T3 intracellular calcium and caffeine

[Iritu1021]

Pretty interesting. pregnenelone definetly turned the lights on for me a few years back. I wonder if we could also get some Bay K 8644.


https://www.tocris.com/products/dl-bay-k-8644_1544

A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca²⁺ release from acidic Ca²⁺ stores.
Fois G1, Hobi N2, Felder E3, Ziegler A4, Miklavc P5, Walther P6, Radermacher P7, Haller T8, Dietl P9.
Author information

Abstract
Ambroxol (Ax) is a frequently prescribed drug used to facilitate mucociliary clearance, but its mode of action is yet poorly understood. Here we show by X-ray spectroscopy that Ax accumulates in lamellar bodies (LBs), the surfactant storing, secretory lysosomes of type II pneumocytes. Using lyso- and acidotropic substances in combination with fluorescence imaging we confirm that these vesicles belong to the class of acidic Ca(2+) stores. Ax lead to a significant neutralization of LB pH, followed by intracellular Ca(2+) release, and to a dose-dependent surfactant exocytosis. Ax-induced Ca(2+) release was significantly reduced and slowed down by pretreatment of the cells with bafilomycin A1 (Baf A1), an inhibitor of the vesicular H(+) ATPase. These results could be nearly reproduced with NH3/NH4(+). The findings suggest that Ax accumulates within LBs and severely affects their H(+) and Ca(2+) homeostasis. This is further supported by an Ax-induced change of nanostructural assembly of surfactant layers. We conclude that Ax profoundly affects LBs presumably by disordering lipid bilayers and by acting as a weak base. The pH change triggers - at least in part - Ca(2+) release from stores and secretion of surfactant from type II cells. This novel mechanism of Ax as a lysosomal secretagogue may also play a role for its recently discussed use for lysosomal storage and other degenerative diseases.

I take calcium three times a day for years, so I don't know if other things would work without it for me.

Before I started T3, I was already taking coffee and cortisone when I had a need for a boost and to avoid PEM.

I still use corticoids but it doesn't work if I take it on a daily basis, so I spare it....


Interestingly, I am low for pregnenolone, and I took it for years ...... with no effect at all...

I also can only get one dose effect from pregnenolone or cortisol and it's not guaranteed that it will be a positive effect - depends on my settings.

I found a blog by a progressive psychiatrist who wrote that he uses T4 for patients who are on the bipolar spectrum because T4 has a mood stabilizing effect, and he uses T3 only for patients with unipolar depression as he found that it destabilizes bipolar patients. It certainly was my experience with T3 - except that it destabilized everything in my nervous system, and not just my mood.

 

[drob31]

A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca²⁺ release from acidic Ca²⁺ stores.
Fois G1, Hobi N2, Felder E3, Ziegler A4, Miklavc P5, Walther P6, Radermacher P7, Haller T8, Dietl P9.
Author information

Abstract
Ambroxol (Ax) is a frequently prescribed drug used to facilitate mucociliary clearance, but its mode of action is yet poorly understood. Here we show by X-ray spectroscopy that Ax accumulates in lamellar bodies (LBs), the surfactant storing, secretory lysosomes of type II pneumocytes. Using lyso- and acidotropic substances in combination with fluorescence imaging we confirm that these vesicles belong to the class of acidic Ca(2+) stores. Ax lead to a significant neutralization of LB pH, followed by intracellular Ca(2+) release, and to a dose-dependent surfactant exocytosis. Ax-induced Ca(2+) release was significantly reduced and slowed down by pretreatment of the cells with bafilomycin A1 (Baf A1), an inhibitor of the vesicular H(+) ATPase. These results could be nearly reproduced with NH3/NH4(+). The findings suggest that Ax accumulates within LBs and severely affects their H(+) and Ca(2+) homeostasis. This is further supported by an Ax-induced change of nanostructural assembly of surfactant layers. We conclude that Ax profoundly affects LBs presumably by disordering lipid bilayers and by acting as a weak base. The pH change triggers - at least in part - Ca(2+) release from stores and secretion of surfactant from type II cells. This novel mechanism of Ax as a lysosomal secretagogue may also play a role for its recently discussed use for lysosomal storage and other degenerative diseases.


I also can only get one dose effect from pregnenolone or cortisol and it's not guaranteed that it will be a positive effect - depends on my settings.

I found a blog by a progressive psychiatrist who wrote that he uses T4 for patients who are on the bipolar spectrum because T4 has a mood stabilizing effect, and he uses T3 only for patients with unipolar depression as he found that it destabilizes bipolar patients. It certainly was my experience with T3 - except that it destabilized everything in my nervous system, and not just my mood.

You gonna try ambroxol?

 

[Iritu1021]

Thanks for the advice.

Did HTCZ lower water retention at all for you?

Yes, it did.

 

[Iritu1021]

You gonna try ambroxol?

Maybe at some point. Right now I'm trying to optimize my lithium +T4 combo.

 

[drob31]

Yes, it did.

Did you ever have any symptoms of diabetes insipidus, even if mild? Nocturia, frequent urination, water pass right through you?

Just wondering if that somehow ties into the calcium thing.

 

[drob31]

@Hip bat signal.

Sorry should have tagged him earlier.

 

[Iritu1021]

Did you ever have any symptoms of diabetes insipidus, even if mild? Nocturia, frequent urination, water pass right through you?

Just wondering if that somehow ties into the calcium thing.

I don't recommend that you use HCTZ unless you have an indication to do so, such as elevated 24 hr urine calcium. It's not a benign drug and it requires routine lab follow up.

I'm also not in favor of trying experimental drugs that have not been approved for human use - but that's just me.

 

[Hip]

@Hip bat signal.

Saw the signal, but not sure what the question is.

 

[drob31]

Saw the signal, but not sure what the question is.

Just thought you may be interested in this thread. Some interesting revelations are occurring.

 

[Gingergrrl]

Just thought you may be interested in this thread. Some interesting revelations are occurring.

I agree and would love to hear your thoughts @Hip (although none of the interesting revelations are from me )

 

[Hip]

would love to hear your thoughts @Hip

I am a bit tired and brain fogged at the moment, and so am having difficulty grasping the gist this thread; though if someone would care to clarify, I am all ears.

There seems to be the suggestion that calcium and caffeine together (and also with corticosteroids) might improve brain functioning?

 

[Iritu1021]

I will summarize the theory as it unfolded during the conversation.

Regular people do not notice immediate effect from thyroid medication. It takes regular hypothyroid people several weeks for them to notice long term changes from using their thyroid hormone. But @pattismitha and I and many others here who use thyroid feel immediate effects both on initiation and withdrawal. So starting from the beginning of this year @pattismith and I have been discussing on this forum various possibilities of what could be causing those immediate (onset within 30 minutes of the dose) changes from T3 (and to a lesser degree T4).

This thread was started off buy @pattismith after she made a connection that both T3 and caffeine release intracellular calcium.

I was not active on the forum at the time and did not know about this threat but around the same time I found out that my ionized (bioactive) fraction of calcium falls below normal and my parathyroid hormone goes up if I abruptly decrease my thyroid dose. I contacted pattismith to tell her about my discovery and she referred me to this thread and as discussion progressed, and more people joined the following hypothesis has become formulated:

Mitochondria depend on calcium to be able to perform oxidative phosphorylation.
Mitochondrial calcium level is dependent on high cytosolic calcium gradient to induce calcium flow which occurs through specialized membrane calcium channel.

Due to some confluence of some genetic predisposition and external stressors, patients with CFS might develop states of cytosolic calcium depletion which in turn leads to mitochondrial calcium depletion which leads to hypometabolic cellular failure that makes it very difficult to climb out from.

We discovered that many of the things that make us better are in fact linked to intracellular calcium release - even IVIG.

One thing I remember about you is that you're taking selenomethionine (I do too). I posted a link in this thread to the article that documents that selenomethionine also stimulates intracellular calcium release.

 

[S-VV]

Fantastic abstract!! There is also the powerful effect Lithium has on the Phospholipase C pathway, permitting the entry of more Ca2+ into the cytosol.

 

[Gingergrrl]

I will summarize the theory as it unfolded during the conversation.

@Iritu1021 I am so glad that you summarized this thread for Hip and even though I had done my best to read through it all, I clearly had not understood a lot of it and your summary was very helpful.

Regular people do not notice immediate effect from thyroid medication. It takes regular hypothyroid people several weeks for them to notice long term changes from using their thyroid hormone. But @pattismith and I and many others here who use thyroid feel immediate effects both on initiation and withdrawal.

Some how I didn't quite get this either and want to share my experience. I was first diagnosed with Hashimoto's in Oct 2013 (and it is a correct diagnosis but sadly not my only diagnosis as I'd hoped at that time). I was put on Armour Thyroid which contains T3. I immediately felt better and the difference was so striking that it allowed me to return to work after being on medical leave for the two months prior. I (stupidly) thought that I had found the answer but within a few months, I started to get very sick again and my POTS (which was still undiagnosed) was really bad.

My Endo increased my Armour dose in case this would help but it did not. It worked as far as getting my TSH and all my numbers into the normal range but I never again achieved the relief in symptoms (from Armour). We ultimately went back down on the dose. I've taken Armour since 2013 (and have no idea what would happen if I stopped it) and a few months ago we ended up raising the dose after all b/c my TSH was creeping up higher (although still in the normal range). So, I have no idea if I would have any "withdrawal" b/c I have never stopped Armour since starting it.

We discovered that many of the things that make us better are in fact linked to intracellular calcium release - even IVIG.

I think I missed this part. How is IVIG related to intracellular calcium release? IVIG was a true miracle medication for me but I never knew it linked to Calcium?!

 

[Iritu1021]

Fantastic abstract!! There is also the powerful effect Lithium has on the Phospholipase C pathway, permitting the entry of more Ca2+ into the cytosol.

I feel a very positive effect from lithium orotate but I'm still on a pretty low dose - 5 mg of elemental lithium three times a day (15 mg/day total). I can feel my brain clarity going down before each dose so I think I'm still not taking enough. When I did my first long course of lithium orotate last summer, I had significant improvement in my brain function and post-T3 depression but at that time I was using higher doses of 30 mg/day which is on the low end of the therapeutic dose in psychiatry. The main reason I stopped at that time is because
I developed severe pain in my throat that felt really worrisome. I got thyroid ultrasound which showed 2.5 cm nodule. However I began taking small doses of Armour again and a week later by the time I made it to endocrinologist the nodule seemed to have mysteriously shrunk back to 1 cm. I read that parathyroid adenomas can appear as thyroid nodules on ultrasound.

I know that at that time I was not taking enough thyroid because I was at first taking none, then when lithium made me hypothyroid, I was only taking small doses. I was able to handle lithium much better this time after I slowly increased my T4 dose to 75 mcg but I feel like I have now raise my dose higher because lithium seems to be clearly shutting down my thyroid production. Not that I really care since I already take thyroid anyway for my Hashimoto's and psych text books say that hypothyroidism is not a reason to stop taking lithium, it's a reason to add thyroid.

I am hesitant about using large doses of lithium orotate long term because I've seen some data that orotate might be carcinogenic. I want to try and switch to lithium carbonate, which is the prescription form.

 

[S-VV]

You seem to have found a good combination of Li+T3/T4. My thyroid results and elemental Li arrive tomorrow, so it's experiment time.

It's interesting that the effects of Li seem so short-lived, much like what people are reporting with T3

On a related note, I have been experiencing pain in my throat for a few months now, so I may have to look into that.

 

[Iritu1021]

[/QUOTE]I think I missed this part. How is IVIG related to intracellular calcium release? IVIG was a true miracle medication for me but I never knew it linked to Calcium?![/QUOTE]
@Gingergrrl
Your story is almost like mine! You can read mine here:
http://www.chronicfatiguediagnosis.com/2018/05/23/thyroid-hormone-my-friend-my-enemy/

I might have mentioned IVIG and calcium in another thread and only alluded to it here. If I understand it correctly, it appear to act on the ryanodine receptor that @pattismith mentioned.

J Neurol Sci. 1998;156(1):35-40.
Intravenous immunoglobulin preparation increases myoplasmic calcium concentration by activating the dihydropyridine-ryanodine receptor complex.
van Engelen BG1, Benders AA, Wevers RA, Gabreëls FJ, Renier WO, Veerkamp JH.
Author information

Abstract
A human intravenous immunoglobulin preparation (IVIg) released Ca2+ from the sarcoplasmic reticulum of cultured human skeletal muscle cells in a dose-dependent manner. Blocking the dihydropyridine-ryanodine receptor complex abrogated the IVIg-mediated Ca2+ response, whereas inhibition of the voltage-operated Na+-channels or acetylcholine receptors did not. This effect of IVIg was not mediated by its main component, the IgG molecules, and differed between preparations from different manufacturers. Heating destroyed the activity. Data shows that an unidentified serum protein present in IVIg can influence human muscle cells by an effect on the dihydropyridine receptor. This phenomenon may be important in interpreting the (side) effects of IVIg in neuromuscular disease.

 

[Gingergrrl]

@Gingergrrl Your story is almost like mine! You can read mine here: http://www.chronicfatiguediagnosis.com/2018/05/23/thyroid-hormone-my-friend-my-enemy/

I had no idea that we have similar stories and I have never looked at your blog (or followed you) but I am about to start! I promise I am not a stalker LOL

I might have mentioned IVIG and calcium in another thread and only alluded to it here. If I understand it correctly, it appear to act on the ryanodine receptor that @pattismith mentioned.

I think it was another thread unless I missed it in this one (which is very possible). Although usually anything about IVIG immediately catches my eye. I just had to Google "ryanodine receptor" and it looks like it is a type of intracellular calcium receptor?

Abstract
A human intravenous immunoglobulin preparation (IVIg) released Ca2+ from the sarcoplasmic reticulum of cultured human skeletal muscle cells in a dose-dependent manner. Blocking the dihydropyridine-ryanodine receptor complex abrogated the IVIg-mediated Ca2+ response, whereas inhibition of the voltage-operated Na+-channels or acetylcholine receptors did not. This effect of IVIg was not mediated by its main component, the IgG molecules, and differed between preparations from different manufacturers. Heating destroyed the activity. Data shows that an unidentified serum protein present in IVIg can influence human muscle cells by an effect on the dihydropyridine receptor. This phenomenon may be important in interpreting the (side) effects of IVIg in neuromuscular disease.

The stuff that is bolded is mine and I have literally never heard of this connection between calcium and IVIG before. Do you happen to know which manufacturer of IVIG they are referring to? My two years of IVIG were all with Gamunex.

I know it has been proven that high dose IVIG helps neuromuscular diseases (like LEMS which they think is part of my problem) but I NEVER knew that IVIG did anything to the calcium channels itself which are the problem in LEMS. I thought the entire mechanism was replacing the bad autoantibodies with the good ones from the donor plasma (IgG). This could be a second reason why IVIG was so incredibly helpful for me (if I am understanding it correctly).

I am tagging @Inara (in case this thread is of interest to you, Inara). I know it is a long thread but I thought you might want to browse it when you have time in case any is relevant or helpful. If not, just disregard

 

[Iritu1021]

I know it has been proven that high dose IVIG helps neuromuscular diseases (like LEMS which they think is part of my problem) but I NEVER knew that IVIG did anything to the calcium channels itself which are the problem in LEMS. I thought the entire mechanism was replacing the bad autoantibodies with the good ones from the donor plasma (IgG). This could be a second reason why IVIG was so incredibly helpful for me (if I am understanding it correctly).

I am tagging @Inara (in case this thread is of interest to you, Inara). I know it is a long thread but I thought you might want to browse it when you have time in case any is relevant or helpful. If not, just disregard

I've never had IVIG and this is an old study so I'm not sure what type they used. I don't think anyone really understand the mechanism by which IVIG works. It was developed to treat immune deficiency, not autoimmune conditions. It's a straightforward leap of faith that because it's an immunoglobulin it works via an immune pathway but not a proven one. And maybe in some cases it does work that way.

However, for most people with serious autoimmune conditions, the regular administration of IVIG does not appear to be necessary like for people with POTS and CFS. When I worked in the hospital, we would get people in critical condition in ICU, let's say something like thromocytopenic purpura, they get a course of IVIG and then they recover and can go years or the rest of their life without IVIG. While the impression I get from CFS/POTS crowd (and maybe I'm wrong) is that there is a dose dependent response that quickly tends to wear off it the dose is omitted.

Jay Goldstein believed that IVIG worked for CFS in non-autoimmune mechanism.

As for my POTS, I only have it if I take thyroid hormone, especially Armour (which also has calcitonin in it to further complicate the calcium regulation, especially if you use it sublingually). I've done the start-stop experiment so many times that there's not a thread of doubt in my mind about the relationship between T3 and my dysautonomia. My choices have been essentially to take thyroid and have POTS and or not to take thyroid and have CFS, and I've spend the last 4.5 years trying to figure out this delicate balancing act.

 

[Hip]

We discovered that many of the things that make us better are in fact linked to intracellular calcium release

Thanks very much for the above summary of this thread, Iritu1021.

When you say "intracellular calcium release", I take you mean the release of calcium from its stores in the cell's endoplasmic reticulum into the cytosol of the cell (rather than release of calcium from the cell out into the extracellular spaces, by pumping calcium out of the cell via the calcium channels on the cellular membrane).



I don't know how this fits into your current discussion, but I've often wondered whether within the neurons in the brain of ME/CFS patients, intracellular calcium levels might be high, due to possibly elevated brain glutamate. Glutamate stimulation of neurons causes high levels of calcium ions to enter these cells — and this calcium influx to the neuron ultimately ends up with excitotoxicity if glutamate levels are very high.

It's been speculated that ME/CFS might involve high levels of extracellular glutamate in the brain, and that these high levels might cause the "wired but tired" hyperaroused feeling of ME/CFS. It has been shown that microglia are chronically activated in ME/CFS, and activated microglia pump out lots of glutamate, so that could be the source of the speculated high brain glutamate in ME/CFS. Though I have not seen any direct evidence for high extracellular glutamate in the brain in ME/CFS, so it's not clear whether or not there are high levels of this neurotransmitter.

But if there is high extracellular glutamate in the brain in ME/CFS, you might expect neurons to have high intracellular levels of calcium.