Fibromyalgia
Fibromyalgia: one cause.
Deborah Barges
Highlights:
· One cause of fibromyalgia is an irreversible molecule containing copper, the copper(II)-Omeprazole complex, which dysregulates copper homeostasis, affecting iron, zinc and thereby the rest of the metabolism as a result, in a ripple effect.
· Sudden onset fibromyalgia can be induced by giving omeprazole to a person with hypercupremia.
· Knowing that fibromyalgia is dysregulation of the copper and iron homeostases and can be caused by an irreversible molecule can give useful insight into other causes of fibromyalgia, and potentially for similar conditions, such as chronic fatigue and cancer-related fatigue.
(Background:)
Fibromyalgia (FM) is a condition characterized by chronic widespread musculoskeletal pain. Fatigue, cognitive disturbance, psychiatric and multiple somatic symptoms often accompany the disorder. Fibromyalgia has been described as having an unknown etiology and uncertain pathophysiology and is described as a pain regulation disorder, and often classifies as a form of central sensitization syndrome, considered to be a neurosensory disorder where the individual is not able to process pain in the brain.[Diagnosing Fibromyalgia as a Disease, an Illness, a State, or a Trait?]
Abnormalities noted in fibromyalgia include:
elevated levels of the excitatory neurotransmitters like glutamate[Trait?, Squitti glutamate], which could be explained by low levels of magnesium in people with fibromyalgia[Romano Mg&Fibro], causing a reduction of glutamine synthetase, because magnesium is an integral element in the enzyme glutamine synthetase[Jezek M, Geilfus CM, Mühling KH. Glutamine synthetase activity in leaves]; therefore a shortage of glutamine synthetase prevents conversion of glutamate to glutamine, allowing glutamate levels to increase[hypoth.?]; high levels of glutamate is one recognized cause of epilepsy[Nuytten intractable].
As fibromyalgia was shown to be a predictor for the diagnosis of psychogenic non-epileptic seizures in patients with undifferentiated paroxysmal spells[Tatum fibro seizures],
Tatum WO, Langston ME, Acton EK. Fibromyalgia and seizures. Epileptic Disord. 2016 Jun 1;18(2):148-54. doi: 10.1684/epd.2016.0823. PMID: 27238051.
https://www.jle.com/en/recherche/recherche.phtml
. this gives insight into a potential medical cause of psychogenic non-epileptic seizures: emotional or environmental stress depleting magnesium[the niacin article], but directly affecting the muscles instead of inducing muscle action from the brain.
Magnesium deficiency has been found in the red blood cells of patients with fibromyalgia, although serum tests were normal[Romano]; serum testing is becoming recognized as not reflecting true levels of magnesium in the body.[JJ&Ww; etc.s]; however, one study found red blood cell testing to effectively recognize significant reduction in magnesium in test subject after 3 weeks on a reduced magnesium diet.[Rude]
Another abnormality in Fibromyalgia is diminished levels of serotonin in the descending anti-nociceptive pathways in the spinal cord [iron emotional behavior] and dysregulation of dopamine.[Trait?, Squitti gluamate]
One study implicated a possible association between FM and decreased ferritin level, which they found even for ferritin in normal ranges.
It suggested that iron deficiency could have a role in these as a cofactor in serotonin and dopamine production.[Ortancil O, Sanli A, Eryuksel R, Basaran A, Ankarali H. Association between serum ferritin level and fibromyalgia syndrome. Eur J Clin Nutr. 2010 Mar;64(3):308-12. doi: 10.1038/ejcn.2009.149. Epub 2010 Jan 20. PMID: 20087382.
https://www.nature.com/articles/ejcn2009149]
Prolonged enhancement of pain sensations <<< Iron deficiency; free radical iron? Cu++? Mg, E, C deficiency?>>>
Degeneration of grey matter in the brain[Underpinnings grey matter changes] could be caused by these deficiencies, also found in long covid[], and in psychogenic non-epileptic seizures[], (which are common in people with fibromyalgia[]. ??)
Happen at a higher rate?
Fibromyalgia has, in its constellation of symptoms, fatigue, memory problems, and sleep and mood disturbances.[Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014 Apr 16;311(15):1547-55. doi: 10.1001/jama.2014.3266. PMID: 24737367
https://jamanetwork.com/journals/jama/article-abstract/1860480]
Fatigue, memory problems, sleep disturbances and mood disorder is all happen similarly with iron deficiency. [Find buncha citations]
The iron deficiency, in turn, could be explained by a disruption of copper homeostasis, directly affecting iron[] and zinc[], and through them in a ripple effect, magnesium[], antioxidant levels[], any neurotransmitters dependant on iron or magnesium such as dopamine and serotonin.[Ortancil]
The copper (II) omeprazole complex has been described as an irreversible molecule[Voltammetric], which might mean not only that its bonds cannot be broken, but also that it cannot accept molecular connections, and thereby cannot be removed from the body by the normal processes.
As example, ceruplasmin can remove copper[], but may not bond to the copper (II) omeprazole complex.
This also could explain why, at lower quantities, omeprazole can reduce diabetes[Mefford Improved], by an action similar to how trientine, a copper chelator, can reduce diabetes[ ] and reverse diabetic heart damage[ ].
The total copper allowable "set point,"
Rephrase
by including non-damaging copper (II) omeprazole in total copper retained without reducing transporters and chaperones, could functionally reduce the damaging free radical copper, and thereby reduce hyperglycemia.
The paper which described the discovery of the copper (II) omeprazole complex defines a voltammetric pulse which successfully determines the level of copper in bottled natural drinking water samples. The pulse is used to measure how much of this complex is in the water.[Voltammetric] This test could be adapted to see whether this molecule is in the human body as well, and thereby be used to diagnose this form of fibromyalgia and differentiate it from other forms from other irreversible molecules or other possible causes. Whether it could quantify severity would have to be determined.
Taking as a working hypothesis that the body somehow perceives the copper in the copper-(II) Omeprazole complex, although that might not be the mechanism, fibromyalgia symptoms can be not only explained, but by removing the molecule, can be treated.
I found three chemicals which improve fibromyalgia in a fashion consistent with removing this molecule from the body, but each time an amount is removed, the body dysregulates, and has to learn the limits how much usable copper it has available again - which it has to do regularly anyway, but is more difficult after a reduction; returning to a previously adapted state seems significantly easier, all from a test subject of one.
This explains some of the benefits of the various treatments already in use, particularly exercise[] (to perceive how the copper is being used, by pushing the body until a limit is reached, so the body can adjust to that limit), and meditation or other mindfulness practices[] (by removing all adrenaline from the body, because adrenaline binds to copper[], which improves regulation and can control the symptoms short-term, but not during sleep, rest or relaxation, allowing more damage from dysregulates to occur when at rest, explaining further sleep issues with fibromyalgia.[])
Knowing that fibromyalgia is dysregulation of the copper and iron homeostases, and that it can be caused by an irreversible molecule, can give insight into other causes of fibromyalgia. Various medications work via irreversible inhibition[Gonzalez, Harney, Ramsay maois]; if they cannot be otherwise removed, possibly due to a genetic defect that would not otherwise become apparent, that could potentially cause fibromyalgia, and potentially be testable to see if the irreversible molecule is still in the body, and a method to remove it be developed. This would need further study to see if that is actually what is going on.
Various cancer treatments either currently in use[ ] or being investigated[Xu, Kwak] use irreversible inhibition. Whether an irreversible enzyme or other molecule, or copper-iron homeostases dysregulation, could be part of the cause of cancer-related fatigue could also be investigated, as well as chronic fatigue[???], a (similar mystery, USE QUOTE) condition.
Xu S, Butkevich AN, Yamada R, Zhou Y, Debnath B, Duncan R, Zandi E, Petasis NA, Neamati N. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16348-53. doi: 10.1073/pnas.1205226109. Epub 2012 Sep 17. PMID: 22988091; PMCID: PMC3479552.
https://www.pnas.org/content/109/40/16348.long
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479552/
Kwak E. The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer. Oncologist. 2011;16(11):1498-507. doi: 10.1634/theoncologist.2011-0087. Epub 2011 Oct 20. PMID: 22016476; PMCID: PMC3233283.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233283/
González-Bello C. Designing Irreversible Inhibitors--Worth the Effort? ChemMedChem. 2016 Jan 5;11(1):22-30. doi: 10.1002/cmdc.201500469. Epub 2015 Nov 23. PMID: 26593241.
https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.201500469
Harney AS, Sole LB, Meade TJ. Kinetics and thermodynamics of irreversible inhibition of matrix metalloproteinase 2 by a Co(III) Schiff base complex. J Biol Inorg Chem. 2012 Aug;17(6):853-60. doi: 10.1007/s00775-012-0902-3. Epub 2012 May 22. PMID: 22729838; PMCID: PMC3418067.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418067/
Ramsay RR, Tipton KF. Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs. Molecules. 2017 Jul 15;22(7):1192. doi: 10.3390/molecules22071192. PMID: 28714881; PMCID: PMC6152246.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152246/
"The major drugs for inhibition of MAO, originally developed as antidepressants are irreversible inhibitors. This means that new protein must be synthesised to replace the inactivated enzyme. The half-life of MAO B in the brain is 30–40 days [29,30], so the effect of these irreversible drugs is long lasting."
Tecchio F, Assenza G, Zappasodi F, Mariani S, Salustri C, Squitti R. Glutamate-mediated primary somatosensory cortex excitability correlated with circulating copper and ceruloplasmin. Int J Alzheimers Dis. 2011;2011:292593. doi: 10.4061/2011/292593. Epub 2011 Nov 21. PMID: 22145081; PMCID: PMC3227495.
https://www.hindawi.com/journals/ijad/2011/292593/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227495/
Copper and zinc have been advocated as primary actors in the neurotransmission of glutamatergic synapses in brain areas that are critical for AD [5, 15, 16]. Iron appears instead mostly involved in dopaminergic neurotransmission [17].
Deborah Barges
Highlights:
· One cause of fibromyalgia is an irreversible molecule containing copper, the copper(II)-Omeprazole complex, which dysregulates copper homeostasis, affecting iron, zinc and thereby the rest of the metabolism as a result, in a ripple effect.
· Sudden onset fibromyalgia can be induced by giving omeprazole to a person with hypercupremia.
· Knowing that fibromyalgia is dysregulation of the copper and iron homeostases and can be caused by an irreversible molecule can give useful insight into other causes of fibromyalgia, and potentially for similar conditions, such as chronic fatigue and cancer-related fatigue.
(Background:)
Fibromyalgia (FM) is a condition characterized by chronic widespread musculoskeletal pain. Fatigue, cognitive disturbance, psychiatric and multiple somatic symptoms often accompany the disorder. Fibromyalgia has been described as having an unknown etiology and uncertain pathophysiology and is described as a pain regulation disorder, and often classifies as a form of central sensitization syndrome, considered to be a neurosensory disorder where the individual is not able to process pain in the brain.[Diagnosing Fibromyalgia as a Disease, an Illness, a State, or a Trait?]
Abnormalities noted in fibromyalgia include:
elevated levels of the excitatory neurotransmitters like glutamate[Trait?, Squitti glutamate], which could be explained by low levels of magnesium in people with fibromyalgia[Romano Mg&Fibro], causing a reduction of glutamine synthetase, because magnesium is an integral element in the enzyme glutamine synthetase[Jezek M, Geilfus CM, Mühling KH. Glutamine synthetase activity in leaves]; therefore a shortage of glutamine synthetase prevents conversion of glutamate to glutamine, allowing glutamate levels to increase[hypoth.?]; high levels of glutamate is one recognized cause of epilepsy[Nuytten intractable].
As fibromyalgia was shown to be a predictor for the diagnosis of psychogenic non-epileptic seizures in patients with undifferentiated paroxysmal spells[Tatum fibro seizures],
Tatum WO, Langston ME, Acton EK. Fibromyalgia and seizures. Epileptic Disord. 2016 Jun 1;18(2):148-54. doi: 10.1684/epd.2016.0823. PMID: 27238051.
https://www.jle.com/en/recherche/recherche.phtml
. this gives insight into a potential medical cause of psychogenic non-epileptic seizures: emotional or environmental stress depleting magnesium[the niacin article], but directly affecting the muscles instead of inducing muscle action from the brain.
Magnesium deficiency has been found in the red blood cells of patients with fibromyalgia, although serum tests were normal[Romano]; serum testing is becoming recognized as not reflecting true levels of magnesium in the body.[JJ&Ww; etc.s]; however, one study found red blood cell testing to effectively recognize significant reduction in magnesium in test subject after 3 weeks on a reduced magnesium diet.[Rude]
Another abnormality in Fibromyalgia is diminished levels of serotonin in the descending anti-nociceptive pathways in the spinal cord [iron emotional behavior] and dysregulation of dopamine.[Trait?, Squitti gluamate]
One study implicated a possible association between FM and decreased ferritin level, which they found even for ferritin in normal ranges.
It suggested that iron deficiency could have a role in these as a cofactor in serotonin and dopamine production.[Ortancil O, Sanli A, Eryuksel R, Basaran A, Ankarali H. Association between serum ferritin level and fibromyalgia syndrome. Eur J Clin Nutr. 2010 Mar;64(3):308-12. doi: 10.1038/ejcn.2009.149. Epub 2010 Jan 20. PMID: 20087382.
https://www.nature.com/articles/ejcn2009149]
Prolonged enhancement of pain sensations <<< Iron deficiency; free radical iron? Cu++? Mg, E, C deficiency?>>>
Degeneration of grey matter in the brain[Underpinnings grey matter changes] could be caused by these deficiencies, also found in long covid[], and in psychogenic non-epileptic seizures[], (which are common in people with fibromyalgia[]. ??)
Happen at a higher rate?
Fibromyalgia has, in its constellation of symptoms, fatigue, memory problems, and sleep and mood disturbances.[Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014 Apr 16;311(15):1547-55. doi: 10.1001/jama.2014.3266. PMID: 24737367
https://jamanetwork.com/journals/jama/article-abstract/1860480]
Fatigue, memory problems, sleep disturbances and mood disorder is all happen similarly with iron deficiency. [Find buncha citations]
The iron deficiency, in turn, could be explained by a disruption of copper homeostasis, directly affecting iron[] and zinc[], and through them in a ripple effect, magnesium[], antioxidant levels[], any neurotransmitters dependant on iron or magnesium such as dopamine and serotonin.[Ortancil]
The copper (II) omeprazole complex has been described as an irreversible molecule[Voltammetric], which might mean not only that its bonds cannot be broken, but also that it cannot accept molecular connections, and thereby cannot be removed from the body by the normal processes.
As example, ceruplasmin can remove copper[], but may not bond to the copper (II) omeprazole complex.
This also could explain why, at lower quantities, omeprazole can reduce diabetes[Mefford Improved], by an action similar to how trientine, a copper chelator, can reduce diabetes[ ] and reverse diabetic heart damage[ ].
The total copper allowable "set point,"
Rephrase
by including non-damaging copper (II) omeprazole in total copper retained without reducing transporters and chaperones, could functionally reduce the damaging free radical copper, and thereby reduce hyperglycemia.
The paper which described the discovery of the copper (II) omeprazole complex defines a voltammetric pulse which successfully determines the level of copper in bottled natural drinking water samples. The pulse is used to measure how much of this complex is in the water.[Voltammetric] This test could be adapted to see whether this molecule is in the human body as well, and thereby be used to diagnose this form of fibromyalgia and differentiate it from other forms from other irreversible molecules or other possible causes. Whether it could quantify severity would have to be determined.
Taking as a working hypothesis that the body somehow perceives the copper in the copper-(II) Omeprazole complex, although that might not be the mechanism, fibromyalgia symptoms can be not only explained, but by removing the molecule, can be treated.
I found three chemicals which improve fibromyalgia in a fashion consistent with removing this molecule from the body, but each time an amount is removed, the body dysregulates, and has to learn the limits how much usable copper it has available again - which it has to do regularly anyway, but is more difficult after a reduction; returning to a previously adapted state seems significantly easier, all from a test subject of one.
This explains some of the benefits of the various treatments already in use, particularly exercise[] (to perceive how the copper is being used, by pushing the body until a limit is reached, so the body can adjust to that limit), and meditation or other mindfulness practices[] (by removing all adrenaline from the body, because adrenaline binds to copper[], which improves regulation and can control the symptoms short-term, but not during sleep, rest or relaxation, allowing more damage from dysregulates to occur when at rest, explaining further sleep issues with fibromyalgia.[])
Knowing that fibromyalgia is dysregulation of the copper and iron homeostases, and that it can be caused by an irreversible molecule, can give insight into other causes of fibromyalgia. Various medications work via irreversible inhibition[Gonzalez, Harney, Ramsay maois]; if they cannot be otherwise removed, possibly due to a genetic defect that would not otherwise become apparent, that could potentially cause fibromyalgia, and potentially be testable to see if the irreversible molecule is still in the body, and a method to remove it be developed. This would need further study to see if that is actually what is going on.
Various cancer treatments either currently in use[ ] or being investigated[Xu, Kwak] use irreversible inhibition. Whether an irreversible enzyme or other molecule, or copper-iron homeostases dysregulation, could be part of the cause of cancer-related fatigue could also be investigated, as well as chronic fatigue[???], a (similar mystery, USE QUOTE) condition.
Xu S, Butkevich AN, Yamada R, Zhou Y, Debnath B, Duncan R, Zandi E, Petasis NA, Neamati N. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16348-53. doi: 10.1073/pnas.1205226109. Epub 2012 Sep 17. PMID: 22988091; PMCID: PMC3479552.
https://www.pnas.org/content/109/40/16348.long
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479552/
Kwak E. The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer. Oncologist. 2011;16(11):1498-507. doi: 10.1634/theoncologist.2011-0087. Epub 2011 Oct 20. PMID: 22016476; PMCID: PMC3233283.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233283/
González-Bello C. Designing Irreversible Inhibitors--Worth the Effort? ChemMedChem. 2016 Jan 5;11(1):22-30. doi: 10.1002/cmdc.201500469. Epub 2015 Nov 23. PMID: 26593241.
https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.201500469
Harney AS, Sole LB, Meade TJ. Kinetics and thermodynamics of irreversible inhibition of matrix metalloproteinase 2 by a Co(III) Schiff base complex. J Biol Inorg Chem. 2012 Aug;17(6):853-60. doi: 10.1007/s00775-012-0902-3. Epub 2012 May 22. PMID: 22729838; PMCID: PMC3418067.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418067/
Ramsay RR, Tipton KF. Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs. Molecules. 2017 Jul 15;22(7):1192. doi: 10.3390/molecules22071192. PMID: 28714881; PMCID: PMC6152246.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152246/
"The major drugs for inhibition of MAO, originally developed as antidepressants are irreversible inhibitors. This means that new protein must be synthesised to replace the inactivated enzyme. The half-life of MAO B in the brain is 30–40 days [29,30], so the effect of these irreversible drugs is long lasting."
Tecchio F, Assenza G, Zappasodi F, Mariani S, Salustri C, Squitti R. Glutamate-mediated primary somatosensory cortex excitability correlated with circulating copper and ceruloplasmin. Int J Alzheimers Dis. 2011;2011:292593. doi: 10.4061/2011/292593. Epub 2011 Nov 21. PMID: 22145081; PMCID: PMC3227495.
https://www.hindawi.com/journals/ijad/2011/292593/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227495/
Copper and zinc have been advocated as primary actors in the neurotransmission of glutamatergic synapses in brain areas that are critical for AD [5, 15, 16]. Iron appears instead mostly involved in dopaminergic neurotransmission [17].
