on cladribine, vit D3, Mg & NO

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jimmylegs
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on cladribine, vit D3, Mg & NO

Post by jimmylegs » Sat Jan 05, 2019 8:49 am

so today i'm into what exactly cladribine does.
  • A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis (2010)
    https://www.nejm.org/doi/full/10.1056/NEJMoa0902533
    "The accumulation of the cladribine nucleotide produces rapid and sustained reductions in CD4+ and CD8+ cells and rapid, though more transient, effects on CD19+ B cells, with relative sparing of other immune cells."
so one of its pluses is apparently cd19+ suppression. cool. anything else do that?
i wondered what vitamin d3 might be up to in the cd19+ department.

scholar search landed here:
  • Vitamin D3 and Its Synthetic Analogs Inhibit the Spontaneous in Vitro Immunoglobulin Production by SLE-Derived PBMC (2001)
    https://www.ncbi.nlm.nih.gov/pubmed/3840173
    Incubating SLE PBMC with 1,25 D3 compounds significantly reduced proliferation, polyclonal and anti-dsDNA IgG production, and the percentages of CD3+/DR+ T and B (CD19+) cells..
and from a search attempt re circulating 1,25-dihydroxyvitamin D in 25-hydroxyvitamin D deficiency, delivered this:
  • Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency (1985)
    https://www.ncbi.nlm.nih.gov/pubmed/3840173

    "mean serum 25OHD concentration was in the low normal range (13.2 +/- 1.5 ng/ml) before magnesium administration and did not significantly change after this therapy (14.8 +/- 1.5 ng/ml)" ...

    "After magnesium therapy, only 5 of the patients had a rise in the serum 1,25-(OH)2D concentration into or above the normal range"...

    "serum vitamin D-binding protein concentration, assessed in 11 patients, was low (273 +/- 86 micrograms/ml) before magnesium therapy, but normalized (346 +/- 86 micrograms/ml) after magnesium repletion."
the authors might have observed more impressive/significant effects on 25OHD3 and 1,25OH2D3 with a larger group, using a different form and/or dose of mag, delivered over a longer time period, to achieve a serum mag level closer to 2.5mg/dl. and that's without considering any other cofactors.

results of a random thought re poss cladribine interactions with magnesium
  • Revisiting the role of cladribine in acute myeloid leukemia: An improvement on past accomplishments or more old news? (2014)
    https://onlinelibrary.wiley.com/doi/ful ... /ajh.23862
    "Table 1. Proposed Mechanisms of Action of Cladribine Across Numerous Malignancies ...
    Inhibition of DNA repair results in DNA strand breaks
    •  Activates calcium and magnesium dependent endonuclease"
and, this is what happens when i look into drugs recommended by my doc :S
for now, i'm happy with having recently boosted serum 25OHD3 from 50 to 166 nmol/l
not forgetting plenty of dietary and supplemental magnesium etc.
take control of your own health
pursue optimal self care at least as actively as a diagnosis
ask for referrals to preventive health care specialists eg dietitians
don't let suboptimal self care muddy any underlying diagnostic picture!

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jimmylegs
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Re: on cladribine, vit D3, Mg & NO

Post by jimmylegs » Sat Jan 05, 2019 10:42 am

and on the CD4+ and CD8+ front:
  • Seasonal Variation in Vitamin D3 Levels Is Paralleled by Changes in the Peripheral Blood Human T Cell Compartment (2012)
    https://journals.plos.org/plosone/artic ... ne.0029250

    "...Here, we investigated if and to what extent seasonality of vitamin D3 levels are associated with changes in T cell numbers and phenotypes. Every three months during the course of the entire year, human PBMC and whole blood from 15 healthy subjects were sampled and analyzed using flow cytometry. We observed that elevated serum 25(OH)D3 and 1,25(OH)2D3 levels in summer were associated with a higher number of peripheral CD4+ and CD8+ T cells ... in summer, CD4+ and CD8+ T cells revealed a reduced capacity to produce pro-inflammatory cytokines"
  • Vitamin D3 inhibits the proliferation of T helper cells, downregulates CD4+ T cell cytokines and upregulate inhibitory markers (2018)
    https://www.sciencedirect.com/science/a ... 5918300545

    "We observed that the stimulation of CD4+ T cells with VitD3, suppressed proliferation capacity, enhanced the expression of PD1, PD-L1 and CTLA4 inhibitory markers on CD4+ T cells, and diminished the percentage of pro-inflammatory cytokines including, IFN-γ, IL-17, and IL-22 except IL-4 in CD4+ T cells."
take control of your own health
pursue optimal self care at least as actively as a diagnosis
ask for referrals to preventive health care specialists eg dietitians
don't let suboptimal self care muddy any underlying diagnostic picture!

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NHE
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Re: on cladribine, vit D3, Mg & NO

Post by NHE » Sat Jan 05, 2019 11:08 pm

jimmylegs wrote:
Sat Jan 05, 2019 8:49 am
results of a random thought re poss cladribine interactions with magnesium
  • Revisiting the role of cladribine in acute myeloid leukemia: An improvement on past accomplishments or more old news? (2014)
    https://onlinelibrary.wiley.com/doi/ful ... /ajh.23862
    "Table 1. Proposed Mechanisms of Action of Cladribine Across Numerous Malignancies ...
    Inhibition of DNA repair results in DNA strand breaks
    •  Activates calcium and magnesium dependent endonuclease"
https://www.thefreedictionary.com/endonuclease
en•do•nu•cle•ase (ˌɛn doʊˈnu kliˌeɪs, -ˌeɪz, -ˈnyu-)

n. any of a group of enzymes that degrade DNA or RNA molecules by breaking linkages within the polynucleotide chains.

How is having our DNA cut up of benefit? Though it may be helpful if you're trying to kill cancerous cells as in the leukemia paper you referenced.

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jimmylegs
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Re: on cladribine, vit D3, Mg & NO

Post by jimmylegs » Sun Jan 06, 2019 6:02 am

question: is there a cladribine magnesium connection? answer: looks like it. related:

https://en.wikipedia.org/wiki/Endonuclease#DNA_repair
"Endonucleases play a role in DNA repair"

1. mag and DNA
Role of magnesium in genomic stability
https://www.sciencedirect.com/science/a ... 0701000744

2. DNA breaks and NO in MS
Blood levels of nitric oxide and DNA breaks assayed in whole blood and isolated peripheral blood mononucleated cells in patients with multiple sclerosis
https://www.sciencedirect.com/science/a ... 1818302304

3. elevated NO in mag deficit (still digging for the relevant human studies)
Magnesium deficiency in rats induces a rise in plasma nitric oxide.
https://europepmc.org/abstract/med/8845288

4. rinse and repeat.
take control of your own health
pursue optimal self care at least as actively as a diagnosis
ask for referrals to preventive health care specialists eg dietitians
don't let suboptimal self care muddy any underlying diagnostic picture!

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jimmylegs
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Re:cladribine,vitD3,Mg &NO

Post by jimmylegs » Thu Jan 17, 2019 8:17 am

related

Magnesium deficiency and oxidative stress: an update (2016)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112180/

Another early marker of MgD is endothelial dysfunction [59]. Under physiological conditions, the endothelium produces signalling molecules, which maintain the dynamic balance between thrombin formation and fibrinolysis. These signalling molecules also control and inhibit excessive synthesis of proinflammatory cytokines [60]. The endothelial dysfunction linked to MgD has one important feature. Endothelial dysfunction is frequently associated with reduced NO production in endotheliocytes [61]. However, preclinical studies in animal and tissue models have demonstrated that MgD actually increased NO production in the endothelium and other cells via the activation of an inducible isoform of NO-synthase [62-65]. Elevated NO production can be a disadvantage because it is accompanied by a simultaneous increase of RS, such as superoxide [66]. Under these conditions, excessive NO does not cause vasodilation, but rather, reacts with superoxide to form peroxynitrite [67]. A potent vasoconstrictor, peroxynitrite easily causes oxidative damage to biomolecules and cellular structures [68, 69]. Mak et al. have shown that, in particular, excessive NO production is responsible for a decreased concentration of GSH in red blood cells [62]. Moreover, hyperproduction of NO can provoke the apoptosis of certain cell types [70]. Finally, endothelial dysfunction and a hyperactivated inflammatory response can potentiate each other [61].

Patterns and Correlates of Serum Magnesium Levels in Subsets of Type 2 Diabetes Mellitus Patients in Nigeria (2017)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434730/

Mg plays a role in glucose and insulin metabolism through tyrosine kinase activity. It transfers phosphate from ATP to proteins. It also releases glucose-1-phosphate from glycogen thereby affecting the phosphorylase b activity. It directly affects glucose transporter protein activity 4 thereby helping to regulate glucose translocation into cells.[3] In HT, it is involved in blood pressure (BP) regulation by hindering calcium depolarization and release of nitric oxide leading to vascular relaxation.[6]

jan 17 2019 11:17 am
take control of your own health
pursue optimal self care at least as actively as a diagnosis
ask for referrals to preventive health care specialists eg dietitians
don't let suboptimal self care muddy any underlying diagnostic picture!

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