Mestinon til behandling af ME

Lægemidlet Mestinon (indholdsstof: pyridostigmine) er en potentiel behandlingsmulighed til ME.

Mestinon hæmmer nedbrydning af acetylcholin og er udviklet til behandling af Myasthenia gravis (1)

Mestinon er allerede på listen over den række lægemidler, som kan anvendes til behandling af ME-komorbiditeten POTS ( se tabel 4 i review fra Neurologisk afdeling, Mayo Clinic, ref 2).

Det har i mange år været kendt viden, at nogle ME patienter opnår bedring af Mestinon. Et pilotstudie fra 2003 viste, at tre ME patienter havde gavn af en dosis på 10 eller 30 mg pyridostigmine (3).

Associate professor of Medicine David Systrom fra Brigham and Women's hospital har på National Institute of Health's ME/CFS konferencen fremlagt foreløbige resultater af behandling af ca. 300 ME patienter med pyridostigmine (4, 5).

Systrom har udført motionstest på ME patienter. Her har han påvist preload failure i hjertet (der pumpes ikke blod nok tilbage til hjertet fra underkroppen ved aktivitet) og nedsat ilt-ekstraktion. Samtidig har han påvist småfiber neuropati. Disse observationer hænger sammen (4, 5, 6)

Systroms hypotese er, at småfiber neuropati er årsagen til preload failure og nedsat ilt-ekstraktion. Dette giver motionsintolerance og post exertional malaise (PEM). Pyridostigmine skulle virke ved at forbedre den vaskulære regulering. Der er et fase 3 studie i gang for at afprøve hypotesen (7).

Samtidig med disse forsøg har Systrom inddraget Seahorse Teknologien  til at måle på respirationen i ME-celler. Det vil sige, at han får data på den arteriel - venøse difference fra motionstesten (det er et udtryk for hvor meget ilt der er fjernes, når blodet cirkulerer i kroppen), som han kan relatere til iltudnyttelsen på celleniveau målt i Seahorse.

Systrom's teknologi er beskrevet i denne artikel: The Invasive Cardiopulmonary Exercise Test

https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.112.104463?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

Vejledning i behandling af unge mennesker med ME/POTS

I Rowe et al's PRIMER for behandling af unge mennesker med ME/POTS kan man i tabel 11 finde følgende oplysning: 

Pyridostigmine bromide

Rapid release: 30 mg daily, increase by 30 mg every 3–7 days to 60 mg BID or TID. Sustained-release: 180 mg daily

Effective in both POTS and neurally mediated hypotension. Can also help with GI motility problems

Table 11. Medications for treating orthostatic intolerance (OI) in adolescents. (uddrag af tabel 11 fra ref 8).


Referencer

1) Min Medicin: Mestinon:  http://min.medicin.dk/Medicin/Praeparater/773

2) Benarroch: POTS A heterogenous and multifactorial disorder. Mayo Clin Proc. 2012 Dec;87(12):1214-25. doi: 10.1016/j.mayocp.2012.08.013. Epub 2012 Nov 1.
https://www.ncbi.nlm.nih.gov/pubmed/23122672

3) Kawamura et al: Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology. 2003 May;9(3):189-194.
https://www.ncbi.nlm.nih.gov/pubmed/14567934

4) National Institute of Health ME/CFS konference april 2019, del 1 med Systrom:
https://videocast.nih.gov/summary.asp?live=31636&bhcp=1

del 2: https://videocast.nih.gov/summary.asp?Live=31640&bhcp=1

5) Bloggen Health Rising's sammendrag af NIH ME/CFS konferencen, april 2019: Del 1 med Systrom: https://www.healthrising.org/blog/2019/04/10/nih-accelerating-chronic-fatigue-exhaustion-inflammation/

Del 2: https://www.healthrising.org/blog/2019/04/15/nih-chronic-fatigue-lipkin-davis-prusty-oh/

6) Interview med professor Systrom https://www.youtube.com/watch?v=FMaKfv8peww

7) NIH Clinical trials: The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure. https://clinicaltrials.gov/ct2/show/NCT03674541

8) Rowe et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer Front Pediatr. 2017 Jun 19;5:121. doi: 10.3389/fped.2017.00121. eCollection 2017. https://www.ncbi.nlm.nih.gov/pubmed/28674681

ME patienter har neuroinflammation

Forskere fra to amerikanske universiteter har undersøgt hjernen med Magnetisk Resonans Spektroskopi (MRS) hos 15 kvinder med ME. Det mest markante fund i dette studie var øget niveau af choline i det område i hjernen, der hedder venstre anterior cingulate cortex (ACC) (1).

MRS kan påvise fri choline og vandopløselige nedbrydningsprodukter af celle-komponent-materialer, som phosphocholine og glycerophosphocholine. Påvisning af choline i hjernescanninger anvendes derfor som indikation på neuroinflammation (1),

Andre undersøgelser har vist, at inflammation i ACC udløser cytokininduceret fatigue og depressive symptomer. I et forsøg behandlede man hepatitis-patienter med cytokinet interferon-alfa. Dette udløste udmattelse og samtidig viste MRS-scanning aktivering af ACC (2).

Forskerne mener, at neuroinflammationen påvist hos ME patienter er på lavt niveau og næppe kan forårsage demyelinering, men det kan være med til at forklare udmattelse og tristhed hos patienterne (1).

Referencer:

1. Mueller et al: Evidence of widespread metabolite abnormalities in ME/CFS. Brain Imaging and Behaviaer 2019
2. Capuron et al: Anterior Cingulate Activation and Error Processing During INF-alfa treatment. Biol Psychiatry 2005

ME versus Sepsis

Research in myalgic encephalomyelitis (ME) has shown:

1. ME patients have impaired pyruvate dehydrogenase (PDH) function (1).
2. Dichloroacetate (DCA) increases PDH activity. A pilot study has shown, that DCA may be a treatment of ME (2, 3).
3. Some ME patients may also have decreased fatty acid oxidation (4, 5, 6).
4. ME patients have:
   * abnormalities in the conversion of citrate to isocitrate in the TCA-cycle (7)
   * a possible flow of metabolites to replenish succinate in the TCA-cycle (7)
   * decreased succinylcarnitine (5)
   * decreased FAD (4)
5. ME is a hypometabolic syndrome, which resembles hibernation (4).
6. ME patients have decreased oxygen extraction (8).
7. A transcriptome of immune cells from ME patients showed the inflammatory response mey be involved in the pathomechanism (FDR, adjusted p-value = 0,00044) (9).
8. The Standford ME symposium 2017 compaired ME with systemeic inflammatory response syndrome (SIRS) (10):

SIRS is an inflammatory state affecting the whole body. It is the body's response to an infectious or noninfectious insult. SIRS is closely related to sepsis, in which patients satisfy criteria for SIRS and have a suspected or proven infection (11).

Reseach in sepsis has shown:

1. PDH-complex activity is impaired in sepsis (12).
2. DCA reactivates PDH-complex activity in a mice model of sepsis (using  Seahorse Technology). This rebalanced innate and adaptive immunity(12).
3. There is a metabolic switch between carbohydrate-fuled hyperinflammation to lipid-fueled hypo-inflammation in sepsis (13).
4. A sepsis-model with LPS-treated monocytes showed (14):
   * a block at isocitrate in the TCA cycle
   * a block at succinate dehydrogenase in the TCA-cycle (thereby limiting FAD)
   * decreased succinylcarnitine
   * increased itaconate
5. Increased oxygen consumption for anabolism during hyper-inflammation in sepsis switch to decreased oxygen consumption during the hypo-inflammatory phase. The immunometabolic paralysis and the catabolic low-energy state is similar to hibernation (13, 14).
6. There is a sepsis-associated dysfunction of the mitochondrial respiratory system. Mitochondria may be challenged by mediators of inflammation that impair oxygen utilization ( cytopathic hypoxia) (15).

Use the knowledge from research in sepsis to solve ME

ME is not sepsis, but we can be inspired by research in sepsis to create new studies in ME. Fx. we could measure itaconate. Is it involved in ME?

CLYBL, itaconate and B12 - involved in ME?:

https://followmeindenmark.blogspot.com/2018/10/clybl-itaconate-and-b12-involved-in-me.html

And we could incubate monocytes from ME patients with DCA in the Seahorse. Would the hibernation be resolved?

DCA is toxic, but there are other medications that may be repurposed to ME.

ME is not the only disease with flat batteries. Several scientists are looking into the metabolic shut-down, which follows a wide range of insults to the body (16).

Information from professor Systrom at the NIH ME/CFS Conference 2019: 40% of the ME patients have small fiber neuropathy (17). Interestingly, small nerve fibers are impaired in patients with sepsis (18).

Further reading about red blood cells, ME and sepsis:

Red blood cell deformability, metabolism and extracellular vesicles in ME/CFS

https://followmeindenmark.blogspot.com/2018/11/red-blood-cell-deformability-metabolism.html

References:

1. Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
2. Comhaire: Med Hypotheses. 2018 May;114:45-48. doi: 10.1016/j.mehy.2018.03.002. Epub 2018 Mar 5. Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial. https://www.ncbi.nlm.nih.gov/pubmed/29602463
3. Comhaire:  Med Hypotheses. 2018 Nov;120:65-67. doi: 10.1016/j.mehy.2018.08.014. Epub 2018 Aug 25. Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not? https://www.ncbi.nlm.nih.gov/pubmed/30220343
4.  Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113
5. Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371 https://pubs.rsc.org/en/Content/ArticleLanding/2017/MB/C6MB00600K#!divAbstract
6. Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.
   https://www.ncbi.nlm.nih.gov/pubmed/30563204
7. Yamano et al: Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Sci Rep. 2016 Oct 11;6:34990. doi: 10.1038/srep34990. https://www.ncbi.nlm.nih.gov/pubmed/27725700
8. J Transl Med. 2014 Jan 23;12:20. doi: 10.1186/1479-5876-12-20.Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. Vermeulen RC1, Vermeulen van Eck IW https://www.ncbi.nlm.nih.gov/pubmed/24456560
9. Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.
   https://www.ncbi.nlm.nih.gov/pubmed/30791746
10.  ME/CFS Standford Symposium 2017, Ron Davis slides: https://www.youtube.com/watch?v=s7bBMXQSmuM
11.  Wikipedia SIRS https://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndrome
12. McCall et al: Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival. JCI Insight. 2018 Aug 9;3(15). pii: 99292. doi: 10.1172/jci.insight.99292. eCollection 2018 Aug 9. https://www.ncbi.nlm.nih.gov/pubmed/30089711
13. Wang et al: Sirtuins and Immuno-Metabolism of Sepsis. Int J Mol Sci. 2018 Sep 13;19(9). pii: E2738. doi: 10.3390/ijms19092738. https://www.ncbi.nlm.nih.gov/pubmed/30216989
14. Zhu et al. Frontline Science: Monocytes sequentially rewire metabolism and bioenergetics during an acute inflammatory response J Leukoc Biol. 2019 Feb;105(2):215-228. doi: 10.1002/JLB.3HI0918-373R. Epub 2019 Jan 11  https://www.ncbi.nlm.nih.gov/pubmed/30633362
15. Kohoutova et al: Variability of mitochondrial respiration in relation to sepsis-induced multiple organ dysfunction Physiol Res. 2018 Dec 31;67(Supplementum 4):S577-S592. https://www.ncbi.nlm.nih.gov/pubmed/30607965 
16. Singer: Critical illness and flat batteries Crit Care. 2017 Dec 28;21(Suppl 3):309. doi: 10.1186/s13054-017-1913-9. https://www.ncbi.nlm.nih.gov/pubmed/29297363
17. National Institute of Health ME/CFS konference april 2019, del 1 med Systrom:
    https://videocast.nih.gov/summary.asp?live=31636&bhcp=1
18. Axer et al: The impairment of small nerve fibers in severe sepsis and septic shock. Crit Care. 2016 Mar 15;20:64. doi: 10.1186/s13054-016-1241-5. https://www.ncbi.nlm.nih.gov/pubmed/26984636

AMPK is a regulator of TRPA1

AMPK is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure (1).

AMPK activation is impaired in muscle cell cultures derived from ME patients (2).

Transient receptor potential ankyrin 1 (TRPA1) channel is a widely recognized chemical and thermal sensor that plays vital roles in pain transduction (1).

Some ME patients have single nucleotide polymorphism in TRPA1 (3).

Wang et al discovered a functional link between AMPK and TRPA1 in dorsal root ganglion (DRG) neurons, in which AMPK activation rapidly resulted in downregulation of membrane-associated TRPA1 and its channel activity within minutes. Treatment with two AMPK activators, metformin or AICAR, inhibited TRPA1 activity in DRG neurons by decreasing the amount of membrane-associated TRPA1. Metformin induced a dose-dependent inhibition of TRPA1-mediated calcium influx (1).

Further reading:

A role for TRPs in ME/CFS/POTS/MCS/pain/endothelial dysfunction...?

TRP blogposts - an overview

A curcumin derivative J147 ameliorates diabetic peripheral neuropathy in streptozotocin (STZ)-induced DPN rat models through negative regulation AMPK on TRPA1

Ingestion of transient receptor potential channel agonists attenuates exercise-induced muscle cramps

Proteinase-Activated Receptor-2 Sensitivity of Amplified TRPA1 Activity in Skeletal Muscle Afferent Nerves and Exercise Pressor Reflex in Rats with Femoral Artery Occlusion

Role of TNF-α in Regulating the Exercise Pressor Reflex in Rats With Femoral Artery Occlusion


Referencer

1) Diabetes. 2018 Jan;67(1):98-109. doi: 10.2337/db17-0503. Epub 2017 Oct 12.
Negative Regulation of TRPA1 by AMPK in Primary Sensory Neurons as a Potential Mechanism of Painful Diabetic Neuropathy.
Wang S1,2, Kobayashi K3, Kogure Y1, Yamanaka H3, Yamamoto S1, Yagi H4, Noguchi K5, Dai Y6,2,3. https://www.ncbi.nlm.nih.gov/pubmed/29025860

2) Biosci Rep. 2018 May 8;38(3). pii: BSR20180242. doi: 10.1042/BSR20180242. Print 2018 Jun 29. Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS. Brown AE1, Dibnah B1, Fisher E1, Newton JL1,2, Walker M3,2. https://www.ncbi.nlm.nih.gov/pubmed/29654166

3) Marshall-Gradisnk et al. Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients https://journals.sagepub.com/doi/10.4137/III.S25147

Bivirkninger ved el-stimulering af muskler

Der er registreret bivirkninger - herunder 9 tilfælde af rabdomyolyse - ved anvendelse af udstyr til el-stimulering af muskler (1).

Rabdomyolyse er en tilstand, hvor beskadigede muskler nedbrydes. Nedbrydningsprodukter strømmer ud i blodet og forårsager videre skade på kroppen (2).

Personer med den medfødte metaboliske sygdom carnitine palmitoyltransferase 2 (CPT2) mangel er særligt udsatte for at udvikle rabdomyolyse (3).

Ophobning af langkædede fedtsyrer og acyl-carnitiner (som set ved CPT2 mangel) kan have en detergent-lignende virkning på membraner og herved påvirke ion-kanaler og elektriske signaler i cellen (4, 5).

ME sygdomsmekanismen har fællestræk med CPT2 mangel:
ME minder om medfødt metabolisk defekt

ME patienter er følsomme over for elektromagnetiske felter. Det er velkendt blandt ME forskere, at en del ME patienter med tiden udvikler elektromagnetisk hypersensitivitet (EHS). (6)

Det får mig til at stille spørgsmålene:

Kan man sammenligne el-stimulering af muskler med den daglige påvirkning fra elektriske felter og trådløs teknologi?

Er man særligt disponeret for at udvikle EHS, hvis man har ophobede metabolitter i cellerne?

Overfølsomhed mod harmløst lys

Fænomenet med hypersensitivitet mod et spektrum af bølgelængder (UV-lys og alm. lys) er kend fra sygdommene porfyri (ophobning af metabolitter fra hæm-syntese stivejen) og Smith-Lemli-Opitz syndrome (ophobning af 7-dehydrocholesterol).  Her er ionkanalerne TRPA1 og TRPV1 involveret (7, 8).

Inflammation kan udløse EHS betinget smerte via TRP ion-kanaler 

TRPV4 er påvist til at være involveret i EHS i forbindelse med inflammation og smerte:
Elektromagnetisk Hypersensitivitet påvist i dyremodel

TRPA1 kan ligeledes mediere inflammation, der vedligeholder makrofag-afhængig neuropatisk smerte i dyremodel (9).

Læs også om dysregulerede iontransport-systemer og beskadigede membraner hos ME patienter:

Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome



Referencer

1) Wien Med Wochenschr. 2018 Aug 23. doi: 10.1007/s10354-018-0655-x.
Side effects of whole-body electro-myo-stimulation.
Stöllberger C, Finsterer J. https://www.ncbi.nlm.nih.gov/pubmed/30141113

2) Wikipedia. https://en.wikipedia.org/wiki/Rhabdomyolysis

3) Mol Genet Metab Rep. 2018 Mar 6;15:69-70. doi: 10.1016/j.ymgmr.2018.02.008. eCollection 2018 Jun. Recurrent rhabdomyolysis caused by carnitine palmitoyltransferase II deficiency, common but under-recognised: Lessons to be learnt https://www.ncbi.nlm.nih.gov/pubmed/29744303

4) Longoet al: Carnitine transport and fatty acid oxidation https://www.ncbi.nlm.nih.gov/pubmed/26828774

5) Ingrid Tein: Disorders of fatty acid Oxidation. Handbook of clinical Neurology, chapter 170. 2013 https://www.sciencedirect.com/science/article/pii/B9780444595652000356

6) Front Physiol. 2017 Feb 17;8:88. doi: 10.3389/fphys.2017.00088. eCollection 2017.

The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).Glassford JA https://www.ncbi.nlm.nih.gov/pubmed/28261110

7) J Neurosci. 2016 May 11;36(19):5264-78. doi: 10.1523/JNEUROSCI.4268-15.2016.
Photosensitization in Porphyrias and Photodynamic Therapy Involves TRPA1 and TRPV1.
Babes A1, Sauer SK2, Moparthi L3, Kichko TI2, Neacsu C2, Namer B2, Filipovic M4, Zygmunt PM5, Reeh PW6, Fischer MJ2. https://www.ncbi.nlm.nih.gov/pubmed/27170124

8) Pain. 2017 Dec;158(12):2475-2486. doi: 10.1097/j.pain.0000000000001056.
Photosensitization of TRPA1 and TRPV1 by 7-dehydrocholesterol: implications for the Smith-Lemli-Opitz syndrome.
Babes A1, Ciotu CI, Hoffmann T, Kichko TI, Selescu T, Neacsu C, Sauer SK, Reeh PW, Fischer MJM.https://www.ncbi.nlm.nih.gov/pubmed/28891864

9) Nat Commun. 2017 Dec 1;8(1):1887. doi: 10.1038/s41467-017-01739-2.
Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice.De Logu F1, Nassini R1, Materazzi S1, Carvalho Gonçalves M1, Nosi D2, Rossi Degl'Innocenti D1, Marone IM1, Ferreira J3, Li Puma S1, Benemei S1, Trevisan G4, Souza Monteiro de Araújo D1,5, Patacchini R6, Bunnett NW7, Geppetti P8. https://www.ncbi.nlm.nih.gov/pubmed/29192190