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Patent filing for the use of nitric oxide with or without B-cell depletion in CFS

Discussion in 'Autonomic, Cardiovascular, and Respiratory' started by deleder2k, Mar 30, 2015.

  1. deleder2k

    deleder2k Senior Member

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    Patent filing for the use of nitric oxide with or without B-cell depletion in CFS


    Patent filing by Olav Mella and Øystein Fluge at Haukeland University Hospital

    A short summary:

     
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  2. alex3619

    alex3619 Senior Member

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    Funny enough I am about to test nitro for myself. I want someone here when I do it, so maybe later today when my cleaner arrives.
     
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  3. Rooney

    Rooney Senior Member

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    How exciting! Our scientist at work. What exactly are you going to take? NOS?
    My fingers are crossed for you.
     
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  4. deleder2k

    deleder2k Senior Member

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    I see that Minoxidil is listed. The same is the combo of L-arginine and L-Citrulline. This is exciting.

    Is Minoxidil available in a pill form? It is used to prevent hair loss in men.. Not sure if you should drink that though ;)
     
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  5. A.B.

    A.B. Senior Member

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    L-arginine 5g twice daily is a huge dose.
     
  6. SaraEngland

    SaraEngland

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  7. Snow Leopard

    Snow Leopard Hibernating

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    Opposite to what I'd expect. They must know something I don't... *shrugs*

    Vaguely relevant studies:
    Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study.
    http://www.ncbi.nlm.nih.gov/pubmed/20469961

    Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome.
    http://www.ncbi.nlm.nih.gov/pubmed/9824439

    Nitric oxide modulation mediates the protective effect of trazodone in a mouse model of chronic fatigue syndrome.
    http://www.ncbi.nlm.nih.gov/pubmed/19066412

    Lastly, nitrous oxide and nitric oxide are two different things. *not naming any names*
     
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  8. Gijs

    Gijs Senior Member

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  9. DanME

    DanME Senior Member

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    Wow. This is big!

    Here some exciting excerpts from the patent:

    NO's function in the body:

    "Nitric oxide (NO) is a neurotransmitter with impact on cognitive function, and with important effects on vasodilalation thus regulating blood flow, also regulating smooth muscle tone in gastrointestinal and urogenital tracts, affecting platelet aggregation and cardiac contractility, and also skeletal muscle. NO has important functions in adequate recovery sleep, and affects sensory hypersensitivity through voltage-gated potassium channels. Thus, a compromised NO system may add to many characteristic symptoms in ME/CFS patients such as cognitive disturbances, sleep problems, and hypersensitivity to stimuli such as light, noise, smell, touch, and pain. Also, disturbance in NO metabolism may explain the lower anaerobic threshold seen in ME/CFS patients, and the inhibited mitochondrial function. Several studies have shown increased lactate in the cerebrospinal fluid in ME/CFS patients (Shungu DC et al., 2012, NMR Biomed 25:1073-1087) and a strong correlation between brainstem grey matter volume and pulse pressure suggested an impaired cerebrovascular autoregulation, findings that may be ascribed to dysregulated nitric oxide. Nitric oxide also impacts on immune cells."

    Experimental treatment with NO:

    "In particular, the present inventors recognized that an immediate relief after administration of an NO donor can be observed. In contrast to medication administered so far for treatment of CFS, which are characterized by a remarkable lag time of treatment success, as described for example for the treatment with Rituximab or Methotrexate, see e.g. WO 2009/083602. Thus, the administration of a NO donor surprisingly allow a treatment of CFS patients for immediate relief of symptoms without any delay as described for e.g. a B-cell depleting agent, like Rituximab, before. An alternative strategy was applied, using supplement with relatively high doses of L-Arginine 5 g twice daily combined with L-Citrulline 200 mg twice daily. L-Arginine is the sole substrate of Nitric Oxide Synthases (NOS), thus this approach aims to overcome the dysregulated nitric oxide system in CFS/ME patients by providing relatively high doses of the substrate."

    Treatment example:

    "The patient was a 48 years old woman with previous thyroiditis. She had ME/CFS following mononucleosis in 1997 (33 years of age). She had a Hodgkin lymphoma stage II-A in 2003, and experienced in 2004 a transient response of her ME/CFS symptoms after chemotherapy for lymphoma relapse which has been described [Fluge O, Mella O (2009) BMC Neurol 9:28], and which later led to a pilot case series using Rituximab, also with a major but transient responses of ME/CFS symptoms for this patient. After high-dose chemotherapy with autologous stem cell support, she has been relapse-free from lymphoma since 2006. In autumn 2012, she was admitted to a local hospital with a transient ischemic attach with paresis in left side of 30 minutes duration. She had previously received radiotherapy to the mediastinum and neck as treatment for limited-stage Hodgkin lymphoma, and due to a reduced left ventricular function, her cardiologist started oral isosorbide mononitrate (Imdur®) 30 mg which she received for five days before cessation of the therapy. She had headache and some dizziness the first days, but also noticed an initial response of her ME/CFS symptoms starting within the first 24 hours. She reported a clear improvement on most ME/CFS symptoms during the next days, which she described to be remarkably alike the response she had previously experienced from 6-7 weeks after Rituximab infusion (as a pilot patient in 2007). After Imdur® treatment was stopped on day five, the symptom improvement vanished during the following two days, consistent with a direct symptomatic effect on her ME/CFS disease."

    Pilot:

    "After discussions with the chairman of the Regional Ethical Committee, we had approval to treat ME/CFS patients that were well-known to us, with Imdur® using low doses (15 mg) initially and then slowly increasing the doses and up to 120mg/day registering subjective symptom changes as compared to baseline, in order to gain experience to draft a protocol in a planned open-label phase-II study.
    [0080] All six patients were diagnosed with ME/CFS according to Canadian criteria [Carruthers BM, et al., (2003) J Chronic Fatigue Syndr 11:7-36.] and had performed standard examinations to exclude other disease explaining their condition. Three patients had previously received Rituximab with a clinical response, but then with a later full or partial relapse of ME/CFS symptoms. One patient with very severe ME/CFS had no response to previous Rituximab treatment, and one patient with a post Giardia lamblia ME/CFS had not been given Rituximab previously."

    "Observations with the pilot patients

    • - Follow-up for more than 3 months.

    • - Pure symptomatic effect of isosorbide mononitrate. If exaggerating to much (exercise...) some ME symptoms recur.
    • - Two patients forgot to take the dose one day, with markedly symptoms same afternoon.

    • - Noctural variation in one (ME symptoms in morning before drug intake, clear improvement during afternoon and

      evening).

    • - One with very severe ME, clear effect on all symptoms except extreme sensitivity to light.

    • - Two patients with no effect after at least two weeks treatment with isosorbide mononitrate. Four out of six had a

      clear symptomatic effect after using the drug more than 2 weeks."
    Possible treatment scheme:

    "The both components may be administered simultaneously, separately or sequentially to said subject suffering from CFS. For example, the NO donor may be administered by inhalation while the B-cell depleting agent is administered by the way of infusion. Furthermore, while the NO donor may be administered on a daily basis, the B-cell depleting agent may be administered initially in once a week over two weeks and, thereafter, in a free determined time of schedule, e.g. every second or every third month.[0075] In particular, the NO donor may be administered during the initial 4 to 12 weeks, like during the first 4 to 8 weeks of treatment, e.g. the initial 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks to allow immediate relief of the symptoms of CFS while the administration at the B-cell depleting agent as defined herein allows relief to the symptoms of the subject suffering from CFS over a long time period due to the delayed effectiveness thereof."
     
    Last edited: Mar 30, 2015
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  10. Sidereal

    Sidereal Senior Member

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    @zzz, your previous experience with nitro springs to mind while reading this.
     
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  11. justy

    justy Senior Member

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    How does this square with Pall's theory that we already have high Nitric Oxide causing symptoms - from Dr Myhill's page:

    http://www.drmyhill.co.uk/wiki/B12_-_rationale_for_using_vitamin_B12_in_CFS
     
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  12. Gijs

    Gijs Senior Member

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  13. Gijs

    Gijs Senior Member

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    One thing is very clear to me, Dysregulation of the bloodflow and vessels is the mechanisme of ME and POTS.
     
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  14. DanME

    DanME Senior Member

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  15. DanME

    DanME Senior Member

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    Maybe Pall's theory was just plain wrong. This happens all the time in science.
     
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  16. A.B.

    A.B. Senior Member

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    I'm not familiar with Dr Pall but from the site you linked I'm getting the impression that it's a hypothesis. The motivation for this patent seems to come from the concrete observation that a NO donor is helpful for CFS symptoms in at least a subset of patients. There's also the possibility that some patient's symptoms are indeed caused by NO, whereas other patient's symptoms are relieved by NO (different definitions and patient heterogeneity must always be kept in mind when comparing studies and results).

    We will have to wait for a larger NO donor study to see what happens. I suspect the patent means that such a study will soon be carried out.

    Edited for clarity.
     
    Last edited: Mar 30, 2015
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  17. melihtas

    melihtas Senior Member

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    I think it is time to remember Fluge and Mella's famous hypothesis slide.

    [​IMG]
     
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  18. MeSci

    MeSci ME/CFS since 1995; activity level 6?

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  19. alex3619

    alex3619 Senior Member

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    Glyceryl trinitrate. I think for someone like me, with ME, NMH and high blood pressure, its a good idea to have this tried at least once. Others who have unexplained chest pain might also benefit. Its not however a panacea or universal cure, this kind of thing has been tried for something like thirty years, off and on. Some respond. Some don't.
     
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  20. Gingergrrl

    Gingergrrl Senior Member

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    @deleder2k thank you for posting this and I recently had a positive experience with Nitro (although my first attempt did not help) so my overall conclusion on this remains unclear. I may be trying a patch vs. Sublingual form depending what my cardio says on Fri.

    I have been told not to take Arginine though as it can increase herpes viruses.

    I also have concerns re: Nitro lowering my BP too much when it is already so low.

    Lastly, what does nitro "donor" mean? I didn't get that part!
     
    merylg, NK17, Never Give Up and 2 others like this.

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