for hypercholesterolemia. His therapy was switched to pravastatin, and memory loss resolved gradually over the next month, with no recurrence of the adverse effect.
from Pharmacotherapy
Posted 06/01/2001
Page 1 of 3: http://www.medscape.com/viewarticle/409738?WebLogicSession=PXke2H8h99pyNVSCajAh5clptzOAHJSZuNBobSwWmi9veWjdJ2A3%7C-1468812056489609316/184161392/6/7001/7001/7002/7002/7001/-1
full printable version: http://www.medscape.com/viewarticle/409738_print

ADR of the Month
September 2001 Vol. 6 No. 9
EDITORS
Michelle W. McCarthy, Pharm.D.
Anne E. Hendrick, Pharm.D.

University of Virginia Health System
Department of Pharmacy Services
Drug Information Center
PO Box 800674
Charlottesville, VA 22908-0674
http://hsc.virginia.edu/pharmacy-services/Newsletters/ADR%20of%20the%20Month/ADRMonth%209-01htm.html


Do HMG-CoA reductase inhibitors impair memory?
The Tablet, a general member benefit published by the British Columbia Pharmacy Association, September 2001, Volume 10 no 8.
Excerpt:
Do HMG-CoA reductase inhibitors impair memory? After taking simvastatin for a year, a 51-year-old patient developed short term memory loss, to the extent of being unable to complete his sentences because he would forget what he was going to say. The drug was discontinued, replaced by pravastatin, and within one month his memory returned.14 In a separate case, a 67-year-old woman developed impaired short-term memory, altered mood, social impairment, cognitive impairment and dementia after one year of atorvastatin therapy. When atorvastatin was discontinued, her memory, mood and cognition improved completely.15 Memory impairment in a patient receiving atorvastatin has been reported to the BC Regional ADR Centre.
REFERENCES:
14. Orsi A, Sherman O, Woldeselassie Z. Simvastatin-associated memory loss.
15. King DS, Jones DW, Wofford MR et al. First report of cognitive impairment in an elderly patient: case report. Pharmacotherapy 2001 Mar; 21: 371.

http://www.bcpharmacy.ca/publications/thetablet/pdf_version/BCPhA_Tablet-Sep2001.pdf
See page 11 of 16:

[Direct neuronal effects of statins.]
Nervenarzt. 2006 Mar;77(3):289-93.
[Article in German]
Bosel J, Endres M.
Neurologische Klinik und Poliklinik, Charite - Universitatsmedizin Berlin, .
Statins, i.e. HMG-CoA reductase inhibitors, reduce the risk of stroke and may have therapeutic potential for other neurologic diseases, including multiple sclerosis and Alzheimer's disease. In addition to lowering cholesterol levels, statins exert a number of cholesterol-independent (pleiotropic) effects. While endothelial, anti-thrombotic, anti-inflammatory, and immunomodulatory, i.e. peripheral, effects of statins are well known, little is known about the direct effects on neurons. This may be of clinical relevance because some statins are able to cross the blood-brain barrier. Recent experimental studies demonstrate that statins reduce the activity of neuronal glutamate receptors and protect neurons from excitotoxic insults. At higher doses, however, statins may also inhibit neurite sprouting and even induce neuronal apoptosis.
PMID: 16028081 [PubMed - in process]

COGNITIVE IMPAIRMENT IN NEUROMUSCULAR DISORDERS
M A R IA G R A Z IA D .A N G E L O , M D , P h D ,1 a n d N E R E O B R E S O L IN , M D 2
1 I s titu to d i R ic e r c a e C u r a a C a r a tte r e S c ie n tiÞ c o E . M e d e a , L a N o s tr a F a m ig lia , V ia d o n L u ig i M o n z a 20 , 23 8 4 2 B o s is io P a r in i, I ta ly
2 C e n tr o D in o F e r r a r i, F o n d a z io n e I s titu to d i R ic e r c a e C u r a a C a r a tte r e S c ie n tiÞ c o , O s p e d a le M a g g io r e P o lic lin ic o M a n g ia g a lli e R e g in a E le n a , D ip a r tim e n to d i S c ie n z e N e u r o lo g ic h e , U n iv e r s it` d i M ila n o , M ila n , I ta ly 2006

ABSTRACT: Several studies have suggested the presence of central nervous system involvement manifesting as cognitive im pairment in diseases traditionally confined to the peripheral nervous system . The aim of this review is to highlight the character of clinical, genetic, neurofunctional, cognitive, and psychiatric deficits in neuromuscular disorders. A high correlation between cognitive feature and cerebral protein expression or function is evident in Duchenne muscular dystrophy , myotonic dystrophy (Steinert disease), and mitochondrial encephalomyopathies; direct correlation b etw een tissue-specific protein expression and cognitive deficits is still elusive in certain neuromuscular disorders presenting with or without a cerebral abnormality , such as congenital muscular dystrophies, congenital myopathies, amyotrophic lateral sclerosis, adult polyglucosan body disease, and limb-girdle muscular dystrophies. No clear cognitive deficits have been found in spinal muscular atrophy and facioscapulohumeral dystrophy . Muscle Nerve 00: 0 0 0 Ð 0 0 0 , 2 0 0 6




Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin.
Thelen KM, Rentsch KM, Gutteck U, Heverin M, Olin M, Andersson U, von Eckardstein A, Bjorkhem I, Lutjohann D.
J Pharmacol Exp Ther. 2006 Mar;316(3):1146-52. Epub 2005 Nov
Department of Clinical Pharmacology, University of Bonn, Sigmund-Freud-Strasse
25, D-53105 Bonn, Germany.
On a global scale, there is an increasing tendency for a more aggressive treatment of hypercholesterolemia. Minor effects of statins on brain cholesterol metabolism have been reported in some in vivo animal studies, and it seems that this is due to a local effect of the drug. We treated male mice of the inbred strain C57/BL6 with a high daily dose of lipophilic simvastatin (100 mg/kg b.wt.) or hydrophilic pravastatin (200 mg/kg b.wt.) or vehicle (controls) by oral gavage for 3 days. To compare the impact of both statins on brain cholesterol synthesis and degradation, levels of cholesterol, its precursor lathosterol, and its brain metabolite 24(S)-hydroxycholesterol as well as statin concentrations were determined in whole-brain lipid extracts using mass spectrometry. The expression of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase mRNA and of other target genes were evaluated using real-time reverse transcription-polymerase chain reaction. In addition, analysis of liver and serum samples was performed. Similar levels of simvastatin and pravastatin were detected in whole-brain homogenates. Cholesterol contents in the brain, liver, and serum were not affected by high-dose statin treatment. Whereas brain cholesterol precursor levels were reduced in simvastatin-treated animals only, no effect was observed on the formation of the brain cholesterol metabolite, 24(S)- hydroxycholesterol. Polymerase chain reaction analysis revealed that mRNA expression of HMG-CoA reductase and ATP-binding cassette transporter A1 in the brain was significantly up-regulated in simvastatin-treated animals compared with pravastatin-treated or control animals. We conclude that, under the present experimental conditions, brain cholesterol synthesis is significantly affected by shortterm treatment with high doses of lipophilic simvastatin, whereas whole-brain cholesterol turnover is not disturbed.
PMID: 16282522 [PubMed - in process]


Brain cholesterol turnover required for geranylgeraniol production and learning in mice.
Kotti TJ, Ramirez DM, Pfeiffer BE, Huber KM, Russell DW.
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3869-74. Epub
2006 Feb 27.

Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway. Here we report that this suppression causes a defect in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices with an inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimination of 24- hydroxylase on LTP are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning. PMID: 16505352 [PubMed - indexed for MEDLINE]





People’s Pharmacy
Are Cholesterol Drugs Linked to Memory Loss?
Newspaper Columns, Editorial February 13, 2006
The article describes letters from readers pouring in about memory loss in association with statin use. Many of the readers had improvement when stopping the statins. The conclusion: “But for those few who develop memory problems, such drugs can be devastating. More research into this complicated issue is urgently needed.”



AMNESIA & STATINS


Lipitor, Thief of Memory
Dr. Duane Graveline, retired family MD, USAF Flight Surgeon, researcher in space medicine and US Astronaut, who suffered adverse effects from Lipitor. The book is available through Amazon.com. Dr. Graveline maintains several websites and is working on a second book about statin drug side effects:
www.spacedoc.net (you can start here and read about his life and his books)
http://www.spacedoc.net/lipitor_thief_of_memory.html
http://www.spacedoc.net/lipitor.htm
http://www.spacedoc.net/statin_dialogues.htm

Australian Adverse Drug Reactions Bulletin (Australia’s equivalent to the FDA)
Volume 17, Number 3, August 1998, section 3, page 3
Simvastatn is listed under “DRUGS THAT MAKE YOU FORGET”
Recognizing the 14 reports of Amnesia under that drug, .8% of the total adverse effects for that drug.
www.health.gov.au/tga/docs/pdf/aadrbltn/aadr9808.pdf


===========
Please see also:


Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins.
Am J Med Genet. 2004 Dec 15;131A(3):287-98.
Edison RJ, Muenke M.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda,
Maryland 20892-3717, USA.
“The cholesterol-lowering "statin" drugs are contraindicated in pregnancy, but few data exist on their safety in human gestation. We reviewed case reports for patterns suggesting drug-related effects on prenatal development and considered a variety of mechanisms by which such effects, if confirmed, might occur. This uncontrolled case series included all FDA reports of statin exposures during gestation, as well as others from the literature and from manufacturers. Exposures and outcomes were reviewed and were tabulated by individual drug. Age-specific rates of exposure to each drug among women of child-bearing age were estimated. Of 214 ascertained pregnancy exposures, 70 evaluable reports remained after excluding uninformative cases. Among 31 adverse outcomes were 22 cases with structural defects, 4 cases of intrauterine growth restriction, and 5 cases of fetal demise. There were two principal categories of recurrent structural defects: cerivastatin and lovastatin were a_ssociated with four reports of severe midline CNS defects; simvastatin, lovastatin, and atorvastatin were all a_ssociated with reports of limb deficiencies, including two similar complex lower limb defects reported following simvastatin exposure. There were also two cases of VACTERL a_ssociation among the limb deficiency cases. All adverse outcomes were reported following exposure to cerivastatin, simvastatin, lovastatin, or atorvastatin, which are lipophilic and equilibrate between maternal and embryonic compartments. None were reported following exposure to pravastatin, which is minimally present in the embryo. Statins reaching the embryo may down-regulate biosynthesis of cholesterol as well as many important metabolic intermediates, and may have secondary effects on sterol-dependent morphogens such as Sonic Hedgehog. The reported cases display patterns consistent with dysfunction of cholesterol biosynthesis and Sonic Hedgehog activity. Controlled studies are needed to investigate the teratogenicity of individual drugs in this cla_ss.”
PMID: 15546153 [PubMed - in process]


Statins and risk of polyneuropathy, A case-control study
D. Gaist, MD, PhD; U. Jeppesen, MD, PhD; M. Andersen, MD, PhD; L.A. García Rodríguez, MD, MSc;
J. Hallas, MD, PhD; and S.H. Sindrup, MD, PhD
http://213.4.18.135/87.pdf full text

Preclinical safety evaluation of cerivastatin, a novel HMG-CoA reductase inhibitor.
von Keutz E, Schluter G.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9737641&dopt=Abstract
Institute of Toxicology, PH-Product Development, Bayer AG, Wuppertal, Germany
Am J Cardiol. 1998 Aug 27;82(4B):11J-17J.
PMID: 9737641
“In dogs, the species most sensitive to statins, cerivastatin caused erosions and hemorrhages in the gastrointestinal tract, bleeding in the brain stem with fibroid degeneration of vessel walls in the choroid plexus, and lens opacity.”

Subchronic toxicity of atorvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, in beagle dogs.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8864188&dopt=Abstract
Walsh KM, Albassam MA, Clarke DE.
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
“The toxicity of atorvastatin (AT), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG), was evaluated in beagle dogs… hemorrhage in gallbladder and brain, demyelination of optic nerve, and skeletal muscle necrosis”


Brain and optic system pathology in hypocholesterolemic dogs treated with a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
Am J Pathol. 1988 Sep;132(3):427-43.

Berry PH, MacDonald JS, Alberts AW, Molon-Noblot S, Chen JS, Lo CY, Greenspan MD, Allen H, Durand-Cavagna G, Jensen R, et al.
Department of Safety Assessment, Merck Sharp & Dohme-Chibret, Riom, France.
The cholesterol lowering compound lovastatin, a competitive inhibitor of 3- hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34 HMG CoA reductase), was given in nine separate experiments to normocholesterolemic dogs at rates up to 180 times the maximum therapeutic dose in man (1 mg/kg/day). Mean serum total cholesterol concentrations were reduced as much as 88% below normal. Clinical evidence of neurotoxicity occurred in up to 37% of animals given 180 mg/kg/day lovastatin for 11 or more days, especially in one laboratory where the dosing regime resulted in higher concentrations of plasma drug levels. Dogs receiving 60 mg/kg/day or less never exhibited neurologic signs. The central
nervous system (CNS) of affected dogs exhibited endothelial degeneration and hemorrhagic encephalopathy. Focal extravasation of horseradish peroxidase occurred frequently (6/8) in the retrolaminar optic nerve of asymptomatic or clinically affected dogs given 180 mg/kg/day lovastatin, with endothelial degeneration and discrete optic nerve degenerative lesions interpreted as ischemic. The association between the degree of hypocholesterolemia and occurrence of clinical signs was not exact. Total brain cholesterol was similar in treated and control dogs. Hypocholesterolemic dogs had proportionally lowered serum concentrations of alpha-tocopherol, but oral supplementation of this vitamin did not prevent the neurologic syndrome. Endothelial degeneration in the CNS and optic nerve may have reflected in vitro morphologic effects of HMG CoA reductase inhibitors due to extreme inhibition of nonsterol isoprene synthesis. Retinogeniculate axonal (Wallerian-like) degeneration occurred in greater than or equal to 12% of dogs given 60 mg/kg/day or more lovastatin, with central chromatolysis of occasional retinal ganglion cells. These neuroaxonal changes may have been secondary to vascular effects, but superimposed direct neurotoxic action at the high dosage levels of lovastatin could not be excluded. There was no evidence of drug induced adverse effects in the CNS of dogs given up to 30 mg/kg/day lovastatin for 2 years. PMID: 3414776 [PubMed - indexed for MEDLINE]


Finally, on memory loss and statins: Sworn testimony from the Baycol trial in Corpus Christi, Texas. From the transcript of the AM Session on 03-05-03, in the case Hollis Haltom Vs. Bayer Corporation. Testifying under oath,., in response to the plaintiff’s attorney’s question, “What is your current position at Bayer?”, LAWRENCE POSNER, M.D of BAYER stated: “I'm the -- currently I'm the head of worldwide regulatory affairs for our prescription drug business, which means I have responsibility in somewhere between 60 and 100 countries where we sell products for registrations, compliance, things of that nature.” Excerpts from the trial transcript follow, with the Q indicating counsel’s Question, and the A indicating Dr. Posner’s Answer:
Q. So there are some concerns addressed here back in 1995 about testing up to .8. And do you know what the nature of the concern was?
A. Yes. It was related to a side effect that occurred in the brain.
Q. Of what kind of animal?
A. It occurred in the brain of dogs.
Q. Okay. So there was a side effect that occurred in dogs, and then there was a concern about whether you wanted to go forward and test at this higher dose level in human beings, given what you had learned about the dogs, right?
A. That's correct.
Q. Okay. Now, did you just say, well, let's forget about these concerns and we'll go ahead and put .8 on the market anyway, or did you do some further analysis that was not mentioned the other day?
A. Yes. The authors of this had -- they had two concerns. One concern was the toxicity that they found in the brain of dogs. But the other was that they had no way to identify this and who might be at risk before it happened. So there was no way to detect that someone was at risk for this side effect.
[skip some testimony on other topics]
Q. Do you remember in one kind of animal there had been some studies done that there could be a particular kind of problem with one kind of animal?
A. Oh, yeah. Yes, from the -- that's correct, from the toxicology studies.
Q. Okay. And were you able to demonstrate to your own satisfaction, to SmithKline's satisfaction, to the FDA's satisfaction, that that particular problem that showed up with that kind of animal is not something that happens in human beings?
A. Yes. We did it -- we did it by explaining the toxicology data. We also explained it on the basis of kinetic data. That actually at the higher levels of drug, what happens is a certain amount of drug is bound to proteins in the body that circulate; and therefore, is not -- cannot cause side effects. And actually, a much smaller proportion of the drug is free. And that what you corrected for that, you actually found out that the margins of safety were in fact greater than you would predict just from the animal data.
Q. And as you move forward then and got approval and sold Baycol from 1997 through 2001, did that problem that had shown up with that one kind of animal ever become a problem with human beings?
A. It was actually shown with other statins as well. It wasn't unique to cerivastatin. It was a problem -- it was identified early on with lovastatin and some of the others. In fact, for none of the statins did it ever predict for any clinical problem or toxicity.
Q. So these animals would have that same problem regardless of which statin -- or at least with other statins?
A. Certainly with lovastatin it was true.
Q. But when it came time to human beings, that just wasn't something that happened to human beings?
A. And I think today no one pays much attention to it.

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