Article about Medicines and Mytochondrial Dysfunction

Discussion in 'Fibromyalgia Main Forum' started by LISALOO, Oct 11, 2008.


    LISALOO New Member

    Funny, just received this in my CO-Cure daily e-mail

    Date: Fri, 29 Aug 2008 13:50:50 +0200
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    Subject: act,med: Medication and ME/CFS?
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    Medication and ME/CFS?

    Margaret Williams

    27th August 2008

    Mitochdondria are the powerhouses of the cells. They are responsible for generating energy as adenosine triphosphate (ATP) and are involved in the apoptosis signalling pathway (apoptosis being programmed cell death).

    There is a significant literature suggestive of mitochondrial defects (both structural and functional)
    in ME/CFS from 1984 to date and it is accepted by informed ME/CFS clinicians and researchers that there is actual biopsy evidence of mitochondrial damage in ME/CFS, for example:

    * Behan WM et al, Acta Neuropathol 1991:83(1):61-65 ("Mitochondrial
    degeneration was obvious in 40 of the
    biopsies, with swelling, vacuolation, myelin
    figures and secondary lysosomes. The
    pleomorphism of the mitochondria in the
    patients' muscle biopsies was in clear
    contrast to the findings in the normal
    control biopsies. Diffuse or focal atrophy
    of type II fibres has been reported, and
    this does indicate muscle damage and not
    just muscle disuse")

    * Pizzigallo E et al, JCFS 1996:2
    (2/3):76-77 ("We performed histochemical
    and quantitative analysis of enzymatic
    activities and studies of mitochondrial DNA
    deletions. All specimens showed
    hypotrophy, fibres fragmentation, red
    ragged fibres, and fatty and fibrous
    degeneration. Electron microscopy
    confirmed these alterations, showing
    degenerative changes, and allowed us to
    detect poly/pleomorphism and cristae
    thickening of the mitochondria. The
    histochemical and quantitative
    determination of the enzymatic activity
    showed important reduction, in particular
    of the cytochrome-oxydase and
    citrate-synthetase. The 'common deletion'
    of 4977 bp of the mitochondrial DNA was
    increased as high as 3,000 times the
    normal values in three patients. Our
    results agree with those of Behan et al
    1991 and Gow et al 1994. The alterations
    are compatible with a myopathy of
    probable mitochochondrial origin (which)
    could explain the drop in functional
    capability of the muscle")

    * Cheney P, Orlando Workshop,
    International Congress of Bioenergetic
    Medicine 1999, audio tape #2 ("The most
    important thing about exercise is not to
    have then do aerobic exercise. If you have
    a defect in the mitochondrial function and
    you push the mitochondria by exercise, you
    kill the DNA"). Cheney's findings were
    supported by Benjamin Natelson, Professor
    of Neurology at New Jersey Medical School
    – in his 1999 lecture at the Fatigue 2000
    Conference in London, Natelson discussed
    his work on muscle metabolism using NMR
    testing the muscle of patients with ME/CFS
    after exercise, in which his team
    demonstrated a problem with mitochondrial
    recovery; this Conference was reported in
    the ME Association Newsletter
    Perspectives, Summer 1999:18

    * Klimas NG et al, Curr Rheumatol Rep
    2007:9(6):482-487 ("Gene microarray data
    have led to better understanding of
    pathogenesis. Research has evaluated
    genetic signatures (and) described biologic
    subgroups. Genomic studies demonstrate
    abnormalities of mitochondrial function").

    * Nestadt P:
    ("These results show that a significant
    proportion of patients diagnosed with
    (ME)CFS have elevated ventricular lactate
    levels, suggesting anaerobic energy
    conversion in the brain and / or
    mitochondrial dysfunction"). (Elevated
    blood lactate levels after mild exercise are
    considered to be a sign of mitochondrial

    * Bell

    ("I agree that ME/CFS is a mitochondrial
    disease (but) ME/CFS is a mitochondrial
    disease like no other. There are lots of
    studies that implicate mitochondrial
    problems: Dr Hirohiko Kuratsune and
    carnitine; Dr Suzanne Vernon and
    genomics; Dr Kenny DeMeirlier (Brussels);
    Dr Martin Pall (New York); Dr Paul Cheney
    and many others").
    That there is evidence of disrupted
    apoptosis in ME/CFS cannot be disputed
    (Increased neutrophil apoptosis in Chronic
    Fatigue Syndrome. Kennedy G et al. J Clin
    Pathol 2004:57(8):891-893)

    Attention is therefore drawn to a paper by Neustadt and Pieczenik which reviews the evidence that medications have now emerged as a major cause of mitochondrial damage (Medication-induced mitochondrial damage and disease. Mol Nutr Food Res 2008:52:780-788).

    In addition to medication-induced systemic dysfunction, systems most affected are listed as being the muscles, brain, nerves, kidneys, heart, liver, eyes and pancreas.

    Acquired conditions in which mitochondrial dysfunction has been implicated include (ME)/chronic fatigue syndrome and fibromyalgia.

    The mechanisms of mitochondrial-induced injury and the damage caused by medication-induced production of free radicals are explained in detail by the authors.

    Medications documented to induce mitochrondial damage include analgesics; anti-inflammatories; anaesthetics; angina medications; antibiotics; antidepressants; anxiolytics; barbiturates; cholesterol-lowering medications (statins); chemotherapy; and the mood-stabiliser lithium, amongst others, including medications for Parkinson's Disease, diabetes, cancer and HIV/AIDS.

    It is a matter of record that psychiatrist Professor
    Simon Wessely advises the prescription of lithium for
    patients with ME/CFS: "There is no doubt that at
    least half of CFS patients have a disorder of mood.
    The management of affective disorders is an essential part of the treatment of CFS/ME. Numerous trials attest to the efficacy of tricyclic antidepressants in the treatment of fatigue states.

    Patients who fail to respond should be treated
    along similar lines to those proposed for
    treatment-resistant depression. Adding a second
    antidepressant agent, especially lithium, may be
    beneficial" (The chronic fatigue syndrome – myalgic
    encephalomyelitis or postviral fatigue. S Wessely PK
    Thomas. In: Recent Advances in Clinical Neurology
    (ed): Christopher Kennard. Churchill Livingstone
    1990: pp 85-131).

    In addition to lithium, specific medications listed
    that are known to induce mitochondrial damage include aspirin; acetaminophen (paracetamol /Tylenol); fenoprofen (Nalfon); indomethacin (Indocin,Indocid); naproxen (Naprosyn); lidocaine; amiodarone (Cordarone); tetracycline; amtitriptyline; citalopram (Cipramil); fluoxetine (Prozac);chlorpromazine (Largactil); diazepam (Valium); galantamine (Reminyl) and the statins, amongst

    The authors state that damage to mitochondria may
    explain the side effects of many medications:
    "Recently it has become known that iatrogenic
    mitochondrial (damage) explains many adverse
    reactions from medicines".

    It was in 1994 at the Dublin International Meeting on
    ME/CFS (held under the auspices of the World
    Federation of Neurology) that Charles Poser,
    Professor of Neurology at Harvard, confirmed that
    adverse reactions to medication is virtually
    "pathognomonic" of ME/CFS, and that a paradoxical
    or inappropriate reaction to medications is one of the
    most important criteria in ME/CFS.

    As Neustadt and Pieczenik state that mitochondrial
    dysfunction has been implicated in fibromyalgia (FM)
    as well as in (ME)CFS, and as FM has been
    recognised as an additional burden of suffering in
    many patients with ME/CFS (Buchwald D et al.
    Rheum Dis Clin N Am 1996:22:2:219-243), it is of
    interest that a 2007 paper estimated the prevalence
    and number of FM patients in ten countries, looking
    specifically at FM patients' AAT (alpha-1 antitrypsin)
    phenotypic distribution worldwide. Those countries
    were Canada, the USA, Denmark, Finland, Germany,
    Italy, the Netherlands, Spain, Sweden and Pakistan.
    The authors noted that during the last few years,
    clinical, epidemiological and pathological evidence
    suggests that alpha-1 antitrypsin (AAT) deficiency
    may play a role in the development of FM. Studies
    on AAT gene frequencies and FM were retrieved from
    all ten countries. Results showed that a severe
    deficiency Z allele was found in all these countries,
    with very high frequencies in Denmark and Sweden;
    high frequencies in Italy and Spain; intermediate
    frequencies in Germany, the Netherlands, Canada
    and the USA, and a low frequency in Pakistan. The
    authors conclude that AAT phentotype
    characterisation should be recommended in all FM
    patients, and that the possible efficacy of AAT
    replacement therapy in severely deficient FM patients
    warrants further study.

    This is evidence that argues robustly against the
    Wessely School belief that, together with "CFS/ME",
    FM is a single somatoform disorder (S Wessely et al.
    Lancet 1999:354:936-939).

    It also adds to the existing evidence that
    demonstrates the lack of scientific rigour accepted by
    the Medical Research Council (MRC) in permitting the
    Wessely School investigators (who are in charge of
    the PACE trials on cognitive behaviour therapy and
    graded exercise therapy in "CFS/ME") intentionally to
    include people with FM in those trials. Including
    different patient populations from the outset will
    inevitably skew the results, and under the WHO
    taxonomic principles, FM is classified separately from
    ME/CFS at ICD-10 M79, whereas ME/CFS is classified
    at G93.3.

    In a separate paper by Professor Julia Newton et al
    comparing mitochondrial function in patients with
    primary biliary cirrhosis (PBC), patients with primary
    sclerosing cholangitis, patients with ME/CFS and
    normal controls (Pilot Study of Peripheral Muscle
    Function in Primary Biliary Cirrhosis: Potential
    Implications for Fatigue Pathogenesis. Hollingsworth
    KG, Newton JL et al. Clin Gastroenterol Hepatol; in
    press, September 2008) the authors state that PBC
    is characterised in 95% of patients by autoantibody
    responses directed against the mitochondrial antigen
    pyruvate dehydrogenase complex (PDC). To define
    mitochondrial function in peripheral muscle during
    exercise, (31)P magnetic resonance spectroscopy was

    Whilst the paper is chiefly concerned with
    mitochondrial dysfunction in patients with primary
    biliary cirrhosis (and the results clearly indicate
    mitochondrial dysfunction in patients with PBC, who
    showed excess muscle acidosis at higher levels of
    exercise), the authors state about ME/CFS patients:
    "Interestingly, prolonged time to maximum proton
    efflux was also seen in the (ME)CFS control group,
    indicating that there are aspects of muscle pH
    handling that are abnormal in this important clinical

    Professor Newton is Lead Clinician in the
    internationally renowned Cardiovascular
    Investigations Unit at the University of Newcastle,
    UK, which is the largest autonomic function testing
    laboratory in Europe; her work focuses on the role of
    the autonomic nervous system in the development of
    fatigue, specifically in primary biliary cirrhosis, but
    also in the pathogenesis of fatigue in ME/CFS. In her
    Conference pack for the ME Research UK
    International Research Conference held at the
    University of Cambridge on 6th May 2008, Professor
    Newton said: "Recent results from a series of MR
    scans have shown impaired proton removal from
    muscle during exercise in patients with ME/CFS
    compared to matched controls. This has led us to
    hypothesise that fatigue arises due to impaired pH
    run off from muscle during exercise which is
    influenced by the degree of autonomic dysfunction".

    Despite the irrefutable evidence of mitochondrial
    dysfunction and damage in patients with ME/CFS, the
    NICE Guideline on "CFS/ME" proscribes mitochondrial
    testing and recommends only behavioural
    modification in the form of cognitive behavioural
    therapy, together with incremental aerobic exercise,
    and refers to "perceived exertion" (52 page
    version, page 30). It claims that it "offers the best
    practice advice on the care of people with
    CFS/ME" (52 page version, page 6) and that its
    advice is "evidence-based". It is notable that the
    alleged evidence-base upon which the Guideline
    Development Group relied specifically states: "If
    patients complained of increased fatigue, they were
    advised to continue at the same level of exercise"
    (Fulcher and White, BMJ 1997:314:1647-1652). Given
    the evidence of mitochondrial damage, such advice
    cannot conceivably qualify as "best practice advice".


    LISALOO New Member

    I wonder if I stop the medicine if the damage will reverse itself?
  3. simonedb

    simonedb Member

    dr cheney warns against stimulant meds (including ssris) and says taking meds on the sedating side safer, neuro protective meds.<BR>
    I was on erythomyocin (for complexion) and prozac (for anxiety) in 89 when some other stuff happened ( a surgery and neck injury) and have been told by cfsexpert that those meds could have been bad for me, contributed to my vulnerability, I did seem to be deteriorating in some ways on then--anyway--after that I got the cfs/me disabilityt thats still with me.<BR>
    right now i am trying the LDN which dr cheney has said is ok to try and I just started in last couple days small dose of lithium orotate (o-t-c) to see if can help with other aspects of energy. there is research showing it is neuroprotective and helps with spinal pain--I think it is much more than a med for "mental illness" I mean its a salt; I think a lot of stuff that is "mental illness" is just another expression of body imbalance like cfs or diabetes etc.Its too bad some stuff has a stigma and other problems don't.<BR>
    It is too early to say for sure because sometimes I am ok on supps/meds for a few days then the bad effects set in but so far I would say it has helped energy subtley and not been invasive with other unwanted effects.<BR>
    As far as Wessely prescribing lithium,perhaps he stupidly hit on something smart for the wrong reasons, maybe lithium helps some cfs people because of other reasons than mental illness, they are researching it for lou gehrigs disease and other stuff. I dont think it gets researched a lot since 70s because like naltrexone its hard for drug companines to make money on old medicaitons so they push the newer ones like ssris snris provigil etc etc that are harder on p450 systems and on cfs than some of the older meds, but they make money. Also with lithium it is given in higher doses perhaps than would be needed for cfs, with the naltrexone I am responding to a fraction of what even the regular low dose is, with the chemically sensitive aspect of cfs/me we are pioneers and need to keep that in mind when experiment with new stuff, its surprising what can help sometimes if you find right dose. Something can be toxic or lifegiving at different doses. That said if anyone takes more than a minute amount of lithium they should have doctor follow them and blood test as I guess any form of it can build up in people, but a doc I consulted told me not to worry with trying minute crumb amounts.

    Lithium has a wide range of uses
    Lithium is sometimes prescribed by doctors for purposes other than those commonly used. Lithium has mood stabilizing effects and is quite useful in manic-depressive illness. Recent studies suggest lithium can be used in the treatment of acute brain injuries (e.g., ischemia) and chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease). Consistent with this novel view, substantial evidences suggest that depressive illness is not a mere neurochemical disease, but is linked to gray matter atrophy due to the reduced number/size of neurons and glia in brain. Importantly, neurogenesis, that is, birth/maturation of functional new neurons, continues to occur throughout the lifetime in human adult brains (e.g., hippocampus); the neurogenesis is impaired by multiple not-fully defined factors (e.g., aging, chronic stress-induced increase of glucocorticoids, and excitotoxicity), accounting for brain atrophy in patients with depressive illness and neurodegenerative diseases. Chronic treatment of lithium, in agreement with the delayed-onset of mood-stabilizing effects of lithium, up-regulates cell survival molecules (e.g., Bcl-2, cyclic AMP-responsive element binding protein, brain-derived neurotrophic factor, Grp78, Hsp70, and beta-catenin), while down-regulating pro-apoptotic activities (e.g., excitotoxicity, p53, Bax, caspase, cytochrome c release, beta-amyloid peptide production, and tau hyperphosphorylation), thus preventing or even reversing neuronal cell death and neurogenesis retardation.

    [This Message was Edited on 10/11/2008]
    [This Message was Edited on 10/11/2008]