Instant relief with inosine + caffeine

[pattismith]

@Jenny TipsforME

@S-VV

I am now experimenting this for a few weeks, so it is rather new to me, and I have not yet found the best protocol.

The association of these two is giving me relief of my muscle weakness/pain and brain fog one hour after the intake.
Caffeine is needed, otherwise I fall asleep instead of getting relief.


My hypothesis is a modulation of my intracellular purine metabolic pathway by increasing intracellular Inosine (caffeine is blocking adenosine receptors but not the entry of adenosine and inosine in cells).





I know nothing about the cause behind, but zinc disruption could be involved, because at less two of the major enzymes have their activity dependent of zinc, adenosine deaminase / ADA and AMP deaminase / AMPD.

Zinc deficiency and low Zinc/Cu ratio have been found to be associated with some autism and Alzheimer cases.
It seems that Zinc is also important to detoxify Mercury and Cu.


I started yesterday to supplement with Zinc, I will see if it helps.

 

[nandixon]

@pattismith, Have you considered that inosine may be acting in an anti-inflammatory capacity (i.e., reducing proinflammatory cytokines)?

For example, see this early (2000) study:

In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-α, IL-1, IL-12, macrophage-inflammatory protein-1α, and IFN-γ, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism.

Inosine Inhibits Inflammatory Cytokine Production by a Posttranscriptional Mechanism and Protects Against Endotoxin-Induced Shock

 

[pattismith]

@pattismith, Have you considered that inosine may be acting in an anti-inflammatory capacity (i.e., reducing proinflammatory cytokines)?

For example, see this early (2000) study:

Thank you for your reply.
As I explained, the effect is quick and transient (some hours), and does not require activation of the adenosine receptors , whereas cytokine modulation seems to occur via the adenosine receptors agonism (which are all located outside the cells)


I tryed to use Dipyridamole with inosine (= adenosine/inosine reuptake inhibitor = blocker of nucleoside transporters), and it didn't work, which means Inosine is active for me via intracellular activity and not via adenosine receptors.

(caffeine is an efficient and non specific adenosine receptor antagonist)

Edit: I forgot to add it also reverts my mood disorders

 

[S-VV]

I'm so glad your getting relief @pattismith !!

What end metabolic product of inosine do you think is helping? I think it could be AMP, as it is AMP and not ADP that allosterically increases the activity of PDH.

Have you tried experimenting with sodium dichloroacetate?

 

[nandixon]

I tryed to use Dipyridamole with inosine (= adenosine/inosine reuptake inhibitor = blocker of nucleoside transporters), and it didn't work, which means Inosine is active for me via intracellular activity and not via adenosine receptors.

I don't think I would interpret the results that way. By using dipyridamole you are effectively increasing the amount of extracellular adenosine. So this would be as if you were taking additional adenosine together with your inosine and caffeine, which seemingly would negate the effects of the inosine and the caffeine. (Adenosine has much too short a half life to be orally taken like inosine and caffeine but you get the idea.)

 

[Jenny TipsforME]

My brain is on holiday, I’ll have to come back another day

 

[pattismith]

I don't think I would interpret the results that way. By using dipyridamole you are effectively increasing the amount of extracellular adenosine. So this would be as if you were taking additional adenosine together with your inosine and caffeine, which seemingly would negate the effects of the inosine and the caffeine. (Adenosine has much too short a half life to be orally taken like inosine and caffeine but you get the idea.)

Maybe you are right, but maybe not.

I started zinc supplementation a few days ago (today is the 6th), and it changed dramatically my reaction to Inosine + caffeine. I don't know yet what lesson I must learn from this, but here a recent article about adenosine and zinc:


Zinc deficiency causes delayed ATP clearance and adenosine generation in rats and cell culture model

(2018)

Abstract
Zinc deficiency causes myriad pathophysiological symptoms, but why distinct phenotypes are generated by zinc deficiency remains unclear. Considering that several ectoenzymes involved in purinergic signaling through extracellular adenine-nucleotide hydrolysis possess zinc ions in their active sites, and disorders in purinergic signaling result in diverse diseases that are frequently similar to those caused by zinc deficiency, herein we examine whether zinc deficiency affects extracellular adenine-nucleotide metabolism. Zinc deficiency severely impairs the activities of major ectoenzymes (ENPP1, ENPP3, NT5E/CD73, and TNAP), and also strongly suppresses adenine-nucleotide hydrolysis in cell-membrane preparations or rat plasma, thereby increasing ATP and ADP levels and decreasing adenosine levels. Thus, zinc deficiency delays both extracellular ATP clearance and adenosine generation, and zinc modulates extracellular adenine-nucleotide metabolism. Since the finely tuned balance between extracellular adenine nucleotides and adenosine is critical for purinergic signaling, these findings provide a novel insight into why zinc deficiency results in diverse symptoms.

 

[pattismith]

Inosine + caffeine still working for me, just wanted to add that Ribose is required too for the cocktail to work well (and zinc).


Glucarate has an interesting vasodilatory effect if I add it too (warm feeling)

 

[YippeeKi YOW !!]

Edit: I forgot to add it also reverts my mood disorders

@pattismith
When you say "reverts" do you mean "reverses mood disorders" or "returns mood disorders"? Not sure ....

 

[pattismith]

@pattismith
When you say "reverts" do you mean "reverses mood disorders" or "returns mood disorders"? Not sure ....

i mean "reverses", sorry it doesn't help me to write a good English though

 

[YippeeKi YOW !!]

i mean "reverses", sorry it doesn't help me to write a good English though

I'm betting that your English is infinitely better than my fluency in your language whatever that may be, unless it's one of the two (other than English) that I actually can mange

 

[wigglethemouse]

@pattismith I have heard that Dr Susan Levine recommends Inosine to some of her patients. Her practice was used for Dr Maureen Hansons metabolites study. Looks like 3 patients in the study are taking Inosine. Might be worth digging to see if you can see any trends with these three patients - P1, P7, P8.

Link to Excel file with raw data :
www.mdpi.com/2218-1989/8/4/90/s1

 

[wigglethemouse]

Might be worth digging to see if you can see any trends with these three patients - P1, P7, P8.

@pattismith
Looks like it may be more difficult due to other supplementation/meds.
Compared to the rest of controls/patients P1, P7, & P8 have high levels of hypoxanthine - probably related to Inosine supplement.

Can see that these three patients also take things other patients do not
P1 & P7 have very high steroidal compounds related to progesterone (eg 5alpha-pregnan-3beta-ol,20-one sulfate)
P7 & P8 have high glutamates such as gamma-glutamylglutamate, gamma-glutamylisoleucine*
and gamma-glutamylvaline. (I read that gamma-glutamylvaline inhibits TNF-alpha to reduce inflammation)

 

[YippeeKi YOW !!]

@wigglethemouse
You are just a deep well of info, attached to a functional analytical brain. I'm adding you to my hero list, like, immediately

 

[YippeeKi YOW !!]

@pattismith
It's a fairly short list , and you're on it, too. . .

 

[pattismith]

@pattismith I have heard that Dr Susan Levine recommends Inosine to some of her patients. Her practice was used for Dr Maureen Hansons metabolites study. Looks like 3 patients in the study are taking Inosine. Might be worth digging to see if you can see any trends with these three patients - P1, P7, P8.
View attachment 30916

Link to Excel file with raw data :
www.mdpi.com/2218-1989/8/4/90/s1

interesting, did you find this figure in the Hanson/Levine study?

@pattismith
Looks like it may be more difficult due to other supplementation/meds.
Compared to the rest of controls/patients P1, P7, & P8 have high levels of hypoxanthine - probably related to Inosine supplement.

Can see that these three patients also take things other patients do not
P1 & P7 have very high steroidal compounds related to progesterone (eg 5alpha-pregnan-3beta-ol,20-one sulfate)
P7 & P8 have high glutamates such as gamma-glutamylglutamate, gamma-glutamylisoleucine*
and gamma-glutamylvaline. (I read that gamma-glutamylvaline inhibits TNF-alpha to reduce inflammation)

yes hypoxanthine is a direct metabolite from Inosine. I expect that increasing hypoxanthine activates the salvage pathway to IMP/AMP/ATP.


Interesting to notice the increased gamma-glutamyl-amino acids. Is it an activated pathway meant to reduce excess glutamate in these patients? I don't think that inosine has any effect on this pathway, but it would need more investigations.

 

[wigglethemouse]

interesting, did you find this figure in the Hanson/Levine study?

The paper states samples were from Susan Levine (one of the authors). I gathered she recommended Inosine/Imunovir from internet search, PR, and blogs (for immune modulating properties)

Blood samples were collected in NYC by ME/CFS expert physician Dr. Susan Levine in EDTA tubes and shipped overnight by FedEx in a Styrofoam box to Cornell University-Ithaca Biotechnology Building, where plasma was separated from cells by centrifugation at 500 g for 30 min, before being stored at 80 C until further analysis.

yes hypoxanthine is a direct metabolite from Inosine

Interesting bit on Hypoxanthine from the Hanson paper

The final combinations included Germain et al. [21] and Armstrong et al. [17], Germain et al. [21]
and Naviaux et al. [19], and Armstrong et al. [17] and Naviaux et al. [19], and the results were very
similar, with 87%, 98% and 91% of metabolites, respectively, not behaving statistically differently
between studies (Table 4).
Of note, is the recurring appearance of hypoxanthine as a metabolite found to be significantly
different between studies, along with a few other metabolites, always involving comparisons with
the Armstrong et al. dataset [17].

 

[Violeta]

Inosine + caffeine still working for me, just wanted to add that Ribose is required too for the cocktail to work well (and zinc).


Glucarate has an interesting vasodilatory effect if I add it too (warm feeling)

@pattismith, do you mean calcium glucarate?

I am just wondering if this is how the glucarate is helping the process.

And I don't know much about this topic, but this morning I saw this about the enzyme apyrase. "Apyrase is a calcium-activated plasma membrane-bound enzyme (EC 3.6.1.5) that catalyses the hydrolysis of ATP to yield AMP and inorganic phosphate."

and

Apyrase has a higher ratio of activity for ATP:ADP (14:1). Apyrase is a calcium-activated enzyme. It is approximately 50% active when Mg2+ substitutes Ca2+ in...

I don't know yet if it has anything to do with adenosine, but I will keep reading. Maybe someone can help me out.

Oh yes, it does have something to do with adenosine, but I don't know if this is favorable or not.

"Apyrase may inhibit an inflammatory response at the feeding site through the subsequent degradation of its end-product, AMP, to adenosine, a potent anti-inflammatory substance, by the ecto-5' nucleotidase activity of neutrophils."

Oh, I guess it wouldn't be favorable if one finds inosine helpful.

Opposing Effects of Adenosine and Inosine in Human Subcutaneous Fibroblasts May Be Regulated by Third Party ADA Cell Providers​

 

[pattismith]

Interestingly I tried Inosine + Theophylline and it still work to rescue my energy level.

Theophylline works like caffeine, but it doesn't make my hands shake like caffeine.

I still don't know why this combo is working, I found some papers about it but I'm not sure it is relevant.

For example, Theophylline might stop inosine from entering cells, so the effect from Inosine might lie in the Adenosine receptors activation only.


https://cdnsciencepub.com/doi/abs/10.1139/y74-140

 

[Anish04]

Interestingly I tried Inosine + Theophylline and it still work to rescue my energy level.

Theophylline works like caffeine, but it doesn't make my hands shake like caffeine.

I still don't know why this combo is working, I found some papers about it but I'm not sure it is relevant.

For example, Theophylline might stop inosine from entering cells, so the effect from Inosine might lie in the Adenosine receptors activation only.


https://cdnsciencepub.com/doi/abs/10.1139/y74-140

Did it helped your muscle weakness too? Also which brand inosine you took and how much ?.
Please answer thank you