CFIDS impaired 450 cytocrome system and meds

Discussion in 'Fibromyalgia Main Forum' started by PaulMark, Sep 15, 2003.

  1. PaulMark

    PaulMark New Member

    dear friends: The lst thing dr. CHeney told me in l998 when i was dx with CFIDS was we have deep brain injury at the level of the hypathlmus adrenal pitituary adrenal axis (HPA) ,and the 450 cytocrome system is impaired (he said the liver is not diseased but centrally strained) our brains are in a state of seizure thereby lowering the bodies threshold I"m resending

    Yet we are prescribed medications, some i don't know if they got thru the 450 system neurontin doesn't magnesium is renal expelled also, what about low dose klonopin i asked my pharmacist and he just he hummed around and said well l mg is very low dose paul, well duh of course in healthy people but our liver is already strained,

    so we are in a catch 22 here vicious cycle of CFS per cheney is pain/fatigue/depression so we need some meds yet do they REsidues in our bodies this is what Pitchford (book Healing foods written in a lot of yin/yen language says "residues in the body from either medicinal or recreational drugs are very often stored througout the a person’s life in the liver, brain, and other tissues, " then he talks more of the recreational drugs harm

    : "DR. cheney has phd from duke in physics and said they don't even teach the MNDA receptor theory in med school, the pain threshold is lowered due to "deep brain injury to the hypathlmus" in CFIDS researchers have found . just don't know why exactly.

    I do not like taking medications. I’ve tried cold turkeying quiting the low doses I take and result inability to cope with pain no sleep, sleep disturbance and lack of stage 4 sleep major hallmark symptom of CFIDS and even fibro.

    The pure holistic view vs. the intergretative approach to medicine has been debated on the CFS message board, I read things like this from Healing foods book by paul pitchford make statements like many pure holistics (and I agree in an ideal world with no pollutants radiation, free reaadicapl pathology) we wouldn’t have as many sick people,

    .

    So I’m asking YOUR opinoin are we in a never ending down spiral cycle by having to take medication, for this illness yet our bodies ability to detox toxins meds most things is impaired by the 450 cytocrome system problem

  2. rdthewave

    rdthewave New Member

    I understand what you are talking about when you speak of the impaired stage 1 and stage 2 450 system. I had the test done and it showed my liver was not functioning right.....unable to detox properly. I for one do think its a viscious cycle........people having to take prescription drugs while the liver is unable to detoxify properly........what is one to do! I cannot suggest what other people do I can only do what I think is right for me. I have chosen not to take any prescription meds........I am still researching this whole thing........I am very much in touch with a more natural approach......that's just me.......I don't down anyone for trying prescription meds........I just think they are too much for my body. Also I have found that each of our chemistry make up is different.....and that some of the very common things that are often prescribed on these message boards would be compounding the problem for some people depending on the chemistry of their body! It is very complex..........I wish I could tell you the right thing to do.......but everyone has to experiment with different things.

    I wish yu well,

    Tammy
  3. Dlebbole

    Dlebbole New Member

    I tried to learn as much as I could about this several years ago. Have you read much about phase 1 vs. phase 2 detoxification and the various methods to try to upregulate the function of each system? I found that a supplement called calcium d-glucarate helped me like nothing else in many years. After taking a sufficient dose, I regained some of my tolerance to foods. I also noticed that I could tolerate more of my needed medications (for example, a med for migraine) in higher doses and they had more of a normal effect. I think you are on the right track in wondering about this. But I believe that we can try to improve the function of this enzyme system. Good luck, Diane
  4. kjan9

    kjan9 New Member

    I've not read anything re: 450 system, but I did want to respond to the hypathalamus. Since the begining 8 years ago, when I was diagnosed and began taking vicodin. I had read that hydrocodone regulates the hypathalamus! I had always felt maybe that is why that drug works best for me. Of course long term use and/over use can damage the liver. Due to the acetametiphen included in vicodin. (spelling wrong you know tylenol!!)Over the years I've never increased the dosage that I take, but I give body a break from it for month's at a time after so long, plus the docs think your an addict when the refills come around. The tolerance threshold and all. An infectious disease specialist once told me cfs patients in general, for some reason, (maybe constantly go the bathroom?) drugs don't stay in our systems for very long. When I took neurontin, up to 4000mg daily it made me feel uneasy about long term use, after 5yrs, I felt no benifet anymore anyway and weaned off. DO you have info on the effects of the liver and neurontin? I don't know much about the liver, but I guess all drugs have a catch 22 in general, for problems.
    kjan9
  5. annepat

    annepat New Member

    check the Neurotin label-if memory serves, it does pass through a P450 enzyme Y126(?? soory-foggy).

    P5450- metabolism impacted by St.john's Wort, and many of the SSRI's. Some major lawsuits over SSRI P450 metabolism-SSRI labels are changing to reflect P450 metabolism.

    I have a good P450 synopsis article from Medscape, but it is
    very lengthy. JAMA has also recently completed a series of articles on Pharmacogenomics, but some of it is too complicated, especially when I'm changing meds.

    Can I post portions of the Medscape article?
  6. Dlebbole

    Dlebbole New Member

    please do! Diane
  7. annepat

    annepat New Member

    Abstract
    Will the genomic revolution deliver a brave new world of gene-based medicine, complete with personal genomes on chips, predictive disease profiling, and gene therapy? Not all the great expectations will come to pass, and those that do probably won't materialize for at least another decade. But one major advance toward gene-based medicine is attainable today. Clinical pharmacogenomics has arrived in the form of rapid, reliable tests that will let clinicians predict how an individual patient will respond to a significant number of drugs. This article offers clinicians a summary of the pharmacogenomic tests that are available now and in the near future and describes how these tests can help optimize dosing regimens, reduce adverse events, and improve clinical outcomes.
    Introduction
    Pharmacogenomics, the study of the genetic basis of therapeutics, identifies discreet genetic differences among individuals that play a critical role in drug response. DNA tests based on these genetic variations can predict how a patient will respond to a particular medicine. Clinicians will use them to select optimal therapy and tailor dosing regimens; the benefits will include reduced incidence of adverse drug events, improved clinical outcomes, and reduced costs.
    The first DNA-based tests are already here, and pharmaceutical companies are developing tests designed for use with new drug introductions. These tests represent the first step toward patient-specific therapeutics. Individually tailored drug therapy will be a reality within the next few years. Physicians will need to know whether a drug is subject to genetic polymorphism that affects expression of drug metabolizing enzymes or drug receptors. They will also have to know how to use this information to improve therapy for their patients.
    Genomics in the Clinic: What Doctors and Pharmacists Can Expect
    Variations in patient response to drugs are a significant therapeutic issue. Although it is a broad generalization, it has long been estimated that as few as one third of individuals derive the intended therapeutic benefit from a prescribed medicine. In the remaining two thirds, the medication either doesn't work as intended or is not well tolerated. The observation of extraordinary responses is relatively common. Adverse drug effects among hospitalized patients in the United States may number as high as 2 million per year; as many as 100,000 of them prove fatal.[1]
    Pharmacogenomics will play a major role in individualizing therapeutics and reducing adverse drug events. The near-term benefits may be underappreciated, because they are often overshadowed by the possibly unrealistic and certainly more distant expectations for gene-based predictive medicine.
    The successful completion of the decade-long mapping and sequencing of the human genome will lead to the discovery of genetic markers of disease susceptibility. But great expectations that the human genome will reveal the genetic basis of most common diseases and transform healthcare from diagnosis and treatment to prediction and prevention remain a futuristic -- and perhaps unrealizable -- vision.
    That the genetic revolution may not create a new paradigm for the prevention of common diseases is persuasively argued by Neil Holtzman and Theresa Marteau in The New England Journal of Medicine commentary, "Will Genetics Revolutionize Medicine?"[2] Although genomics will identify genes that cause Mendelian disorders such as Huntington's disease, the genetic basis of common diseases is probably too complex to provide accurate predictions of future illness based on genotype.
    However, genetic differences do determine how individuals metabolize drugs. Polymorphisms have been identified in more than 20 human drug-metabolizing enzymes that can determine whether an individual will fail to respond to a drug or suffer an exacerbated clinical response. Pharmacogenomics is making dramatic progress in developing tests to predict which patients are likely to benefit from a medicine and which patients are likely to suffer a toxic side effect. DNA-based tests designed for clinical use will give physicians the ability to predict patient response to a broad range of drug therapies.
    The Role of Genetic Variation in Drug Response
    Even though the genomes of individuals are 99.9% identical, the small 0.1% difference predicts as many as 3 million polymorphisms, the most common being the single nucleotide polymorphism (SNP). Many polymorphisms in the 100,000 or so genes in the human genome will have no effect. Many, however, will affect protein expression and function, resulting in phenotypes affected for disease or drug response.
    Mode of action for most drugs depends on the drug's interaction with specific protein targets such as receptors, transporters, and cell-signaling pathways. Many of these drug targets have been shown to have polymorphisms that can influence response to specific medicines. Furthermore, polymorphisms in known disease pathways can predict a specific drug's potential for efficacy.
    There are a number of examples in which genotyping studies have elucidated clinically relevant associations between genetic polymorphisms in drug targets and disease pathways with certain drugs:
    • A polymorphism in the cholesteryl ester transfer protein (CETP) determines the efficacy of pravastatin in patients diagnosed with coronary atherosclerosis. The absence of the polymorphism is associated with diminishing efficacy. This finding is based on the study by Kuivenhoven[3] and has not been duplicated.
    • Recently described polymorphisms in beta-adrenergic receptors affect their sensitivity to beta-agonists such as albuterol. Asthma patients carrying the Gly-16 (glycine at codon 16) polymorphism show an increased response to beta-agonists compared with those carrying Arg-16 (arginine at codon 16).[4]
    • Polymorphisms in the serotonin neurotransmitter receptor (5HT2A) have been associated with the effectiveness of the antipsychotic drug clozapine. Patients carrying a thymine-to-cytosine conversion at position 102 are particularly likely to respond to clozapine.[5]
    • Other reported associations with putative drug targets include angiotensin-converting enzyme (ACE) and sensitivity to ACE inhibitors,[6] and apolipoprotein E (ApoE) in response to tacrine therapy among patients with Alzheimer's disease.[7]
    At present, however, the greatest opportunities for clinical application come from genetic variations related to enzymes involved in drug metabolism.
    Polymorphisms in Drug-Metabolizing Enzymes
    A relatively small number of drug-metabolizing enzymes (DMEs) are responsible for metabolizing the majority of drug therapies in clinical use today. There are a relatively small number of relevant polymorphisms within these enzymes, and many of them can result in lack of therapeutic effect or in exacerbated clinical response.
    Genetic polymorphism in DMEs gives rise to 3 distinct subgroups of people who have measurable differences in their ability to metabolize drugs to either inactive or active metabolites. Individuals capable of efficient drug metabolism are called extensive metabolizers (EMs). Individuals with deficiencies in metabolism, which typically require mutation or deletion of both alleles of a gene, are termed poor metabolizers (PMs). Conversely, overexpression due to gene amplification results in ultra-rapid metabolizers (UMs).
    Standard doses of drugs with a steep dose-response curve or a narrow therapeutic range may produce adverse drug reactions, toxicity, or decreased efficacy in PMs. When taken by UMs, the standard dose may be inadequate to produce the desired effect.
    Two examples of polymorphisms in drug-metabolizing enzymes that have considerable potential to affect clinical medicine include those affecting the cytochrome P450 enzyme family, CYP2D6, and the enzyme thiopurine methyltransferase (TPMT). These genetic variations affect a significant percentage of the population and influence therapeutic outcomes of drugs commonly used to treat cardiovascular disease, cancer, central nervous system disorders, and pain.
    2D6 Testing for Specific Drug Classes
    CYP2D6, or 2D6, is responsible for the metabolism of nearly 25% of all drugs. There are more than 20 drugs known to be 2D6 substrates (Table). They include cardiovascular agents, antidepressants, antipsychotics, and morphine derivatives. Examples are amitriptyline, fluoxetine, perphenazine, timolol, propafenone, codeine, and dextromethorphan. Genetic variations in the level of expression or function of 2D6 have profound effects on the efficacy and toxicity of these drugs.
    Mutations leading to 2D6 enzyme deficiency are found in 7% to 10% of whites and 1% to 2% of Asians. In the context of treatment, these variants can affect determination of the proper initial dose for many drugs. For drugs with a narrow therapeutic profile and steep dose-response curve, this can result in either overdose or the inability to maintain a therapeutic efficacy. Since many psychotropic drugs have a narrow therapeutic profile and adverse events are common, predetermining 2D6 activity levels for patients treated with these agents can have significant clinical benefit.
    As an example of dosage determination, nortriptyline is dosed in most patients at a range of 75-150 mg. But in poor 2D6 metabolizers, the effective tolerable dose is 10-20 mg. In ultra-rapid metabolizers, a genetic variation results in the inheritance of as many as 13 copies of the gene. Patients with this genetic amplification metabolize the drug so quickly that they may require a dose increase to more than 500 mg to achieve therapeutic effect.[12] It should be noted, however, that many drugs that undergo biotransformation by 2D6 -- particularly antidepressants -- produce pharmacologically active metabolites, and this tends to complicate the interpretation of toxicity/efficacy relationships.
    CYP2D6 can also influence prodrug efficacy. In their discussion of effects in ultra-rapid metabolizers, Ingleman-Sundberg and his colleagues[13] note that high doses of the prodrug codeine can generate extensive formation of morphine and trigger adverse effects. The lack of 2D6 in poor metabolizers can reduce efficacy of prodrugs requiring 2D6 activation, such as the analgesic tramadol.[13]
    Until recently, pharmacogenomic testing has been used primarily in a limited number of academic centers and teaching hospitals. Examples include the pharmacology laboratory of Georgetown University (Washington, DC), which provides 2D6 analyses. Predetermination of a patient's 2D6 profile will soon be possible in the physician's office. A clinical 2D6 test kit has been developed in a collaboration between Hoffman-La Roche and the genomics company Affymetrix. Availability of the 2D6 diagnostic kit is anticipated within the next 2 years, following approval by the US Food and Drug Administration. PPGx has also developed a 2D6 test.
    A Wealth of Future Applications
    The CYP gene family may offer a treasure trove of opportunities to develop clinically valuable genomic tests. High on the list are polymorphisms of CYP2C19, which affect a significant percentage of the Asian population and predict the metabolism of commonly prescribed medicines.
    Mutations in the CYP2C19 gene that result in compromised drug metabolism are found in 18% to 23% of Asians and in 2% to 5% of whites. Seventy-five percent of all PMs are accounted for by 1 allele. There is a unique allele in Asians that accounts for 25% of PMs in that population.[14] There are correlations between CYP2C19 polymorphisms and both the pharmacokinetics and pharmacodynamics of drugs including citalopram, clomipramine, diazepam, propranolol, omeprazole, and the tricyclic antidepressants. For example, individuals with 2C19 polymorphisms resulting in inactive enzymes show higher levels of the antiulcer drug omeprazole and increased drug response, as measured by the surrogate marker plasma gastrin.[15]
    Researchers are investigating the potential of numerous other drug-related polymorphisms. Dempsey and colleagues[16] found that CYP2A6 plays a role in nicotine metabolism; subsequent studies suggest a genetic factor in nicotine addiction and increased risk for lung cancer. Among disease-related genes, receptor 5HTT may be involved in the etiology of migraine headaches, and genetic variation might be exploited to improve migraine therapy.
    Patient-Specific Therapy Is Emerging
    Someday we will consider today's one-size-fits-all approach to drug selection and dosing a primitive stage in therapeutics. By 2005, genotype testing will be a routine procedure before prescribing many drugs. In the future, it will be considered unethical to expose patients to the risks of adverse events without first performing these fast, simple DNA tests.[8] Improving patient outcomes and avoiding adverse reactions will reduce the costs of hospitalizations, the number of office visits, and the waste incurred by ineffective therapy.
    Social and economic benefits may be far-reaching, according to Glaxo-Wellcome's head of Genetics, Alan Roses: "Selection of predicted responders offers a more efficient and economic solution to a growing problem that is leading governments and healthcare providers to deny effective medicines to the few because a proportion of patients do not respond to treatment. The economy of predictable efficacy, limited adverse events, lower complications owing to targeted delivery and increased cost-effectiveness of medicines will improve healthcare delivery and eliminate the need for rationing."[17]
    Conclusion
    Will all drugs that physicians prescribe someday be designed and formulated specifically for an individual patient's genotype? Probably not. Genetic variation is only 1 factor in human drug response, which also depends on concomitant drug therapies, environment, lifestyle, health status, and disease status. Unlike TPMT and CYP2D6, where 1 gene divides the population into 2 or 3 distinct groups (ie, monogenic traits), response to most medications involves interaction between multiple genes (ie, polygenic traits), which are more difficult to discover and distinguish from environmental factors. A more realistic expectation is that pharmacogenomic applications such as those described will, in the near term, provide the basis for drug selection and dose adjustments that will reduce adverse drug reactions and increase therapeutic effectiveness.
    In the longer term, research in clinical genomics will reveal polymorphisms that affect susceptibility to common diseases. Understanding the functions and frequencies of these genetic variations will be a greater challenge. It will take much more time before those discoveries lead to new strategies for disease intervention. Whatever the future holds, pharmacogenomic testing is here and now. And it is proving to be an important tool in the evolution of drug therapy from an empiric art to a clinical science.
    Table. Medicines Affected by the 2D6 Gene
    Cardiovascular Agents
    Antiarrhythmics Beta-blockers Antihypertensives
    Propafenone Timolol Indoramin
    Encainide Metoprolol Debrisoquine
    Flecainide Propranolol Guanoxan
    Sparteine
    N-propylajmaline
    Mexiletine
    Psychoactive Agents
    Neuroleptics Tricyclic antidepressants MAOIs
    Perphenazine Nortriptyline Amiflamine
    Trifluperidol Amitriptyline Methoxyphenamine
    Fluphenazine Clomipramine SSRIs
    Thioridazine Desipramine Fluoxetine
    Clozapine Imipramine Paroxetine
    Tomoxetine Sertraline
    Morphine Derivatives
    Analgesics Antitussives
    Codeine Dextromethorphan
    Miscellaneous
    Phenformin Methoxyamphetamine Perhexilene

    MAOIs = monoamine oxidase inhibitors; SSRIs = selective serotonin reuptake inhibitors

[ advertisement ]