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Medical Forum / General / Cardiology / April 2006statins, dolichol and neuromelanin in the substantia nigra
contained in introduction of an NDA #20-702 submission date:6-17-1996; review completed 10-28-96 Medical reviewer: Dr. David G. Orloff (NDA presented by Parke Davis to the FDA): "HMG-COA reductase catalyzes the synthesis of mevalonate from two molecules of HMG-COA, which is further metabolized in a series of enzymatic steps to cholesterol. Mevalonate is an intermediate not only in the pathway to cholesterol, but also in the synthesis of the prenyl, geranyl and farnesyl pyrophosphates (used in post- translational modifications of proteins), ubiquinones (compounds of the electron transport chain and critical in energy metabolism), dolichols (used in the maturation of glycoproteins), and isopentenyl adenine (a compound of tRNA). Cellular depletion of any or all of these metabolic products could theoretically be deleterious." the following is important because "it is the pigmented dopaminergic neurones of the substantia nigra that preferentially degenerate in idiopathic Parkinson's disease": Federow, Heidi, Pickford, Russell, James M Hook, Kay L double, Glenda M. Halliday, et al. "Dolichol is the major lipid component of human substantia nigra neuromelanin" Journal of Neurochemistry, 2005, 92, 990-993. Condensed from abstact: ...Early electron microscopic examinations of neuromelanin fine structure revealed a significant neutral lipid component; however, the identity of this lipid has remanied unknown. Here we show that the lipid component of neuromelanin pigment derived from human SN is the poly-isoprenoid dolichol...Established methods were used to isolate the pigment from the SN of 32 brains and the lipid fraction was recovered in high purity and yield...Dolichol accounted for 14% of the mass of neuromelanin pigment; low levels of other hydrophobic compounds were detected (e.g. ubiquinone-10, alpha tocopherol and cholesterol together accounted for <5% of the neuromelanin lipid mass). This is the first time that dolichol has been identified in such a physiological setting and significantly advances our understanding of neuromelanin pigment structure and biosynthetic pathways. Furthermore these studies identify a potential novel role for the isoprenoid pathway in the regulation of neuromelanin function and neurodegeneration within the SN. >From the "Results and Discussion" section:...An antioxidant role for dolichol has been postulated (Bergamini et al. 2004) but the potential mechanisms of dolichol antioxidant action in neuromelanin-containint dopaminergic neurones need to be addresed...the precise role that dolichol plays in neuromelanin formation or function and in degeneration of dopaminergic neurones in the SN requires further investigation. no comments from anyone about this finding? the implications of depleting the body of a lipid that is the major component of the Substantia nigra thru the use of a statin should at least generate some discussion--or at least thought. > no comments from anyone about this finding? the implications of > depleting the body of a lipid that is the major component of the > Substantia nigra thru the use of a statin should at least generate some > discussion--or at least thought. Studies that imply are a dime a dozen. Real studies are obviously more useful. > Studies that imply are a dime a dozen. Real studies are obviously more > useful. Perhaps you did not read the abstract--this was not a clinical trial--all the specimens were brain tissue obtained from individuals who were dead. there was no implication--there was PROOF that Dloichol accounted for 14% of the mass of neuromelanin pigment in a PHYSIOLOGICAL setting--the lipid was isolated from the pigment in 32 brains. the PROOF was that dolichol is the major lipid component of human substantia nigra neuromelanin. what kind of study would you suggest one perform to determine the lipid content within the substantia nigra????? are you certain you responded to the correct posting? Your comment is a non sequitur . at least read the post before responding.... and at least Parke Davis thought there was proof that their drug , Lipitor , interrupted the pathway to the production of dolichol. dolichol shares the same pathway for cholesterol production, the mevalonate pathway, which IS BLOCKED by HMG-CoA reductase inhibitors..... so what "real study" would you find more "useful"????? >> Studies that imply are a dime a dozen. Real studies are obviously more >> useful. [quoted text clipped - 18 lines] > > so what "real study" would you find more "useful"????? Excellent post and accurate observation on the response. The severity of some statin AEs is far beyond comprehension for too many. That this has been known and documented publicly for a full decade, yet studiously avoided in any discussion of statin AEs is unconscionable. The ongoing number of new reports of "unmasking" of Parkinson's, Huntington's and ALs, as well as OPCA and MSA associated with statin treatment should also be raised. Instead, we are insulted with pitiful attempts at assuring the masses that because the retrospective studies of the literature, consisting of studies that did not look for or document AEs, contain few reports of AEs, the drugs must be safe. How many autopsies will it take to convince the medical profession to monitor for AEs, rather than deny or ignore them? >>> Studies that imply are a dime a dozen. Real studies are obviously more >>> useful. [quoted text clipped - 24 lines] > That this has been known and documented publicly for a full decade, yet > studiously avoided in any discussion of statin AEs is unconscionable. Why don't you write a letter to the FDA including all your documentation and demanding a black box warning? In fact, what documentation do you have? > The ongoing number of new reports of "unmasking" of Parkinson's, > Huntington's and ALs, as well as OPCA and MSA associated with statin [quoted text clipped - 7 lines] > How many autopsies will it take to convince the medical profession to > monitor for AEs, rather than deny or ignore them? So you are saying that evidence exists and does not exist at the same time. Note, the argument "after that - therefore because of that" is not scientific when applied to individual instances. There are probably numerous instances of people who died from an MI after eating chili within the last 48 hrs. When are people going to stop hiding the association? Bill "Sharon Hope" <shope@anet.net> wrote in message > How many autopsies will it take to convince the medical profession to > monitor for AEs, rather than deny or ignore them? These are not autopsies. Nor is it used in monitoring AE's. This was looking at brain tissue fat content. That's a pretty severe way to check for AE's isn't it and so it's implication is what? Is this study going to collect dust at the FDA or is the FDA going to recommend they pull the drug off the shelf? > These are not autopsies. Nor is it used in monitoring AE's. This was looking > at brain tissue fat content. That's a pretty severe way to check for AE's > isn't it and so it's implication is what? > Is this study going to collect dust at the FDA or is the FDA going to > recommend they pull the drug off the shelf? Robert--the post was a report of 1) a study determining the lipid components of the neuromelanin in the substantia nigra--(you may recall that it is the pigmented dopaminergic neurones of he substantia nigra that preferentially degenerate in idiopathic parkinson's disease) the MAJOR LIPID COMPONENT of the substantia nigra was found to be DOLICHOL. 2) Even the pharmaceutical company noted in THEIR INITIAL NDA to the FDA (I will re-post this information from the original--statins inhibit HMG-COA reductase thus inhibiting the synthesis of mevalonate--keep this in mind while reading the following:). "HMG-COA reductase catalyzes the synthesis of mevalonate from two molecules of HMG-COA, which is further metabolized in a series of enzymatic steps to cholesterol. Mevalonate is an intermediate not only in the pathway to cholesterol, but also in the synthesis of the prenyl, geranyl and farnesyl pyrophosphates (used in post- translational modifications of proteins), ubiquinones (compounds of the electron transport chain and critical in energy metabolism), dolichols (used in the maturation of glycoproteins), and isopentenyl adenine (a compound of tRNA). Cellular depletion of any or all of these metabolic products could theoretically be deleterious." Do you purposefully misinterpret the information I post? This WAS NOT a report of AEs. This was a report of science facts--perhaps you could connect the dots---this is a drug that depletes the body of dolichol, the MAJOR LIPID COMPONENT within the Substantia Nigra --the area of the brain that "preferentially degenerates" in idiopathic parkinson's disease. the brains utilized in the study were not chosen because of drug taking history or disease--the aim of the study was to determine what was the major lipid component of human substantia nigra neuromelanin.......it was Dolichol, the same lipid that is depleted by statins, the same lipid that is the major component of the substantia nigra. > Do you purposefully misinterpret the information I post? > This WAS NOT a report of AEs. I was responding to Sharon. > This was a report of science > facts- These were findings. These were initial findings that must be reproduced. Your use of terms like Proof and Facts are just inappropriate. Is is one study in which they came up with observations. -perhaps you could connect the dots---this is a drug that > depletes the body of dolichol, the MAJOR LIPID COMPONENT within the > Substantia Nigra --the area of the brain that "preferentially [quoted text clipped - 4 lines] > was Dolichol, the same lipid that is depleted by statins, the same > lipid that is the major component of the substantia nigra. So you are telling me to connect the dots now? You connect the dots and see if they connect. A drug company that makes statins did a study on brains. It is so concerned about the study it sends it to the FDA? It is so concerned that it stops making the drug because it wants to avoid lawsuits based on the initial findings it presented? It is so concerned it places a voluntary warning on the label about PD? I think you misrepresent the study. There is no doubt in my mind why you posted this from day one. We know you EML and yes we can connect the dots. > > Studies that imply are a dime a dozen. Real studies are obviously more > > useful. > > Perhaps you did not read the abstract--this was not a clinical > trial--all the specimens were brain tissue obtained from individuals > who were dead. Perhaps you didn't read my post. I didn't say clinical trials. I said studies. there was no implication--there was PROOF that Dloichol > accounted for 14% of the mass of neuromelanin pigment in a No proof but findings. > and at least Parke Davis thought there was proof that their drug , > Lipitor , interrupted the pathway to the production of dolichol. > dolichol shares the same pathway for cholesterol production, Parke Davis is a subsidiary of Pfizer. I am glad you believe drug companies now. the > mevalonate pathway, which IS BLOCKED by HMG-CoA reductase > inhibitors..... > > so what "real study" would you find more "useful"????? Not I but you. > > > Studies that imply are a dime a dozen. Real studies are obviously more > > > useful. perhaps the researchers from the study would be delighted if it were "a dime a dozen"--they garnered major international prizes from the neurochemistry world for their contribution to neuroscience with this finding..... > > > > Studies that imply are a dime a dozen. Real studies are obviously more > > > > useful. [quoted text clipped - 3 lines] > neurochemistry world for their contribution to neuroscience with this > finding..... As people die with PD and they get awards, ok. The purpose of such studies are to come up with drugs to counteract any pathophysiology. Then the drug company with the same individuals you claim are devils can come up with a treatment that will have AE's and the cycle continues. It will be done for money and not awards. This is a first. We have always seen a predictable pattern of responses from the same few who demand that any post involving statins, even peripherally, must be wildly pro-statin. 1) They ignore the facts in the post and respond with non sequiturs 2) They conduct ad hominem attacks on the poster But this one is unique! It takes the mandatory-pro-statin-mind-control another step! It is an ad hominem attack on ALL researchers, within and outside of the pharmco industry, in ALL future research! AND it combines the Non Sequitur with the Ad Hominem attack! We are somehow asked to believe that no only are all these POTENTIAL FUTURE researchers morally tainted, but that their motives will somehow nullify the findings. Morally tainted, by the way, is any research that is common, dime-a-dozen, exemplary and award worthy, or for profit. Pity it isn't just a sophomoric response to a complicated post. Immaturity and lack of self esteem are at least understandable. No, this is the perfect example of the predictable censorship of any statin-related facts that appear on this ng and are perceived as other than marketing hype. Interestingly, there is often a half-life on the censorship of these AE posts. It ends when the marketing department spins the AE into claims of pleiotropic effects! Statin apoptosis (muscle cell death, potentially leading to rhabdomyolysis) is heralded as a novel potential cancer cell killer because it works in test tubes (in vitro) - no mention in the press releases of increased incidence of cancer in some studies.) Statin damage to the immune system heralded as an antiinflammatory advance. Statin increase in CK so high that it increases the CK count in the urine, heralded as 'evidence' the kidneys work better because they filter out more CK than when not on statins! (no mention that there wasn't more CK to filer pre-statin) it goes on and on. >> > > > Studies that imply are a dime a dozen. Real studies are obviously > more [quoted text clipped - 10 lines] > treatment that will have AE's and the cycle continues. It will be done for > money and not awards. > This is a first. > > We have always seen a predictable pattern of responses from the same few who > demand that any post involving statins, even peripherally, must be wildly > pro-statin. I hope I am predictable. I have seen people die every day and try to intervene medically by use of surgery medications or anything else that could help people who are suffering. This was not a study of statins. I was a study of brains in people who have PD and not related to this NG which is why I ignored it originally. > 1) They ignore the facts in the post and respond with non sequiturs Which facts? A new novel approach in diagnosing PD by cutting up a brain? > 2) They conduct ad hominem attacks on the poster This is just a wild guess here but he was dissappointed when nobody succumbed to his provocation and he tried again. Ask him and see if he would have been happier being ignored. > But this one is unique! It takes the mandatory-pro-statin-mind-control > another step! > > It is an ad hominem attack on ALL researchers, within and outside of the > pharmco industry, in ALL future research! Correct. I was initiated by the NIH and they are so pissed off at both researchers and drug companies. I saw a C-SPAN broadcast of the NIH with all these national organizations and the problem was nobody is doing translational research with primary research finding. Not the initial researchers and not the drug companies involving specfically as they mentioned was chronic conditions in which no biomarkers were involved. They mentioned specifically PD and Alzehimers. This study simply adds to the problem. It takes out a piece of brain and looks at it. People can not take out a piece of brain and look at to see if a drug works or not in treating this disease PD. > AND it combines the Non Sequitur with the Ad Hominem attack! > > We are somehow asked to believe that no only are all these POTENTIAL FUTURE > researchers morally tainted, but that their motives will somehow nullify the > findings. Drug manufacturers don't want to invest in drugs used in treatments which would last 20 years because of liability experience with drugs like statins. There is no short term biomarker that one can see if a drug works or not. This is from the drug manufacturers themselves at the conference. You can not do an expensive drug trial for 20 years to find out if a drug works or not. The bottom line from the conference and the reason for the conference is that these primary studies are a dime a dozen and go nowhere when it comes to translational research into doing things that affect peoples lives. > Morally tainted, by the way, is any research that is common, dime-a-dozen, > exemplary and award worthy, or for profit. Just my personal opinion as I am more interested in applied research. I see some researchers as whores not really dedicated to any cause or disease but simply go from one area of interest to another unrelated one. > Pity it isn't just a sophomoric response to a complicated post. Immaturity > and lack of self esteem are at least understandable. That is the position of the NIH which is why it was trying to break that cycle of people only interested in primary research and get awards and not give a sh.t about going further with it. > No, this is the perfect example of the predictable censorship of any > statin-related facts that appear on this ng and are perceived as other than > marketing hype. What censorship? LOL Now the spin begins. With have a study of brains with no mention of statins actually involved in the research to now it is a study about statins. > Interestingly, there is often a half-life on the censorship of these AE > posts. It ends when the marketing department spins the AE into claims of > pleiotropic effects! So now it's an AE study. > Statin apoptosis (muscle cell death, potentially leading to rhabdomyolysis) > is heralded as a novel potential cancer cell killer because it works in test > tubes (in vitro) - no mention in the press releases of increased incidence > of cancer in some studies.) That's a good example of what findings are and not called Proofs. The measuring of lipids cut out of brains is a test tube in vitro study. Good catch. Statins affecting the brains lipid fractions in PD would be an invivo affect. That is what I meant by real studies. Good catch again. "Robert" <Robertsnospam2@hotmail.com> wrote in news:nsKdnZIbjsV0VrPZRVn- ug@got.net: >> > > > Studies that imply are a dime a dozen. Real studies are obviously > more [quoted text clipped - 10 lines] > treatment that will have AE's and the cycle continues. It will be done for > money and not awards. Robert, There's no figuring out eml and her alter ego, Sharon. I'm surprised you're even responding to eml's plea why no one resonded. (DUH!) L. > "Robert" <Robertsnospam2@hotmail.com> wrote in news:nsKdnZIbjsV0VrPZRVn- > ug@got.net: [quoted text clipped - 26 lines] > > L. I am actually more sympathetic to eml. She is caught in a catch 22. She doesn't realize that attacking drug safety to require 20 safety studies for one drug would require that same amount of time for all drugs including those treating PD. She is biting the hand that feeds her and then wonders why nothing is being done in the field. PD was around long before statins were. Now all of a sudden it's got to be due to the statins. >> "Robert" <Robertsnospam2@hotmail.com> wrote in news:nsKdnZIbjsV0VrPZRVn- >> ug@got.net: <snip>> >> > > >PD was around long before statins were. Now all of a > sudden it's got to be due to the statins. "it" pronoun usage is too inspecific. From the Original Poster to you (although you seem to have ignored it twice before): Robert--the post was a report of 1) a study determining the lipid components of the neuromelanin in the substantia nigra--(you may recall that it is the pigmented dopaminergic neurones of he substantia nigra that preferentially degenerate in idiopathic parkinson's disease) the MAJOR LIPID COMPONENT of the substantia nigra was found to be DOLICHOL. 2) Even the pharmaceutical company noted in THEIR INITIAL NDA to the FDA (I will re-post this information from the original--statins inhibit HMG-COA reductase thus inhibiting the synthesis of mevalonate--keep this in mind while reading the following:). "HMG-COA reductase catalyzes the synthesis of mevalonate from two molecules of HMG-COA, which is further metabolized in a series of enzymatic steps to cholesterol. Mevalonate is an intermediate not only in the pathway to cholesterol, but also in the synthesis of the prenyl, geranyl and farnesyl pyrophosphates (used in post- translational modifications of proteins), ubiquinones (compounds of the electron transport chain and critical in energy metabolism), dolichols (used in the maturation of glycoproteins), and isopentenyl adenine (a compound of tRNA). Cellular depletion of any or all of these metabolic products could theoretically be deleterious." Do you purposefully misinterpret the information I post? This WAS NOT a report of AEs. This was a report of science facts--perhaps you could connect the dots---this is a drug that depletes the body of dolichol, the MAJOR LIPID COMPONENT within the Substantia Nigra --the area of the brain that "preferentially degenerates" in idiopathic parkinson's disease. the brains utilized in the study were not chosen because of drug taking history or disease--the aim of the study was to determine what was the major lipid component of human substantia nigra neuromelanin.......it was Dolichol, the same lipid that is depleted by statins, the same lipid that is the major component of the substantia nigra. >>> "Robert" <Robertsnospam2@hotmail.com> wrote in news:nsKdnZIbjsV0VrPZRVn- >>> ug@got.net: [quoted text clipped - 4 lines] > > "it" pronoun usage is too inspecific. I love it when you go into passive-aggressive schoolteacher mode. L. Okay I apologize for not making the original post more clear--the original study (reported in the jounal of neurochemistry) was conducted on the brains of individuals who died from random causes---NOT PARKINSON''s, --THESE INDIVIDUALS HAD NO HISTORY OF NEUROLOGICAL OR NEURODEGENERATIVE DISEASES. . the finding: the MAJOR lipid component within the substantia nigra neuromelanin is DOLICHOL. It was a study conducted by an international group of academic researchers--They were not studying parkinson's. The study was NOT supported by pharm industry money. It was not reported in the "usual" clinical neurology journals--the study was reported in the Journal of neurochemistry. 2) it is the pigmented (neuromelanin) dopaminergic neurones of the substantia nigra that perferentially degenerate in idiopathic parkinson's disease--the study cited did not make this determination--IT IS A WELL ESTABLISHED FINDING AND HAS BEEN FOR THE PAST DECADE. the above study was not conducted to determine this fact--it IS A FACT--IT HAS BEEN REPLICATED AND REPORTED IN MANY STUDIES. 3) it is ALSO A WELL ESTABLISHED FINDING THAT STATINS INTERRUPT THE PATHWAY TO THE PRODUCTION OF DOLICHOL IN THE LIVER THRU ITS INHIBITION OF HMG-COA REDUCTASE here is where the information from the application for a New Drug comes in--tHIS INFORMATION IS NOT CONTAINED IN THE STUDY CITED. It is taken verbatim from the New Drug application made by Parke Davis to the FDA in 1996 for its newest statin at that time, atorvastatin.atorvastatin IS an HMG COA reductase inhibitor--and Yes i know Pfizer subsequently bought Parke davis--To reiterate: "HMG-COA reductase catalyzes the synthesis of mevalonate from two molecules of HMG-COA, which is further metabolized in a series of enzymatic steps to cholesterol. Mevalonate is an intermediate not only in the pathway to cholesterol, but also in the synthesis of the prenyl, geranyl and farnesyl pyrophosphates (used in post- translational modifications of proteins), ubiquinones (compounds of the electron transport chain and critical in energy metabolism), dolichols (used in the maturation of glycoproteins), and isopentenyl adenine (a compound of tRNA). Cellular depletion of any or all of these metabolic products could theoretically be deleterious." (I do not wish to misrepresent, so continue to quote from their application) concerning the association among the above 3---whenever one becomes aware of a drug that produces an effect that could potentially be deleterious in individuals with a specific disease-ie why deplete the cells of dolichol in individuals who have a disease in which the very same lipid is the MAJOR component of the area of the body (the substantia nigra) which is diseased/compromised --does that make sense to you as a medical practitioner????? would you be completely at ease giving atropine to someone who suffers from significant prostatic hypertrophy? How about digitalis to someone with symptoms of advanced AV block? The ionotropic effect of digitalis is a wanted effect; the effect of prolonging conduction thru the AV node is not wanted, esp in someone with depressed conduction thru the AVnode already. One could continue with these types of examples--knowledge of the effects of drugs, the pathophysiology of diseases and the potential for deleterious effects from a specific category of drugs and action to either with hold the drug or at least provide some action (ie insert a foley) to ameliorate the effects--is that not what medical practitioners do every day? the findings that there is "cellular depletion" of dolichol by statins the findings that dolichol is the Major lipid component in the neuromelanin dopaminergic neurones of the substantia nigra the fact that it is these VERY SAME PIGMENTED DOPAMINERGIC NEURONES in the substantia nigra that PREFERENTIALLY DEGENERATE IN IDIOPATHIC PARKINSON'S these 3 findings have NO IMPLICATIONS? FURTHERMORE, NO PHARMACEUTICAL ENTITY HAS EVER PUBLISHED STUDIES ON THE "POTENTIAL DELETERIOUS" EFFECTS CAUSED BY THE CELLULAR DEPLETION OF 3 OF THE METABOLIC PRODUCTS NOTED IN THE APPLICATION---THOSE BEING: PRENYL, GERANYL AND FARNESYL PYROPHOSPHATES, DOLICHOLS OR ISOPENTENYL ADENINE, Guess they were so focused on the positive "pleiotropic" effects of statins, they just forgort about these cellular depletions.....THE ONLY MENTION OF CELLULARLY DEPLETED METABOLIC PRODUCTS CONCERNS UBIQUINONE--WHICH BY THE WAY IS USED IN MEGADOSES FOR EARLY ONSET PARKINSON'S---AND THESE STUDIES WERE CONDUCTED ONLY BECAUSE THE FINDINGS OF LOW COQ10 WERE BROUGHT OUT BY RESEARCHERS/CLINICIANS NOT ASSOCIATED WITH THE PHARM INDUSTRY THERE ARE TWO MAJOR METABOLIC PRODUCTS DEPLETED BY STATINS THAT ARE CONCERNED WITH PARKINSON'S--COQ10 LEVELS ARE FOUND TO BE ABNORMALLY LOW IN PATIENTS WITH PARKINSON'S --ALL PATIENTS WITH PARKINOSN'S--NOT JUST THOSE WHO ARE TAKING STATINS--LOW COQ10 IS THOUGHT TO BE A PRODUCT OF THE DISEASE PROCESS IN PARKINSON'S...AND MEGA DOSE COQ10 IS FOUND TO BE EFFECTIVE TREATMENT IN EARLY ONSET PARKINSON'S , AND DOLICHOL IS FOUND TO BE A MAJOR COMPONENT OF THE VERY STRUCTURE THAT IS COMPROMISED IN PARKINSON'S. Mo matter how you represent what I have posted, looks to me like statins, esp the lipophilic ones that cross the blood brain barrier ARE NOT DRUGS TO BE USED IN PATIENTS WITH PARKINSON'S. AS SHARON HOPE HAS POINTED OUT MANY TIMES--AND THERE ARE 3 CASES CITED IN THE LITERATURE--STATINS ARE THOUGHT TO "UNMASK" PARKINSON'S. THERE ARE PROBABLY INDIVIDUALS WHO WOULD NEVER DEVELOP PARKINSON'S WITHIN THEIR LIFE TIME, BUT TAKING STATINS 'UNMASKS' THE DISEASE BY DEPLETING THE BODY OF BOTH COQ10 AND DOLICHOL. or THE OTHER METABOLIC PRODUCTS WITH WHICH STATINS INTERFERE Absolute scientific proof of the above---NOT as long as statins are the biggest money makers ever--and not as long as the pharmaceutical industry determines what clinical trials are held--what information to be collected, what outcomes to be measured.. > Okay I apologize for not making the original post more clear--the > original study (reported in the jounal of neurochemistry) was conducted [quoted text clipped - 87 lines] > SHARON HOPE HAS POINTED OUT MANY TIMES--AND THERE ARE 3 CASES CITED IN > THE LITERATURE--STATINS ARE THOUGHT TO "UNMASK" PARKINSON'S. Are these not simply cases where an individual developed Parkinson's after taking statins - with no cause and effect shown? (It is hard to read your posts with all caps.) Bill > THERE ARE > PROBABLY INDIVIDUALS WHO WOULD NEVER DEVELOP PARKINSON'S WITHIN THEIR [quoted text clipped - 6 lines] > industry determines what clinical trials are held--what information to > be collected, what outcomes to be measured.. > Okay I apologize for not making the original post more clear--the > original study (reported in the jounal of neurochemistry) was conducted [quoted text clipped - 9 lines] > substantia nigra that perferentially degenerate in idiopathic > parkinson's disease--the study cited did not make this I don't think the same way you do by simply somebody noting "major component" and then all of a sudden have all this cascade of inferences. It makes no difference whether it is a minor or major component. The sodium in the blood is around 145 meq/l with a range of 120 to 180 and is a major component. Potassium is a minor component of around 4 meq/l and ranges from 2-8. They kill people with K when they execute them. The other secret that the drug companies don't tell people is that the drug is intended to lower lipids and usually around the 50% blood level. It doesn't go down to zero. I know and people like yourself and Sharon are going to mention a Zillion times To reiterate: "HMG-COA reductase catalyzes the synthesis of mevalonate............" as if it is suppose to mean something. Every cell in the human body utilizes lipids including red cells. Kidney cells, you name it and to go to every tissue and organ out there like Sharon does and noting major lipids in each cell type and then saying it must cause disease because of lipid alternations simply does not register with me. I know you love it and the theory that follows. Peanut better is a major lipid fraction inside enterocytes and because HMG-COA reductase catalyzes the synthesis and it interferes with peanut butter production and causes ulcerative colitis. There's going to be a major fat lipid component in every cell in the human body. There is zero correlation with disease. I don't know how much clearer I can be. There's a guy out there that says all disease is caused by iron. He does the same thing you do. There's one out there that says all disease is caused by oxidative stress and you need to eat coconut oil. Here we have Sharon who says all disease is caused by lowered lipid levels with statins. Ask her what organ or tissue is spared. Instead at looking at hyptheticals one looks to actual in vivo effects. "Robert" <Robertsnospam2@hotmail.com> wrote in part: >> Okay I apologize for not making the original post more clear--the >> original study (reported in the jounal of neurochemistry) was conducted [quoted text clipped - 40 lines] > >Instead at looking at hyptheticals one looks to actual in vivo effects. This is the crux of it, I think. Excellent post, Robert. The trouble will all these multistage inferences about health effect from a drug is that it only takes one false guess to make the inference invalid. That's why in vivo studies are essential. Most tests of new drugs show that they fail to produce in humans the effects intended. The researchers' logic was good, but the body's chemical milieu is just too complex to allow much confidence when making predictions. And we pretty much know that everything affects everything. What we don't know in most cases is whether an effect matters. It may be compensated for by the body's intricate system of controls, or it might not. And even if it isn't, it may not matter. -- Jim Chinnis Warrenton, Virginia, USA > She is biting the hand that feeds her and then wonders why nothing is being > done in the field. PD was around long before statins were. Now all of a > sudden it's got to be due to the statins. robert---all i want is for the pharm company to perform the phase 4 trials that were PROMISED in the original correspondence with the FDA after receiving acceptance of their application for marketing Atorvastatin. With TRUE post marketing studies to determine whether there is an association between the use of statins and neurodegenerative diseases, If an association is found, further research into the damage wrought and how to treat it could be undertaken. as long as there are no post marketing studies looking for these associations, there will be NO scientific studies designed to help these individuals. Do I feel this is a waste of $$$--the $14 BILLION Pfizer made on Lipitor alone last year should be sufficient to undertake those studies......and parkinson's is now thought to be due to a genetic variability interacting with an environmental agent (in my husband's case, Lipitor) to produce a disease --parkinson's--Yes Parkinson's has been around a long time--there are many suspected "environmental agents" in the development of Parkinson's---several drugs are included in those suspected agents.... A worthy goal and these trials are long overdue. The results of which, for those of us capable of drawing conclusions, and understanding inferences, will be quite valuable. It may save thousands, even hundreds of thousands of lives, and quality of life in countless others. For those who wish to obscure and ignore and claim to be incapable of drawing inferences, it will be of dubious benefit. >> She is biting the hand that feeds her and then wonders why nothing is >> being [quoted text clipped - 18 lines] > "environmental agents" in the development of Parkinson's---several > drugs are included in those suspected agents.... > A worthy goal and these trials are long overdue. And they should be made by those including inferences or implying something like this study did. Rather than implying isn't more worthy to do an actual study that addresses the question and just imply? > For those who wish to obscure and ignore and claim to be incapable of > drawing inferences, it will be of dubious benefit. Inferences are bad science. It is better to have direct evidence or findings. Where are the findings in this article? Where are the brains of those taking statins compared to those not on statins? Where are the brains of those with PD and how do they compare to those normal and those with statins? Nowhere. Lets just make half a.s inferences and get something published and get some awards and then move on to eractile dysfunction neurobiology or some other unrelated work to get a paycheck. There is no follow up by these people. You and I know that the drug companies won't do it and all you are left with is inferences. "the precise role that dolichol plays in neuromelanin formation or function and in degeneration of dopaminergic neurones in the SN requires further investigation." I stand by my earlier posts. "Studies that imply are a dime a dozen. Real studies are obviously more useful." > I stand by my earlier posts. > "Studies that imply are a dime a dozen. Real studies are obviously more > useful." robert, you are being disingenuous--there are NUMEROUS studies whose findings are "implications" and enable one to obtain funding for further studies upon the power of these "implications". many basic science studies are based upon others' findings, implications from previous studies, etc. --but I love your conclusion---finally we are on the same page--all i want are "real studies" also. the Phase 4 studies promised by the drug cos upon receiving marketing okay from the FDA....and would you really take a drug that depletes your body of an essential element that is found within the main structure that is profoundly diseased in a condition from which you suffer? or in the case of Parkinson's and statin use--try 2 major elements that are depleted by the drug. and all for "primary prevention of heart disease"? > > I stand by my earlier posts. > > "Studies that imply are a dime a dozen. Real studies are obviously more > > useful." > > robert, you are being disingenuous--there are NUMEROUS studies whose > findings are "implications" Not interested in implications for further research. It's what have you done for me lately and not tomarrow. and enable one to obtain funding for > further studies upon the power of these "implications". many basic > science studies are based upon others' findings, implications from > previous studies, etc. --but I love your conclusion---finally we are on > the same page--all i want are "real studies" also. the Phase 4 studies > promised by the drug cos upon receiving marketing okay from the > FDA.... No still not on the same page. Why would you make a company do studies that you don't believe in. Clinical studies were already done. You want more studies in which you claim the company hides things. What's the point? We would be on the same page if you got some of those clowns who cut up brains and make half-a.s inferences. Get them to do real studies. Dr colombo did a study at UCSD. Where is it? It's going to show all those PD patients right? and would you really take a drug that depletes your body of an > essential element that is found within the main structure that is > profoundly diseased in a condition from which you suffer? or in the > case of Parkinson's and statin use--try 2 major elements that are > depleted by the drug. and all for "primary prevention of heart > disease"? That's what studies are for and not simply inferences for further studies to answer. "eml" <mmlevy46@hotmail.com> wrote in part: >"HMG-COA reductase catalyzes the synthesis of mevalonate from two >molecules of HMG-COA, which is further metabolized in a series of [quoted text clipped - 5 lines] >the maturation of glycoproteins), and isopentenyl adenine (a compound >of tRNA). Question: The brain manufactures cholesterol via pathway(s) which differ from those of the liver. Is the same true of brain dolichols? Do they derive from mevalonate produced in the liver, or--like cholesterol--from other substrates? -- Jim Chinnis Warrenton, Virginia, USA > "eml" <mmlevy46@hotmail.com> wrote in part: > Question: The brain manufactures cholesterol via pathway(s) which differ [quoted text clipped - 3 lines] > -- > Jim Chinnis Warrenton, Virginia, USA Hello Jim, as far as I can ascertain, that question has not been adressed. the study i cited was published in 2005. most of the recent work with dolichols seems to be directly related to glycosylation disorders--the inherited multisystem disorders associated with severe psychomotor and mental retardation. no mention of whether dolichol is produced de novo in the brain or only thru the mevalonate pathway in the liver "eml" <mmlevy46@hotmail.com> wrote in part: >> "eml" <mmlevy46@hotmail.com> wrote in part: >> Question: The brain manufactures cholesterol via pathway(s) which differ [quoted text clipped - 11 lines] >produced de novo in the brain or only thru the mevalonate pathway in >the liver Based on what we know about other related compounds, I'd say that dolichol is produced in the brain, but whether from hepatic-derived mevalonate, i can't say. It's a question that needs answering, especially given your original post in this thread. Apparently, though, normal isoprenoid synthesis can still occur in the brain even when mevalonate levels are too low to sustain adequate cholesterol synthesis. Given that statins appear to cross the blood-brain-barrier rather poorly, maybe all this is irrelevant. Interesting post, though, and lots of research needed. -- Jim Chinnis Warrenton, Virginia, USA >. > > Interesting post, though, and lots of research needed. > -- thank you for your question and response--i did write to 2 of the study authors, and one of the questions I asked concerned the production of dolichol within the brain. will let you know if i receive a response. "eml" <mmlevy46@hotmail.com> wrote in part: >>. >> [quoted text clipped - 3 lines] >authors, and one of the questions I asked concerned the production of >dolichol within the brain. will let you know if i receive a response. Please do. -- Jim Chinnis Warrenton, Virginia, USA > > >> Jim Chinnis Warrenton, Virginia, USA sis. Given that statins appear to > cross the blood-brain-barrier rather poorly, maybe all this is irrelevant. > > Interesting post, though, and lots of research needed. > -- Hello Jim--in refernce to your comment that statins crossing the blood brain barrier rather poorly may render the discussion irrelevant: Brain cholesterol turnover required for geranylgeraniol production and learning in mice Tiina J. Kotti, Denise M. O. Ramirez, Brad E. Pfeiffer, Kimberly M. Huber, and David W. Russell PNAS 2006;103 3869-3874 http://www.pnas.org/cgi/content/abstract/103/10/3869?etoc abstract: " the mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholessterol 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 mavalonate pathway. Here we report that this suppression causes a defect inlearning. 24-hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in the hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices iwth an inhibitor of the mavalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimation of 24-hydroxylase on LTP were reversed by a 20 min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mavalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP learning." "...The mevalonate pathway is regulated at multiple levels to prevent the buildup of cholesterol and to ensure a constant supply of nonsterol isoprenoids. The accumulation of cholesterol in membranes activates a negative feedback loop that reduces the levels of transcrioption factors required for the expression of multiple enzymes in the mevalonate pathway, including HMG CoA reductase. Cholesterol and isoprenoids also act postranscriptionally to accelerate the degradation of HMG CoA reducatse thereby potentially limiting the synthesis of all isoprenoids. A class of drugs called statins inhibits HMG Co A reductase directly and therefore has the ability to reduce synthesis of isoprenoids." Thus, need to cross the blood brain barrier is not necessary for statins to affect brain cholesterol and isoprenoid levels--though I was under the impression that the lipophilic statins are the ones used in alzheimer's research because of their ability to cross the blood brain barrier----although ..other statins that are hydrophilic also affect the brain cholesterol as per "though pravastatin obviously does not readily enter the brain, it affects cholesterol homeostasis and gene regulation in the brain...Statin induced supression of geranylgeranylprophosphate formation causes changes in the microtubule stabilizing protein tau leading to transient increase in tau phosphorylation and finally cell death. " (G.P. Eckert, W. G. Wood, and W. E Miller Statin: drugs for Alzheimer's Disease?. J Neural Transm [2005] 112: 1057-1071 no answers yet about dolichol production in the brain.... "eml" <mmlevy46@hotmail.com> wrote in part: >"...The mevalonate pathway is regulated at multiple levels to prevent >the buildup of cholesterol and to ensure a constant supply of nonsterol [quoted text clipped - 10 lines] >Thus, need to cross the blood brain barrier is not necessary for >statins to affect brain cholesterol and isoprenoid levels My knowledge of this stuff is being really stretched here, but I don't see why you draw that conclusion. -- Jim Chinnis Warrenton, Virginia, USA > "eml" <mmlevy46@hotmail.com> wrote in part: > [quoted text clipped - 17 lines] > -- > Jim Chinnis Warrenton, Virginia, USA Jim, Excerpt from the intro of the full text version of this study. Note it is the cholesterol, not the statin, that crosses the BBB: Although the human brain accounts for only a small percentage of body mass (2%), it contains 25% of the body's cholesterol. A majority of brain cholesterol is located in the myelin membranes of oligodendrocytes that surround axons, whereas smaller amounts are found in the plasma membranes of neurons and other support cells. Cholesterol in the adult brain is largely metabolically inert; however, a small fraction of the pool, estimated to be 0.02% in humans and somewhat larger in the mouse (0.4%), turns over each day (7). The major mechanism by which cholesterol is metabolized in the brain is by conversion to 24(S)-hydroxycholesterol (8). This reaction is catalyzed by the enzyme cholesterol 24-hydroxylase (24- hydroxylase), a cytochrome P450 (CYP46A1) that is selectively expressed in the brain (ref. 9; Fig. 1). The 24(S)-hydroxycholesterol diffuses out of cells, crosses the blood-brain barrier, and is cleared by the liver (10, 11). Knockout (KO) mice lacking 24-hydroxylase have an 50% reduction in brain cholesterol excretion (12). This decrease is compensated for by a reduction in de novo synthesis such that steady state levels of cholesterol in the brains of KO mice are the same as those of wild-type (WT) mice. This reduced synthesis is likely to be mediated by a decrease in the activity of HMG CoA reductase. And, since this study indicates that the statin interruption of the mevalonate pathway alters the replenishment of brain cholesterol in a way that increases tau in the brain, that is significant. Many of the rarer forms of fronto-temporal dementia and other neurodegenerative diseases involve increases in tau (or other tau effects). These include a list that COINCIDES REMARKABLY with the cognitive and some of the other neurodegenerative effects of statin adverse effects, including, specifically, effects that eml's family and my husband have developed as statin AEs. See, for example, AFTD, The Association for Frontotemporal Dementias website, http://www.ftd-picks.org/?p=learnmore.overview Note in particular, some of the statin AEs our families have experienced which are associated with FTD/tau increase: Dementia Aphasia Distractability and impersistence Parkinsonism Muscle Dysfunction Movement Dysfunction Have all the dots been connected? No. Have all the statin studies to date looked explicitly for these effects, which according to the results of the study eml posted we now know would be expected, or highly possible, when the HMG CoA Recductase is inhibited (by Statins, HMG CoA Reductase Inhibitors)? No. Have there been multiple publications of patients expressing exactly these effects. Yes. It is the elephant hiding in the living room. One of these days it will be impossible to continue to pretend like it is not there. Until then, more and more patients will suffer these AEs with no hope for corrective treatment, and high likelihood of misdiagnosis. Dr. Muldoon's repeated studies showing consistent measurable loss of cognitive ability in statin patients, and even showing which neuropsych tests reliably identify these cognitive damages notwithstanding. Not one of the major statin studies even attempts to look for such adverse effects. All the while, the off-label marketing of statins garners a wider and wider treatment population.... > "eml" <mmlevy46@hotmail.com> wrote in part: > [quoted text clipped - 17 lines] > -- > Jim Chinnis Warrenton, Virginia, USA "Sharon Hope" <shope@anet.net> wrote in part: >And, since this study indicates that the statin interruption of the >mevalonate pathway alters the replenishment of brain cholesterol in a way >that increases tau in the brain, that is significant. Back to the question re BBB. -- Jim Chinnis Warrenton, Virginia, USA . > Back to the question re BBB. > -- > Jim Chinnis Warrenton, Virginia, USA eml wrote: the blood brain barrier and statins: Brain Cholesterol, Statins and Alzheimer's Disease C. Kirsch1, G. P. Eckert1, A. R. Koudinov2, W. E. Müller1 1 Department of Pharmacology, Biocenter Niederursel, University of Frankfurt, Frankfurt/M., Germany 2 Berezov Academic Laboratory, Russian Academy of Medical Sciences, Weizmann Institute, Biological Regulation, Rehovot, Israel ... Although some HMG-CoA reductase inhibitors seem to influence the central cholesterol pool in vivo, the above epidemiological findings are probably not linked to statin-induced changes in brain membrane cholesterol levels per se since not all statins active in preventing AD enter the central nervous system (CNS). Recently, we reported that different statins, regardless of their brain availability, induce alterations in cellular cholesterol distribution in the brain. Such pleiotropic, cholesterol-synthesis independent statin effects might be indirect and are possibly mediated at the blood-brain barrier (BBB) via nitric oxide (NO) or apolipoprotein E (ApoE). AHHHH--but not so fast---- Journal of Pharmacology And Experimental Therapeutics Fast Forward First published on September 9, 2004; DOI: 10.1124/jpet.104.0750 NEUROPHARMACOLOGY Chronic Administration of Statins Alters Multiple Gene Expression Patterns in Mouse Cerebral Cortex Leslie N. Johnson-Anuna, Gunter P. Eckert, Jan H. Keller, Urule Igbavboa, Cornelia Franke, Thomas Fechner, Manfred Schubert-Zsilavecz, Michael Karas, Walter E. Müller, and W. Gibson Wood ...We demonstrate that statins have pleiotropic effects on gene expression in the brain of mice treated with lovastatin, pravastatin, and simvastatin. The three statins altered expression of numerous genes in the brain, particularly genes associated with cell growth and signaling and trafficking that could be fundamental contributors to neuroprotection. Overlap in effects of the three statins on gene expression was high. However, simvastatin altered expression of more genes than the other statins that could be due to differences in brain levels or targeting of specific genes. Levels of the three statins were detected in brain suggesting that all three drugs were able to cross the blood-brain barrier and that statin levels declined quickly in the brain. Simvastatin was detected at the highest concentration in the brain followed by lovastatin and pravastatin. Cholesterol levels were reduced between 8% and 13% in the cerebral cortex. Statins have pleiotropic effects on gene expression in brain in addition to acting on cholesterol levels suggesting potential pathways of neuroprotection... Note the "suggesting potential pathways of neuroprotection"--could just as easily be suggestive of "potential pathways of neurodegeneration"......interference with cell growth and signaling and trafficking via altered gene expression of the numerous genes in the brain, this sounds like something someone taking a statin for "primary prevention" needs???? another article addressing the blood brain barrier question with statins Nervenarzt. 2006 Mar;77(3):289-93. Related Articles, Links [Direct neuronal effects of statins.] [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] > insults. At higher doses, however, statins may also inhibit neurite > sprouting and even induce neuronal apoptosis. And those of us who have read Jay Cohen MD's books on prescription overdose are painfully aware that the initial FDA approved dosage is always a median - too strong for 50% of the population. Lipitor, for example, was approved at 10 mg/day, and was at that dosage too high for 50%. So, at the dosages currently being pushed - 80 mg and 40 mg, is it any wonder that there is not only speculation at nerve apoptosis and an inhibition of normal replenishment via neurite sprouting, but that Gaist's populational studies and others show statins are neurotoxic? 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 From the abstract: "The authors verified a diagnosis of idiopathic polyneuropathy in 166 cases. The cases were classified as definite (35), probable (54), or possible (77). The odds ratio linking idiopathic polyneuropathy with statin use was 3.7 (95% CI 1.8 to 7.6) for all cases and 14.2 (5.3 to 38.0) for definite cases. The corresponding odds ratios in current users were 4.6 (2.1 to 10.0) for all cases and 16.1 (5.7 to 45.4) for definite cases. For patients treated with statins for 2 or more years the odds ratio of definite idiopathic polyneuropathy was 26.4 (7.8 to 45.4). CONCLUSIONS: Long-term exposure to statins may substantially increase the risk of polyneuropathy." Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? David Gaist, Luis Alberto García Rodríguez · Consuelo Huerta · Jesper Hallas · Søren H. Sindrup http://213.4.18.135/75.pdf full text http://213.4.18.135/76.2.pdf full text http://213.4.18.135/87.pdf full text text Pharmacodynamics: Statins and peripheral neuropathy U. Jeppesen (2), D. Gaist (1)(2), T. Smith (1), S. H. Sindrup (1)(2) (1) Department of Neurology, Odense University Hospital, DK-5000 Odense C, Denmark Tel.: +45-6541-2474, Fax: +45-6541-3389 (2) Department of Clinical Pharmacology Odense University, Odense, Denmark Received: 6 July 1998 / Accepted in revised form: 1 October 1998 Abstract Volume 54 Issue 11 (1999) pp 835-838 http://link.springer-ny.com/link/service/journals/00228/bibs/9054011/90540835.htm "Within the past 3 years seven cases of reversible peripheral neuropathy apparently caused by statins have been reported. Here we report seven additional cases associated with long-term statin therapy, in which other causes of neuropathy were thoroughly excluded. The neuropathy was in all cases axonal and with affection of both thick and thin nerve fibers. The symptoms of neuropathy persisted during an observation period lasting from 10 weeks to 1 year in four cases after statin treatment had been withdrawn. We suggest that long-term statin treatment may be associated with chronic peripheral neuropathy." Association of HMG-CoA reductase inhibitors with neuropathy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1 2549960&dopt=Abstract Ann Pharmacother. 2003 Feb;37(2):274-8. Backes JM, Howard PA. Department of Pharmacy Practice and Lipid, Atherosclerosis, Metabolic and LDL-Apheresis Clinic, University of Kansas Medical Center, Kansas City, KS 66160-7231, USA. jbackes@kumc.edu "Epidemiologic studies and case reports suggest an increased risk of peripheral neuropathy with statin drugs. The majority of cases were at least partially reversible with drug cessation." (emphasis added) Statin-associated peripheral neuropathy: review of the literature.Chong PH, Boskovich A, Stevkovic N, Bartt RE. Pharmacotherapy. 2004 Sep;24(9):1194-203. Review. PMID: 15460180 [PubMed - indexed for MEDLINE]http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15460180"Based on epidemiologic studies as well as case reports, a risk of peripheral neuropathy associated with statin use may exist; however, the risk appears to be minimal. On the other hand, the benefits of statins are firmly established. These findings should alert prescribers to a potential risk of peripheral neuropathy in patients receiving any of the statins; that is, statins should be considered the cause of peripheral neuropathy when other etiologies have been excluded." Disorder resembling Guillain-Barre syndrome on initiation of statin therapy.Rajabally YA, Varakantam V, Abbott RJ. Muscle Nerve. 2004 Nov;30(5):663-6. PMID: 15389662 [PubMed - indexed for MEDLINE]http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15389662"We report a disorder resembling Guillain-Barre syndrome, occurring on initiation of simvastatin, in a 58-year-old man, who had experienced a similar but milder episode after starting pravastatin 6 months earlier. This case suggests that acute polyradiculoneuropathy may represent a rare but serious side-effect of statin treatment. It also raises the issue of the pathophysiology of acute neuropathy on statin exposure, with a hypersensitivity reaction resulting in an immune-mediated process being possible instead of the hypothesized mitochondrial dysfunction in chronic cases." Simvastatin-induced mononeuropathy multiplex: case report.Scola RH, Trentin AP, Germiniani FM, Piovesan EJ, Werneck LC. Arq Neuropsiquiatr. 2004 Jun;62(2B):540-2. Epub 2004 Jul 20. PMID: 15273860 [PubMed - in process]http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15273860"The association between the use of statins and neuromuscular disease is currently being intensely discussed. We relate a 63 years old man with possible case of statin-induced neuropathy in a patient with dislipidemia in use of simvastatina at high doses. The electrophysiologic studies disclosed findings compatible with mononeuropathy multiplex, suggested by clinical prescutation of asymmetrical numbness and weakness. More common causes of mononeuropathy multiplex were excluded and the patient improved after the discontinuation of the drug." Selenoprotein synthesis and side-effects of statins.Moosmann B, Behl C. Lancet. 2004 Mar 13;363(9412):892-4. Review. PMID: 15031036 [PubMed - indexed for MEDLINE]http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15031036 "We noted that the pattern of side-effects associated with statins resembles the pathology of selenium deficiency, and postulated that the mechanism lay in a well established, but often overlooked, biochemical pathway--the isopentenylation of selenocysteine-tRNA([Ser]Sec). A negative effect of statins on selenoprotein synthesis does seem to explain many of the enigmatic effects and side-effects of statins, in particular, statin-induced myopathy." Statin therapy and small fibre neuropathy: a serial electrophysiological study. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1 2639733&dopt=Abstract Lo YL, Leoh TH, Loh LM, Tan CE. J Neurol Sci. 2003 Apr 15;208(1-2):105-8. Department of Neurology, Singapore General Hospital, Outram Road, Singapore. gnrlyl@sgh.com.sg Describes 3 patients who developed neuropathy after ONE MONTH of statin therapy. "One patient redeveloped small and large fibre neuropathy when the similar drug was readministered." Peripheral Neuropathy and Lipid-Lowering Therapy Paul E. Ziajka, MD, PhD, and Tammy Wehmeier, RN, Orlando, Fla. Abstract: We report a case of peripheral neuropathy induced and excerbated by several commonly used HMG-CoA reductase inhibitors including lovastatin, simvastatin, pravastatin, and atorvastatin, and the vitamin niacin. A review of the literature shows similar cases with individual lipid-lowering drugs, but this case shows the cross-reactivity of the neuropathic process to different HMG-CoA reductase inhibitors, and is the first reported case of a peripheral neuropathy exacerbated by the use of niacin. http://www.sma.org/smj1998/julysmj98/ziajka.pdf Peripheral neuropathy associated with simvastatin. Phan T, McLeod JG, Pollard JD, Peiris O, Rohan A, Halpern JP. J Neurol Neurosurg Psychiatry. 1995 May;58(5):625-8. PMID: 7745415 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7 745415&dopt=Abstract "Four patients are described who developed sensorimotor neuropathy while being treated with simvastatin and had complete or partial resolution of clinical abnormalities after withdrawal of treatment. In one case onset was within days of commencing treatment, but in two cases symptoms did not develop for two years. The electrophysiological and pathological features of the neuropathy were those of axonal degeneration. Clinical evidence of proximal and distal weakness and muscle fasciculations and persistent abnormalities of sensory conduction after recovery suggest the possibility of toxic damage to anterior horn cells and dorsal root ganglia. Thirty eight other cases with symptoms suggestive of peripheral neuropathy have been reported to the Australian Adverse Drug Reactions Advisory Committee, 22 of whom recovered after cessation of treatment; in five cases there was recurrence after re-exposure to the drug. Simvastatin should be considered among the causes of peripheral neuropathy, and the drug should be withdrawn if patients receiving it develop muscle weakness or sensory disturbances." Lovastatin and peripheral neuropathy. Ahmad S. Am Heart J. 1995 Dec;130(6):1321. No abstract available. PMID: 7484806 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7 484806&dopt=Abstract Vestibular vertigo and lovastatin therapy. Ahmad S. South Med J. 1996 Feb;89(2):257-8. No abstract available. PMID: 8578368 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=8578368 HMG-CoA reductase inhibitor therapy and peripheral neuropathy. Jacobs MB. Ann Intern Med. 1994 Jun 1;120(11):970. No abstract available. PMID: 8172444 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8 172444&dopt=Abstract Medication-induced peripheral neuropathy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1 2507417&dopt=Abstract Curr Neurol Neurosci Rep. 2003 Jan;3(1):86-92. Review. Weimer LH. Neurological Institute of New York, 710 West 168th Street, Unit 55, New York, NY 10032, USA. Lhw1@columbia.edu PMID: 12507417 [PubMed - indexed for MEDLINE] "Although most cases demonstrate acute or subacute onset after exposure, recent experiences with statin drugs raise the possibility of occult toxic causes of chronic idiopathic neuropathy." Neuropathy due to drugs. Le Quesne PM. In: Dyck PJ, Thomas PK, Griffin JW, et al, eds. Peripheral neuropathy. 3rd ed. Philadelphia: Saunders, 1993:1571-1581. (Book, no link) > another article addressing the blood brain barrier question with > statins [quoted text clipped - 25 lines] > > PMID: 16028081 [PubMed - in process] > "Sharon Hope" <shope@anet.net> wrote in part: > [quoted text clipped - 5 lines] > -- > Jim Chinnis Warrenton, Virginia, USA Looks like you're about to get the old one-two, eml-Hope punch. Enjoy. L. listener <listener@nospam.net> wrote in part: >> "Sharon Hope" <shope@anet.net> wrote in part: >> [quoted text clipped - 11 lines] > >L. Actually, during a flurry of additions to my kill files yesterday, I accidentally blocked most of this thread's participants. Just got a look at the posts... -- Jim Chinnis Warrenton, Virginia, USA |
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