Exactly, beagle dogs are a good predictor of statin cognitive adverse
effects.

From the Lipitor Prescribing Information:

http://www.lipitor.com/cwp/appmanager/lipitor/lipitorDesktop?_nfpb=true&_pageLab
el=prescribingInformation

CNS Toxicity

Brain hemorrhage was seen in a female dog treated for 3 months at 120
mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another
female dog that was sacrificed in moribund condition after 11 weeks of
escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a
systemic exposure approximately 16 times the human plasma
area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80
mg/day. A single tonic convulsion was seen in each of 2 male dogs (one
treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS
lesions have been observed in mice after chronic treatment for up to 2 years
at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These
doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC
(0-24) based on the maximum recommended human dose of 80 mg/day.

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and
mononuclear cell infiltration of perivascular spaces, have been observed in
dogs treated with other members of this class. A chemically similar drug in
this class produced optic nerve degeneration (Wallerian degeneration of
retinogeniculate fibers) in clinically normal dogs in a dose-dependent
fashion at a dose that produced plasma drug levels about 30 times higher
than the mean drug level in humans taking the highest recommended dose.

Sworn testimony from the Baycol trial in Corpus Christi, Texas.

From the trial 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.

Statin Adverse Effects FAQ: MEMORY LOSS & STATINS, AMNESIA & STATINS

MEMORY LOSS & STATINS, AMNESIA & STATINS

References (updated as of  January 7, 2005):

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=Abstra
ct&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=1
0806282&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.eduPharmacotherapy. 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=Abstra
ct&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=1
2885101&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=1
2820814&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=PXke2H8h99pyNVSCajAh5
clptzOAHJSZuNBobSwWmi9veWjdJ2A3%7C-1468812056489609316/184161392/6/7001/7001/700
2/7002/7001/-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/ADR
Month%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:

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=9
737641&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=8
864188&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"

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.

I have suffered serious damage from statins. They have virtually ended
a career requiring extraordinary complex language use and
multi-tasking. They have also caused me serious permanent vision
damage, myopathy, myosisits, rhabdomyolysis, joint pain, tendon and
ligament pain and damage, skin lesions, severe and dangerous memory
loss, and the loss of a life time of savings in order to live because I
have lost the skills one needs to work as a reporter, journalist,
writer and editor.

Warning: statins can and do cause serious sometimes permanent damage.

If you possibly can, do not take these drugs. Lowering cholesterol, if
one feels this is absolutely necessary, can be achieved to reasonable
levels by diet and exercise.

Zee

no cardiovascular disease, total cholesterol 9.7

To: Dr. Harman:

Is the treatment you are speaking about is 'Arricept' (spelling) ? If so, my
mother is on that, and to be quite truthful, it is not working very well.
She has become very obstinate, not to mention mean. I guess right now, mean
describes my mother. It is very difficult dealing with her tantrums.

Barb