BBB and Statins
 

I previously posted the link between the Blood-brain barrier (BBB) permeability and PD. Everything that increases permeability increases PD symptoms, everything that decreases permeability improves symptoms. In other words, we parkies have a defective BBB, with higher porosity than normal.
I mentioned that statins reduce the permeabilty of the BBB, see
http://www.ncbi.nlm.nih.gov/sites/en..._uids=16729291
and predicted statins should improve PD symptoms.
Now, evidence has been recently published showing Simvastastin reduces the incidence of PD.
http://www.eurekalert.org/pub_releas...-rfs071707.php

"Boston, MA -- Researchers from Boston University School of Medicine (BUSM) have found that the statin, simvastatin, reduces the incidence of Alzheimer’s disease and Parkinson’s disease by almost 50 percent. This is the first study to suggest that statins might reduce the incidence of Parkinson’s disease. These findings, will be published in the July online open access journal BioMed Central (BMC) Medicine."
See also,
http://www.medpagetoday.com/Neurolog...isease/tb/6202


I have found a professor who specialises in the BBB, who is interested in the connection with PD, and intends to work on it when she finishes travelling in August.

One other point on the BBB. We know stress has a catestrophic effect on PDers, and opens the pores of the BBB. Could it be that when stress widens the perneability, that carbidopa is able to enter the brain, and prevent the decarboxylation of levodopa to dopamine, causing a freeze.
Carbidopa is added to levodpa in Sinemet, to prevent breakdown of the levodopa whilst it is in the body. Carbidopa cannot normally pass the BBB.
Ron

Statins
 

Seems like another contradictory study to what we were all reading just a few months ago. Who knows what to believe. I stopped taking a statin as a result of reading this article below. Now maybe I should start taking it again???

---------------------------

Low cholesterol levels linked with higher risk of Parkinson's disease
• Fears that statins could cause increase in illness
• Health charities urge caution over findings

Polly Curtis, health correspondent
Monday January 15, 2007
The Guardian, United Kingdom
http://www.guardian.co.uk/frontpage/...990648,00.html

Scientists are to investigate why people with low cholesterol levels appear to be more likely to develop Parkinson's disease, following concerns that statins - given to control cholesterol - could cause an increase in the numbers of people with the illness.

About 2.3 million adults in the UK take statins to help control their cholesterol levels; the American scientists have found that those with lower levels of cholesterol are more likely to develop the degenerative neurological disorder of Parkinson's disease.

The link between statins and Parkinson's is not yet understood, and health charities last night urged caution. But the scientists behind the research warn that if they get confirmation of the finding, in their follow-up study of 16,000 people, there could be a surge in Parkinson's diagnoses in the next five years as the effects of the drug set in.

The initial study compared 124 people diagnosed with Parkinson's with a control group of 112. They found that the people with low levels of "bad" LDL cholesterol were in excess of three times more likely to be in the Parkinson's group than those with high cholesterol.

But they also found that those in the trial who took statins were less likely to develop Parkinson's disease, though the study's leader suggested this could be because the group with Parkinson's had had low cholesterol all their lives and that the effect of low cholesterol could be cumulative.

Statins are the world's biggest selling drug. The drug company Pfizer reported sales of $12.2bn (£6.2bn) for its statin, Lipitor, in 2005. The National Institute for Clinical Excellence last year recommended more people take them in the UK, raising the number of customers from 2.3 million to 5.2 million.

The head of the study, Xuemei Huang, at the University of North Carolina, said: "I'm definitely concerned [about the initial findings] which is why I'm conducting a prospective study of 16,000 people."

People should not stop taking statins, she said. The risk of heart disease in those who should be taking statins far outweighed the risk of developing Parkinson's.

The study, which is reported today in the journal Chemistry and Industry, has raised more questions than it has answered. It has not, for example, established whether low cholesterol is a cause or consequence of Parkinson's.

David Dexter, senior lecturer in neuropharmacology at Imperial College London, said: "Although the association is worrying, the study was carried out only in a small number of subjects and hence needs confirming in a larger population. Lower LDL-C levels may also be a consequence of Parkinson's and not a cause. Indeed, the study did not take into account the dietary intake of the two groups in the study, [which] may be important since some Parkinson's patients find it difficult to eat or even swallow food, thus reducing the intake of fats."

Dr Huang said the well-established link between Parkinson's and apoE2, a gene associated with lower LDL cholesterol, supported her theory that low LDL was the culprit in many cases of Parkinson's.

Kieran Breen, director of research at the Parkinson's Disease Society, said people should be wary of such a small study. "Further research into any link between low LDL cholesterol and cholesterol-lowering drugs with Parkinson's is needed. We hope that the proposed study will shed further light on this. The exact causes of Parkinson's are unknown. Research is ongoing. It is generally understood that Parkinson's [arises] from genetic and environmental factors."

Peter Weissberg, medical director of the British Heart Foundation, said: "We are concerned that any suggestion of a link between statins and Parkinson's disease would unnecessarily scare the millions of people benefiting from statins in the UK. There is no evidence to suggest that statins cause [the] disease. On the other hand, there is overwhelming evidence that statins save lives by preventing heart attacks and strokes."
blueline2.gif


'Link' Between Statins and Parkinson's Probed

Posted on: Monday, 15 January 2007, 12:00 CST
http://www.redorbit.com/news/health/...ource=r_health

EXPERTS sought to reassure patients after scientists announced they were planning an in-depth study on the link between statins and Parkinson's disease. The cholesterol-lowering drugs are taken by an estimated three million Britons and are renowned for preventing heart attacks and strokes. But now scientists are planning a detailed study after research showed a link to Parkinson's disease, which affects about 120,000 people in the UK. Charities urged people to continue taking their statins, saying the drugs saved lives. According to a report in the magazine Chemistry & Industry, researchers in the United States are planning a largescale clinical trial on the link. It comes after experts, led by Xuemei Huang from the University of North Carolina, said they had found the strongest link yet between low-density lipoprotein (LDL) cholesterol levels and Parkinson's. High levels of LDL cholesterol are linked to heart disease. Statins are known to reduce these LDL levels. The study of 124 patients revealed that those with low levels of LDL cholesterol were about three times as likely to develop Parkinson's disease as those with higher levels. Study leader Dr Xuemei Huang told the magazine she was worried by the results. "Yes I am very concerned, which is why I am planning a 16,000-patient prospective study to examine the possible role of statins, " she said.She said there could be big surges in the number of Parkinson's cases in the next five years if a link is confirmed.British experts sought to calm fears, saying there was little or no evidence of a link.Dr David Dexter, senior lecturer in neuropharmacology at Imperial College, London, said: "With the evidence we have at the moment, I would say there is not much cause for concern that statin use may cause Parkinson's disease. "The study by Huang and colleagues indicating an association between lower LDL levels and Parkinson's disease goes against current scientific beliefs."

statins and BBB
 

One of the primary problems with the use of statins is that they possess "pleiotrophic" effects--too many biological functions depend upon, or are related to, cholesterol and /or the mavelonate pathway that is blocked by statins (HMG-CoA reductase inhibitors). On the positive side, statins are very powerful anti-inflammatory agents and are able to wonderously increase perfusion everywhere . Their short term use immediately post heart attack seems to be of unquestionable use. but to take this medication for life?

At present, research is underway determining if statins could be utilized for immunosuppression due to the effect upon T-cell suppression. and also as a cancer chemotherapeutic agent, due to statins' effects upon the small GTPases (Rho, Ras, Rab)-- statins interfere with prenylation of these translational proteins. I will make the glib observation that if you are planning on a transplant or developing cancer, possibly statins are a good bet (though the original Pravachol trial "CARE" found a 1200% relative increase in breast cancer in the women in their trial--this statistic was deemed "an anomoly" due to the fact that the placebo group only had 1 incident, a # less than expected, though increases in cancer have been found in statin treatment groups from many other studies, esp. in elderly (>70 yrs) males.

Cholesterol has recently been found to be ESSENTIAL to the neuronal synapses in the brain and
ApoE is the most abundant apolipolipid in the brain and delivers cholesterol to the neurons. (studies with statins and alzheimer's utilizing statins to decrease ApoE4 are Still underway. Problem with these studies is that initially one would expect some benefit from statins due to their anti inflammatory effects, but IF they ran long enough (ie >5 ys) any effects w/ depletion of cholesterol would be evident. Cholesterol is made de novo in the brain itself; cholesterol cannot cross the blood brain barrier, so the brain has its own mavelonate pathway to its production. and fortunately, brain cholesterol has a VERY LONG HALF LIFE--5 yrs. any studies that last <5yrs (almost ALL pharmaceutical studies) will not pick up the effects of lowered brain cholesterol and ApoE. Recently, Alzheimer's reserach has been shifting toward increases in tau phosphorylation as etiopathogenic in Alzheimer's--and statins increase tau phosphorylation. statins are studied in alzheimer's because they specifically decrease ApoE--the substance responsible for transporting cholesterol to the neurons for synaptic functions to occur. with the newest information that Apoe is essential for neuronal synapses, manipulating cholesterol and apoe for alzheimer's seems more than a questionable undertaking.

NEUROBIOLOGY:
Cholesterol--Making or Breaking the Synapse
Ben A. Barres and Stephen J. Smith
Synapses are regions where neurons meet and communicate. But how is their formation regulated in the developing and adult brain? As Smith and Barres explain in their Perspective, the answer could not be simpler. It turns out that, at least in the culture dish, a type of glial cell called an astrocyte produces the molecule cholesterol, which is taken up by neurons and then directs formation of synapses perhaps by regulating vital signaling pathways (Mauch et al.).

Neurons need cholesterol secreted by glial cells to form and maintain functional synapses. And cholesterol is necessary for synaptogenesis and probably for production and transport of vesicles necessary for neurotransmission. If one accepts the concept of neuronal plasticity in the adult brain, then deliberately suppressing cholesterol metabolism in the brain seems questionable.

(to be continued in next post)
madelyn

additional article --in vitro effects of statins
 

Journal of Neurochemistry
Volume 89 Page 24 - April 2004
doi:10.1046/j.1471-4159.2003.02305.x
Volume 89 Issue 1


HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranylpyrophosphate synthesis
Joachim G. Schulz, Julian Bösel, Magali Stoeckel, Dirk Megow, Ulrich Dirnagl and Matthias Endres
Abstract

To determine whether neurite outgrowth depends upon the mevalonate pathway, we blocked mevalonate synthesis in nerve growth factor-treated PC12 cells or primary cortical neurones with atorvastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and substituted different intermediates of the mevalonate pathway. We show that HMG-CoA reductase inhibition causes a profound reduction of neurite length, neurite loss and ultimatively cell death in undifferentiated and pre-differentiated PC12 cells and also in rat primary cortical neurones. Geranylgeranylpyrophosphate, but not farnesylpyrophosphate, squalene or cholesterol, completely compensated for the lack of mevalonate. Our data indicate that, under HMG-CoA reductase inhibition, geranylgeranylpyrophosphate rather than farnesylpyrophosphate or cholesterol is critical for neurite outgrowth and/or maintenance. Loss of neurites is an early manifestation of various neurodegenerative disorders, and dysfunction of isoprenylation might play a role in their pathogenesis.

#2:
Neurodegenerative Disorders and Cholesterol
Author: Makoto Michikawa1

Source: Current Alzheimer Research, Volume 1, Number 4, November 2004, pp. 271-275(5)

Abstract:

It has been suggested that a high serum cholesterol level is a risk factor for Alzheimer's disease (AD), that treatment with cholesterol-lowering drugs (statins) reduces the frequency of AD development, and that the polymorpholism of genes encoding proteins regulating cholesterol metabolism is associated with the frequency of AD development. However, the mechanism by which high serum cholesterol level leads to AD, still remains unclarified. Several recent studies have shown the results challenging the above notions. Here another notion is proposed, that is, a low high-density lipoprotein (HDL) level in serum and cerebro-spinal fluid (CSF) is a risk factor for the development of AD; moreover, the possibility that AD and Niemann-Pick type C disease share a common cascade, by which altered cholesterol metabolism leads to neurodegeneration (tauopathy) is discussed. In this review, the association between cholesterol and AD pathogenesis is discussed from different viewpoints and several basic issues are delineated and addressed to fully understand the mechanisms underlying this relationship.

case presesntation of patient with statin induced PD
 

Do statins induce Parkinsons?
The following study and letter in response was
published in the German
medical journal Der Nervenarzt.
~~~~~~~~~~~~~~~~~~~~
Study on statin myopathy:

Der Nervenarzt
Publisher: Springer-Verlag Heidelberg
ISSN: 0028-2804 (Paper) 1433-0407 (Online)
DOI: 10.1007/s00115-002-1445-6
Issue: Volume 74, Number 2
Date: February 2003
Pages: 115 - 122
Fibrat-/Statin-Myopathie


~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Letter in response with case study of
statin-unmasked Parkinsons

"To the excellent review about the development
of myopathies following long-term medication of
cholesterol level decreasing fibrates and statins, there
should be considered additional differential diagnostic
possibilities.

Because of the similar clinical symptomatology
with muscle aches and increased stiffness, the
diagnosis of statin-> induced aggravated
Parkinson Disease Syndrome should be
discussed. The development of such muscular
side effects is seen more with statins than with
fibrates.

The case report in Table 1 indicates the
history of a 60 year old patient with statin-induced
Parkinson Syndrome occurring over a long time.

On the other hand, with central effective
statins, a possible neuro-protective effect in
neuro-degenerative diseases has been considered,
especially in dementia. But long term use of statins,
especially Lovastatin, leads to the reduction of
coenzyme Q10 and can cause damage of the
mitochondrial breathing chain. Co Q-10 is an electron
receptor in the mitochondrial complexes 1 and 2 and
very effective absorber of radicals. This antigen
substance increases the complex 1 activity.
Co-Q10 shows a certain therapeutic effect with
encephalomyopathy where there is a lack of
various enzyme functions of the breathing chain.

Dysfunction of various parts of the mitochondrial
breathing chain is also considered in the
pathophysiological mechaism of idiopathic
Parkinson's disease.

Treatment with Co-Q10 in patients who are not
treated with Dopamine for Parkinson patients,
caused less disease symptomatology and
progression than patients treated with
placebo, though placebo treatment can cause
stimulation of dopaminergic neurotransmission.
Therefore, the long-term treatment with Co-Q10
possibly is neuroprotective in idiopathic morbid
Parkinson, though new evidence shows it
appears to cause mild symptomatic effect.

Under these circumstances treatment with
prophylactic medication of Co-Q10 which has
been well tolerated in doses up to 1200mgm in
patients with neurodegenerative diseases should
be considered for statin myopathy or statin-
induced Parkinson syndrome in addition to
discontinuation of the cholesterol decreasing
medication.

The Table 1 summarizes a patient with Parkinson
syndrome.

1995: start of therapy with Fluvastatin 40 mg.

1997: increasing weakness with shoulder and hip
pain on the right

1999: diagnosis of right sided Parkinson
syndrome of akinetic dominance type.
Careful induction of Pergolid with daily doses
of 3 mg and Salagen 7.5 mgm

2000: complaints about increasing edema
development in legs, loss of hair, start of a
potas.sium sparing diuretic and increasing
of Pergolid medication from 4.5 mg
in June 2000 to 6 mgm in December.

March 2001: discontinuation of Fluvastatin,
continuation of Pergolid 6 mg

June 2001: reduction of Pergolid to 4 mgm

Sept 2001 Pergolid 3 mgm. Improvement of edema

December 2001 discontinuation of Pergolid and
diuretics

March, 2002 discontinuation of Salagen"

Dr. Th. T. Muller

onto another "pleiotrophic effect: of statins--lowering coenzyme Q10. Of the 15 studies published concerning coq10 levels and statin use in humans, 9 have unequivocally shown decreases in either muscle coq10, platelet CoQ10, or plasma coq10. In 1990, Merck received 2 patents for manufacturing a preparation containing a statin and coenzyme Q10:

Patent Number: 4,933,165 Patent Number: 4,929,437

Below is a verbatim sample from Patent Number 4,933,165.

"What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutical carrier and an effective antihypercholesterolemic amount of an HMG-CoA reductase inhibitor and an amount of Coenzyme Q.sub.10 effective to counteract HMG-CoA reductase inhibitor-associated skeletal muscle myopathy.

2. A composition of claim 1 in which the HMG-CoA reductase inhibitor is selected from: lovastatin, simvastatin, pravastatin and sodium-3,5-dihydroxy-7-[3-(4-fluorophenyl)-1-(methylethyl)-1H-Indole-2yl]- hept-6-enoate.

3. A method of counteracting HMG-CoA reductase inhibitor-associated skeletal muscle myopathy in a subject in need of such treatment which comprises the adjunct administration of a therapeutically effective amount of an HMG-CoA reductase inhibitor and an effective amount of Coenzyme Q.sub.10 to counteract said myopathy.

4. A method of claim 3 in which the HMG-CoA reductase inhibitor is selected from the group consisting of: lovastatin, simvastatin, pravastatin and sodium-3,5-dihydroxy-7-[3-(4-fluorophenyl)-1-(methylethyl)-1H-Indole-2yl]- hept-6-enoate."

The company answer as to why the preparation was never manufactured, but patented, was that they wanted the exclusive patent in case somewhere in the future it was shown that depleting coq10 was not desirable and needed therapy.....(complicating the manufacturing of these combined suibstances is the fact that coenzyme q10 is manufactured almost exclusively by 4 companies in Japan these companies hold the patents on the manufacturing processes--interestingly enough one of these processes is based upon Tobacco leaves fermentation!)--they cannot make enough of the substance to be included in every statin taken by the millions of people who are on them.)

Ghirlanda G, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA
reductase inhibitors, J of Clin Pharm 1993;33(3):226-229.

The abstract concludes:“Our data show that the treatment with HMG-CoA
reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels
in normal volunteers and in hypercholesterolemic patients. CoQ10 is
essential for the production of energy and also has antioxidative
properties. A diminution of CoQ10 availability may be the cause of membrane
alteration with consequent cellular damage."

CoEnzyme Q10 is a major component of the mitochondrial electron
transport system, intricately involved in the production of ATP. Loss of
this function of Coenzyme Q10 results in dramatic energy depletion for all
cells. Coenzyme Q10 also functions as a major antioxidant in the central
nervous system,“neutralizing" reactive oxygen species produced during ATP
production. Reactive oxygen species that are not neutralized may cause cell
death, the definition of oxidative stress.

coq10 and statins
 

I am repeating several earlier posts, but recall the original article authored by clifford Shults, et al published in annals of neurology, 2002, showing a decrease in progression of disease in early onset PD patients who received 1200 mgm/day of coenzyme Q10. this was a small study (80 patients total),thus multiple center studies are underway using megadose coq10 in PD, ALS and huntington's. (recent published data from these studies concluded that use of megadose coq10 was "safe and tolerable".)

there are published studies in humans looking at statins and coq10 levels--in many of these studies, incontrovertible evidence that statins use lowers muscle, platelet or serum coq10 is available. 3 other studies were "inconclusive". CoQ10 is an essential element of the mitochondrial process that makes cellular energy--ATP. It also functions as one of the major anti-oxidants within the mitochondria, helping decrease reactive oxygen species. (important information, relating to the theory that PD is caused in part by mitochondrial dysfunction)
Again a repeat: Dr. Lieberman did a small study looking at progression rates of 2 different groups of PD patients--one taking a statin, the other not on statins., His conclusion after following these 2 groups after a period of (i think ~2yrs) was that their rates of progression were "similar". Included in this study was a small paragraph noting that of the original group who were not taking a statin, 5 patients were started on a statin during the trial period. Importantly (to me anyway) was the fact that ALL FIVE PATIENTS EXPERIENCED AN INCREASE IN SEVERITY OF THEIR SYMPTOMS AFTER STARTING A STATIN. I know that is a small #, but that's 100% of all the patients who were started on a statin during the trial period. the statin was stopped for a "washing out" period and when the symptoms did not revert, the drug was re-started. Does not increasing severity of symptoms qualify as "progression of disease?
There are NO scientific studies determining time for "wash out" of statins. Dr. Paul Phillips, interventional cardiologist from san diego who has been studying statin maintains that the plasma half life of statins is known, but the muscle tissue half life is not known, and may be the more important # in determining half life of statins.

Pleiotrophic effects of statins and some consequences
 

Excerpted from an article available online:
Steven K Baker MD and Mark A. Tarnoplasky, MD PhD. Statin myopathies: phathophysiologic and clinical perspectives. Clin Invest Med 2001; 24(5): 258-72

Cholesterol biosynthesis and the isoprenoids:
The inhibition of HMG-CoA reductase by the HMGRIs
is approximately 14 steps and 9 to 10 enzymatic
reactions removed from the terminal step(s) in cholesterologenesis
Furthermore,
mevalonic acid, the immediate product of HMG-CoA
reductase, is a pivotal precursor intermediate which
gives rise to the vital isoprenoids en route to cholesterol.
It is not surprising, therefore, that inhibiting this
important biosynthetic pathway causes pleiotropic
metabolic consequences33,34 (Fig. 1).
Prenylation is a fundamental element of posttranscriptional
lipid modification of proteins and other
compounds and affects their function. Some of the
known isoprenoids include the following: (1)
isopentyladenosine, required for transfer RNA synthesis;
(2) dolichols, required for glycoprotein synthesis;
(3) heme A, a polyisoprenoid component of the electron
transport chain; and (4) ubiquinone, a polyisoprenylated
quinoid cofactor of the electron transport
chain, which accepts electrons from complexes I and
II.6,35,… It is estimated that
over 1% of mammalian cellular proteins are isoprenylated.
38 Isoprenylated proteins have been implicated in
smooth muscle cell migration and proliferation,33 and
skeletal muscle cell growth and differentiation.39–42
These conclusions were borne out of experiments in
which statin treatment impaired cell development in
culture, whereas the coapplication of mevalonate or
its distal metabolites (i.e., farnesol or geranylgeraniol)
reversed many of the inhibitory cellular effects of
statins.

in reference to #1--interference with tRNA--statins interfere with selenoprotein tRNA, and specifically decrease selenoprotein N. the glutathione peroxidase family, and the thioredoxin reductases, were recently identified as selenoproteins. theoretically, thru this action, statins could interfere with glutathione reductase activity which re-cycles glutathione within the brain--the major anti-oxidant within the brain.

in reference to #2--dolichols--the substantia nigra is composed largely of lipids. the Most abundant lipid comprising the Substantia Nigra is DOLICHOLS- accounting for up to 45% of the total amt of lipids within this structure.

# 3--decreasing heme A--recent evidence that reduced heme A is a pathologic finding in alzheimer's

statins also interfere with the funciton of lipid rafts --important functions of lipid rafts in refererence ot neuro system:

excerpted from "Membrane Lipid Rafts and their role in Axon Guidance. Guirland, C and Zheng, J Q.


"...Lipid rafts have recently received considerable attention because they are thought to be involved in many cellular functions, in particular, signal transduction for extracellular stimuli. Many of these functions
are also intimately related to the processes involved in neural development, including neurotrophic factor signaling and synaptic plasticity. Recent studies from our lab and others have indicated an important role for lipid rafts in axonal growth and guidance. Specifically, our data show that lipid rafts on the plasma membrane provide platforms for spatial and temporal
control of guidance signaling by extracellular cues..."

statins
 

Okay, even I am getting on my nerves with all this now-- and I research this stuff most days. forgive my perseverance.

I am aware with posting on this controversial subject i will provoke many who are taking statins or feel they may be worthwhile in treating PD....If you feel conflicted, discuss it with your physician. I do not have answers--just lots and lots of unanswered questions combined with lots and lots of research that makes me suspicious of statin use and neuro diseases..
I will end by stating that I do not have the qualifications to tell anyone what to do in terms of treatment with statins. The evidence that statins are beneficial for middle aged men who have suffered a cardiovascular event is not in question---(I feel they should be used in acute situations, briefly)the use for any one else, I feel is in question. there has NEVER been evidence showing statins decrease mortality in women or men >65. the use of statins for primary prevention (ie for individuals with minor cardiac risk, has not been shown to decrease mortality--as a matter of fact in a study of older men, the mortality in the treated group was higher than in the placebo group.....)

I am sharing the (obviously selected) information about statins and their relationship to the neurological system. I am convinced statins played a major role in my husband's development of PD, as I am almost convinced it did in my niece's husband's development of PD with lewy body disease and my dear friend's husband's development of PD. If these are instances of a genetic predisposition interacting with an environmental stimulus (in this case a statin) to produce parkinson's, given the millions of people taking statins., the numbers affected with a neurological diseasse could be enormous.
there have been several case reports of neuromuscular disorders being "unmasked" by statin use (and the internet is filled with self reported instances of ALS related statin cases).

there exists a web site, founded and maintained by a physician who suffered 2 episodes of transient global amnesia he attributes to statins. He presents his research findings and a forum for members to discuss their symptoms, etc. He was trained as an astronaut, thus his web address:\


http://www.spacedoc.net.

madelyn

Statins
 

Madelyn,
Many thanks for your input, putting the alternative, or contradictory evidence on the effects of taking statins.
Like you, I am not recommending what people should take. I am just trying to assemble all the evidence I can find relating to the BBB. Maybe the conflict of whether statins improve or exacerbate the symptons of PD depends on which statin you use. The researchers from Boston University found Simvastatin gave the best improvement in PD. Do you know which statins the 3 people you mention who had adverse effects? Possibly atorvastatin or lovastatin? I have not yet been able to find what effect these other statins have on the BBB.
Thanks again for the terrific amount of work you have posted on the topic.
Best wishes
Ron

statins
 

Hi Ron, all 3 men were taking Lipitor (atorvastatin). It is considered one of the more potent statins (after crestor, rosuvastatin). Simvastatin (zocor) is in the same category as lipitor; they are both lipophilic statins (as is crestor), meaning they are fat soluble. being fat soluble, they cross the blood brain barrier. I assume statins can directly affect the mavelonate pathway in the brain that makes brain cholesterol, just as statins affect this pathway in the liver. Pravachol (pravastatin)and Lescol (fluvastatin) are water soluble statins and thus theorized to be unable to cross the BBB.
madelyn

In the study first mentioned, only one specific statin, simvastatin, reduced the risk of PD by 50%, and they suggested it may be because it enters the brain easily. Other statins like Lipitor did not do the trick.

I've been taking zocor (simvastatin) for a few years.

"The researchers speculate that the selective benefit observed with simvastatin might be due to the combination of high potency and the ability to enter the brain."

patent for lead author
 

I am not suggesting that the following info skewed the lead author's interpretation of the data from the study; just think it is emblematic of the time: $$$$$$$

Seems the lead author, dr. Benjamin Wolozin, has a patent for using statins to reduce the risk of onset of alzheimer's--(hopefully this willl not be upheld !!)



Patents
Methods for treating, preventing, and reducing the risk of the onset
of Alzheimer's disease using an HMG CoA reductase inhibitor
United States Patent 6,472,421 / Wolozin / October 29, 2002

Inventors: Wolozin; Benjamin (Hinsdale, IL)
Assignee: Nymox Corporation (St. Laurent, CA)
Appl. No.: 190439
Filed: November 13, 1998

I should have begun with the obvious--that the study reported is an observational study-not an experimental study.

madelyn

Statins and Parkinsons' - and ALS, and neuropathy
 

I was surprised to find such a comprehensive discussion of this subject here. Not because statins aren't associated with PD, they certainly are. But because almost no discussion that I've seen before included so many informative points.

May I join in? (Nods own head, assuming a 'yes' answer . . .)

Of course you, meaning 'you-all', are aware of the neuropathy connection. But are you also aware that many people with ALS (or can we say ALS-mimic condition) strongly believe that their ALS was brought on, or at least triggered, by use of statin(s).

The article below is the most direct and complete way for me to provide some background about this. I'll have more comments, and probably some questions, in subsequent posts.

Those who are already aware of this, apologies for going over it again.

Here's the article:

A Risk in Cholesterol Drugs Is Detected, but Is It Real? - WSJ.com
avery.johnson@wsj.com

DOCTOR'S DILEMMA
A Risk in Cholesterol DrugsIs Detected, but Is It Real?
Data Crunching HintsAt Tie to Lou Gehrig's;FDA Isn't Concerned
By AVERY JOHNSON
July 3, 2007; Page A1

As he examined data on a computer one day last fall, drug-safety reviewer Ralph Edwards saw something that concerned him: Of 172 people in his database who developed Lou Gehrig's disease or something similar while taking prescription medicines, 40 had been on statins, the huge-selling cholesterol drugs.

Dr. Edwards, director of the World Health Organization's drug-monitoring center, has amassed about four million reports of medical problems experienced by people taking prescription drugs. His job is to sift through these so-called adverse events, looking for "signals" of potential side effects.

The number of Lou Gehrig's cases associated with statins struck Dr. Edwards as high. He would have expected a number in the single digits, judging from how often other drugs in the database were linked to the disease. Still, the analysis didn't prove anything. Dr. Edwards hesitated to publicize his finding, wary of creating a drug scare and mindful that statins have been shown to reduce heart attacks significantly.

INTERVIEW
Excerpts from Dr. Edwards's conversations with The Wall Street Journal.

It's an increasingly common dilemma nowadays. Sophisticated software allows health authorities to troll through huge databases looking for possible drug dangers. The data mining can detect rare side effects that didn't show up in clinical trials. But it can also raise false alarms and force regulators to divert time and money from more pressing dangers.

"People reach different judgments on when to shout and when not to shout," says Robert Temple, medical director at the Food and Drug Administration division that evaluates drugs. "It's the hardest single thing -- the value and danger to screaming early."

The issue is likely to grow as regulators expand access to their databases. The FDA and other national drug regulators used to keep a tight lid on the adverse-event reports they collected, but now the WHO can freely disseminate them. Also, since 2004, the FDA has posted its quarterly data files on the Internet, and anyone can download them free of charge. Some companies have started offering software to crunch the data for side-effect patterns.

Adverse-event reports are a major way to identify side effects after a drug is on the market, but the data can be flawed or misleading. The reports can be turned in by anyone -- patients, doctors, even plaintiffs' lawyers. Media coverage or Internet postings claiming dangers in a particular drug may lead doctors and consumers to report more problems with that drug. Meanwhile, many problems never get reported.

Determining causation is another issue. If people taking a drug are older or more overweight than usual, an adverse-events database may show more links to heart attacks. That wouldn't necessarily point to any problem with the drug -- it would just reflect the less-healthy state of the people taking it.

Clinical trials in which patients randomly receive either a drug or a placebo are usually the best way to identify side effects, because any significant difference between the two groups is likely to be a result of the drug. However, trials are often too small or too short to identify unusual side effects, and they don't necessarily reflect how patients take a drug in the real world.

Drug Monitoring
The WHO, a United Nations body, set up its collaborating center for drug monitoring in 1968 after the thalidomide scandal, in which pregnant women who took the medicine for morning sickness gave birth to children with stunted limbs and other malformities. Now based in the Swedish university town of Uppsala, the center pools adverse events from 83 countries,
including the U.S.

Dr. Edwards, a 64-year-old Briton with a background in internal medicine and clinical pharmacology, took the center's helm in 1990. His first experience with puzzling side effects came during a stint at the University of Zimbabwe almost 30 years ago. There, he noticed some patients with a rare skin condition, and tracked down some antibiotics they were taking as the cause.

In the mid-1990s, Dr. Edwards's team developed a software program to mine data with the help of artificial-intelligence Ph.D.'s from a local university. The software made it easier to analyze adverse events for one drug in the context of all event reports and fish out signals of problems.

At first, Dr. Edwards needed permission to publish from the national drug regulators on whose data he relied. Then, at a conference in Hong Kong in 2002, national drug agencies - including the FDA - loosened their grip, allowing the WHO to publish without permission. Dr. Edwards also received the right to share his data with anyone who requested it, he says.

He gets about 200,000 new adverse-event reports and pinpoints about 60 serious signals a year. Usually he notifies national health authorities and goes no further. Only rarely does he publish his concern. One such case involved babies getting withdrawal symptoms when their mothers took certain antidepressants. That report appeared in 2005 in the Lancet.

Last fall, Dr. Edwards decided to see what his database could tell him about statins and Lou Gehrig's disease, known medically as amyotrophic lateral sclerosis or ALS. The progressive neurodegenerative disease is almost always fatal. He had heard from an American doctor about an ALS-like case that was seemingly related to statins. Dr. Edwards himself had a friend who developed another serious nerve disease, called peripheral neuropathy, after taking a statin.

With a few clicks, Dr. Edwards came upon the 40 cases of ALS in people taking statins, and his software told him the number was much higher than expected.

DATA DEBATE

• The Issue: An analysis by a drug-monitoring group suggests a link between cholesterol-lowering statins and Lou Gehrig's disease, but U.S. regulators say they don't believe there's a risk.

• The Background: Scientists are increasingly using data-mining software to sift through reports of adverse events involving drugs.

• What's Next: More studies to figure out what's happening.Reviewing scientific literature, Dr. Edwards came up with a theory about the cases.

All statins carry a warning on their label about a rare disorder that causes muscle pain or weakness, a long-known side effect of the drugs. More recently, studies have linked statins to peripheral neuropathy. Dr. Edwards speculated these diseases and ALS might be connected, since they involve some kind of neuromuscular degeneration, and he thought all might be triggered by statins in unusual instances.

Yet Dr. Edwards also learned that pharmaceutical companies and other researchers are studying statins as potential treatments for brain or nervous-system diseases such as Alzheimer's, multiple sclerosis and even ALS. Some believe the anti-inflammatory effects of statins may be useful in these diseases.

As Dr. Edwards reflected on whether to publish his findings, one point weighed heavily. ALS is rare -- it strikes about five in 100,000 people and affects some 350,000 people world-wide. By contrast, heart attacks are a leading cause of death, and statins have helped millions of people reduce their heart risk. Dr. Edwards didn't want to raise unwarranted fears about drugs whose value is well-documented.

"We were on the horns of a dilemma and it wasn't easy to resolve," Dr. Edwards says.

Behind the scenes at the FDA, officials were facing a similar dilemma. Ana Szarfman, an agency official who pioneered statistical analyses of adverse events, had noticed the ALS-statin signal in March 2006, about six months before it caught Dr. Edwards's attention. She was using the FDA's database, which overlaps with the WHO's but isn't identical. The FDA says that through the end of last year, about one-third of the ALS adverse-event reports in its database -- 99 of 298 -- involved people on statins.

Dr. Szarfman was known at the FDA for her sleuthing into unexpected side effects, such as the odd link between a Parkinson's-disease medicine, Mirapex, and isolated cases of compulsive gambling. She also helped confirm in 2001 that Baycol, a Bayer AG statin later withdrawn from the market, was linked to an especially high number of muscle-disease cases.

Dr. Szarfman took the ALS signal seriously and considered publishing an article about it. But she held off while the FDA took a closer look. The agency didn't want to jump to any conclusions about a life-saving class of drugs, officials say. Unlike the WHO, the FDA has the ability to press drug companies for more information. That's what it did in this case, asking Pfizer and other statin makers for all their clinical-trial data.

Statin Trials
Taken together, the long-term statin trials involved 120,000 patients. The number of ALS cases came to 20, spread equally between statin takers and those on placebo. "The result of the analysis was very reassuring," says Dr. Temple, who takes a statin himself. "I personally was relieved because I like my statins."

Dr. Temple says a close look at the FDA's adverse-event data suggested some reports might be unreliable. Slightly more than half of the adverse-event reports in the FDA's database about statins and ALS were submitted by consumers, which is unusual because doctors usually account for the lion's share. Also, some of the ALS cases were reported soon after the patients had started taking statins, raising doubts about whether the drug could have been the cause. Officials noted that the incidence of ALS in the general population hasn't risen since statins became popular.

The FDA plans to publish an academic paper about its statistical findings soon, says an agency official. But based on the analysis of clinical trials, it decided it didn't need to issue any caution about statins.

Dr. Edwards came to a different conclusion. He talked the issue over with his staff and P. Murali Doraiswamy, an expert in neurodegenerative diseases at Duke University who has done research on statins and the brain. Dr. Doraiswamy agreed that the ALS signal was worrisome and should be investigated.

After months of hesitation, Dr. Edwards came across a study by Greek researchers that helped make up his mind. Typically, ALS leads to death within three to five years, usually because the lungs fail when the neurons that send instructions to the respiratory system stop working. But in some rare cases, ALS-like symptoms could be halted or even reversed, the study said. Dr. Edwards decided his finding might help some patients prevent their disease from deteriorating. He wrote a paper and submitted it to two prestigious journals.

Both journals, the British Medical Journal and the Lancet, rejected it, he says.

Fiona Godlee, the BMJ's editor, says she can't comment on specific papers, but she calls adverse events hard to interpret. "You only have a record of the people who developed problems, without knowing how many people took the drug and didn't develop problems," she says.

The Lancet declined to comment.

Dr. Edwards pitched his paper to Drug Safety, a little-known journal based in New Zealand, which rushed it into print last month.

The paper acknowledges that some Internet sites have been discussing an ALS-statin link for at least a year, raising the possibility of skewed reporting of adverse events. But it notes that the number of events was also high earlier in the decade, before the majority of the Internet postings.

The paper calls on patients using statins to talk to their doctor about stopping if they experience severe neuromuscular symptoms.Pfizer, which brings in nearly $13 billion a year from Lipitor, says it too noticed the ALS signal last year in adverse-event reports, but concluded there was nothing to it after examining all its data. The company says Dr. Edwards has the right to publish what he found, but signals derived from adverse events can unnecessarily alarm the public and create needless headaches for drug companies.

Manfred Hauben, a Pfizer medical director, has long specialized in analyzing adverse events, and several years ago started using sophisticated software adopted by Pfizer. A math junkie who jokes that he suffers from an impulse-control disorder and stays awake at night studying statistics, Dr. Hauben says his enthusiasm for data mining has cooled.

He says with so many drugs and diseases, mere coincidence will create some worrisome-looking links. "Especially when you're looking for rare events, most positive results are going to be false positives," he says. Also, data mining presents "a lot of opportunities to retrofit an analysis to pre-existing expectations," he says. "Two different vendors' software can give two different results."

Prompting Research
Dr. Edwards says his paper is merely intended to prompt more research into the matter -- not cause millions of heart patients on statins to panic and stop the drugs.

But he hopes it will be useful to some patients. "Suppose you started to get symptoms and your doctor said, 'Now you have two years to live,' " he says. "Wouldn't you want to know that there's some possibility that the disease is linked to the drug so you could stop taking the drug?"

Dr. Edwards isn't persuaded by the clinical-trial data collected by the FDA. The signal wouldn't necessarily show up there, he says, because ALS is so rare.

Sheila O'Donovan, a 62-year-old retired journalist who lives in Delray Beach, Fla., wishes the signal had been publicized sooner. Ms. O'Donovan was on Lipitor when she started losing control of her right thumb in 2005. Soon, she was limping and slurring her words. After going off the drug in April of last year, she suddenly felt "brighter," her muscle cramps stopped and she was able to swallow more easily, she wrote in an email.

But the improvement was short-lived. Her neurologist diagnosed her with ALS last September and she's gone downhill since. Her voice is now almost gone and she needs a wheelchair to get around.

More evidence could be available in a year or two. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego, is analyzing case reports of people who developed ALS-like symptoms after taking statins. And researchers at Stanford University are looking at patient records in Northern California kept by Kaiser Permanente, a big
health-maintenance organization, to see whether people who developed ALS were more likely than control subjects to have used statins.


Write to Avery Johnson at avery.johnson@wsj.com

About statins
 

Olsen pointed out that there are lipophilic and hydrophobic statins. (Or whichever exact words are used for those two conditions - one is water soluble and the other is fat or oil soluble, right?)

I saw something recently, and it might be added to the mix of information. It was an editorial about "natural" and "synthetic" statins.

It was an editorial in the journal Circulation, from 1999, by Curt Furberg, MD PhD, and this is an excerpt:

Are All Statins Created Equal?
Two subtypes of statins are currently on the US market: the
fermentation-derived, or natural, statins (lovastatin, pravastatin, and
simvastatin) and the synthetic statins (atorvastatin, cerivastatin, and
fluvastatin).

The chemical structures of the 3 natural statins are very similar. However, the structures of the 3 synthetic statins are dissimilar, and all 3 are very different from the natural ones.

Compare the information above to that below (from The American Journal of Managed Care, Nov. 2004, by Michael B. Bottorff, PharmD):

Atorvastatin, pravastatin, fluvastatin (Lescol), and rosuvastatin (Crestor) are given in the active acid form. Active acid refers to the pharmacophore, the component of the chemical structure responsible for the activity that defines the statins as a class-binding to the HMG-CoA reductase enzyme to produce lowering of LDL cholesterol.

In contrast, lovastatin (Mevacor, Altocor) and simvastatin are administered in inactive form as lactones, some portion of which is then hydrolyzed into the active acid form to produce their clinical effects.

Statins and Vitamin D
 

About this idea of a Vitamin D connection with statins, I believe that has been pretty well proven. What hasn't been proven is - exactly what the connection is. The paper below suggests that "statins activate vitamin D receptors." I think he's wrong; I think there's a better explanation than that.

The full text is available on line at The Lancet.

Are statins analogues of vitamin D?
The Lancet 2006; 368:83-86
DOI:10.1016/S0140-6736(06)68971-X
Are statins analogues of vitamin D?
David S GrimesMD

Summary
There are many reasons why the dietary-heart-cholesterol hypothesis should
be questioned, and why statins might be acting in some other way to reduce the risk of coronary heart disease. Here, I propose that rather than being cholesterol-lowering drugs per se, statins act as vitamin D analogues, and explain why. This proposition is based on published observations that the unexpected and unexplained clinical benefits produced by statins have also been shown to be properties of vitamin D. It seems likely that statins activate vitamin D receptors.

One possibilty
 

I am still on the learning curve on this one so take this for what it is worth...

The bacterial endotoxin lipopolysaccharide (LPS) plays a critical role in PD. Exposure in the womb sets the stage and further exposure after puberty triggers autoimmune problems through microglial activation. Also, because LPS is a constant presence and because of the prenatal sensitization, it results in a chronic inflammatory state which, in turn, induces the body to produce glucosteroids such as cortisol - a natural anti-inflammatory that becomes destructive itself when chronically present.

LPS is, literally, everywhere. It is the main component of ordinary house dust, for example. It is in our food supply (milk and grain in particular). Our immune system constantly creates a residue of it by killing the bacteria that release it pon their death. There is no getting away from it.

Since it is a constant, the body obviously has to have a way of disarming it as a problem in a normal human. And it does indeed. It uses the lipoproteins such as HDL and LDL in a process that binds the toxin and renders it harmless.

The medical community has made the assumption that those substances are dangerous above a certain level that applies to everyone. I don't think that consideration has been given to the possibility that in some situations our bodies may need those higher levels and in fact may create them.

If that were true then statins may be thwarting the attempts and thus leading to God knows what in PD or ALS.

If you want to delve into this you might start with looking at the work of a team at the NIH headed by a rsearcher named Bin Liu. If you do find connections I would like to know. Good luck.

statins
 

thanks rick, will let you know if I uncover any linkage...i am always intrigued with the wording in the statins' literature. Recent journal, annals of Internal Medicine, contained an article concerning all aspects of dyslipidemia written by annals of int med editors. Under the heading of "who should be screened for dyslipidemia?" is the following:" No direct evidence links lipid screening and subsequent treatment with reduced adverse outcomes from CVD or stroke. However, moderate-quality indirect evidence supports routine dyslipidemia screening for men older than 35 yrs of age and women older than 45." Thus with the literally hundreds of studies done with statin drugs, there exists No direct evidence, but "moderate-quality indirect evidence"? what IS "moderate quality indirect evidence " anyway? is that a scientific or statistical term with which I am unfamiliar? (yes, my bias is showing) madelyn

vitamin d
 

NTLegend, hopefully statins DO act as vitamin D analogues-- cholesterol is a precursor to any Vitamin D that is synthesized in the body, utilizing sunlight in the process.