Propentofylline, Pentoxifylline and Glutamate.

[Hip]

@Hip, how is it going with the propentofylline? Are you still taking it?

My box of propentofylline tablets has run out now, but I did get the impression that my conscious awareness was sharpened and made more sensitive and perceptive when taking propentofylline. But I only had enough tablets for a short series of experiments, and I'd like to take this drug a few more times to try to repeat these results before I come to a conclusion.

The problem with propentofylline is that its oral bioavailability only 4%, so that means you have to start taking a lot of tablets to ensure you get a reasonable dose. A box of 60 x 100 mg tablets costs around $70. I was taking oral doses of around 5 to 10 of these tablets in one go.

Then I read here that propentofylline suppositories in coconut oil-based gels achieve 100% bioavailability, so I started experimenting with 200 to 300 mg of propentofylline in coconut oil and applied this sublingually and on the mucous membranes of my mouth; or at other times just on my skin transdermally.

The only side effect I had occurred when I took propentofylline with my morning coffee, and this made me feel very strange, as if not enough blood or oxygen was getting to my brain. So coffee and propentofylline are not a good combination. But apart from that, I had no side effects at all from propentofylline.

Note that propentofylline is not licensed for human use (it is a veterinary drug), but has been used in human trials for a number of health conditions.

 

[Ema]

My box of propentofylline tablets has run out now, but I did get the impression that my conscious awareness was sharpened and made more sensitive and perceptive when taking propentofylline. But I only had enough tablets for a short series of experiments, and I'd like to take this drug a few more times to try to repeat these results before I come to a conclusion.

The problem with propentofylline is that its oral bioavailability only 4%, so that means you have to start taking a lot of tablets to ensure you get a reasonable dose. A box of 60 x 100 mg tablets costs around $70. I was taking oral doses of around 5 to 10 of these tablets in one go.

Then I read here that propentofylline suppositories in coconut oil-based gels achieve 100% bioavailability, so I started experimenting with 200 to 300 mg of propentofylline in coconut oil and applied this sublingually and on the mucous membranes of my mouth; or at other times just on my skin transdermally.

The only side effect I had occurred when I took propentofylline with my morning coffee, and this made me feel very strange, as if not enough blood or oxygen was getting to my brain. So coffee and propentofylline are not a good combination. But apart from that, I had no side effects at all from propentofylline.

Note that propentofylline is not licensed for human use (it is a veterinary drug), but has been used in human trials for a number of health conditions.

Interesting, @Hip.

It looks like pentoxifylline may also be a workable alternative to the propentofylline. That drug is on generic and is pretty cheap (about $30) for a month's supply.

Pentoxifylline has some interesting effects on the immune system and looks to decrease TNF-a pretty substantially. It also works on the adenosine 2 receptors. It also decreases interferon gamma and reduces the innate immune response. I think that this would be a good thing possibly as being stuck in the initial immune response to a pathogen doesn't seem to be helpful. I've read some where people say that is the difference between developing chronic Lyme or not - whether or not the interferon gamma drops and one switches into adaptive immune responses.

One of the metabolites of pentoxifylline is lisofylline...which is also an interesting anti-inflammatory molecule.

From wikipedia:

As well, LSF improves cellular mitochondrial function and blocksinterleukin-12 (IL-12) signaling and STAT-4 activation in target cells and tissues. IL-12 and STAT-4 activation are important pathways linked to inflammation and autoimmune damage to insulinproducing cells. Therefore, LSF and related analogs could provide a new therapeutic approach to prevent or reverse type 1 diabetes. LSF also directly reduces glucose-induced changes in human kidney cells suggesting that LSF and analogs have the potential to treat the complications associated with diabetes.

Part of my theory is also that high adenosine concentrations will put mammals into a state of hibernation. It looks like high glutamate levels can also stimulate adenosine so that all fits together. I'm very curious if lowering glutamate would be sufficient to causee adenosine levels to drop as well and possibly reverse the hibernation effect.

I'm also curious to know if vinpocetine would work in this regard even though it is structurally different.

Differences in the anti-inflammatory effects of theophylline and pentoxifylline: important for the development of asthma therapy?
Authors
Entzian P, et al. Show all
Journal
Allergy. 1998 Aug;53(8):749-54.

Affiliation
Abstract
Antiasthma drugs are now being re-evaluated for their anti-inflammatory effects. Theophylline is an immunomodulator; however, weak effects and the narrow therapeutic window make it a controversial drug. We compared the immunomodulatory potencies of theophylline with those of the xanthines pentoxifylline (POF) and A802715. Using a whole-blood, cell-culture system, we studied the effects on the release of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) in six healthy subjects, and, in granulocyte suspensions, the effects on the release of reactive oxygen species (ROS). We also studied the influence of a 14-day treatment with theophylline or POF on the release of the cytokines named above in 14 asthmatics. We found that equimolar concentrations of A802715 most effectively inhibit ROS generation, followed by POF; the effects of theophylline were weakest. A802715-inhibited release of TNF-alpha was four times as potent as that of theophylline, and POF two times as potent. Inhibition of IFN-gamma by A802715 was three times as potent, and by POF two times. Neither drug influenced IL-6 release. After a 14-day treatment of asthmatics, POF proved to inhibit TNF-alpha release more effectively (by 44.3%) than theophylline (7.5%). It is concluded that study of xanthine derivatives in asthmatics might help the development of asthma therapy. POF seems to be an especially promising candidate.

 

[Hip]

I did look at pentoxifylline, but I does not seem to increase EAAT2 glutamate transporter expression like propentofylline does. So for the purpose of clearing excess extracellular glutamate from the brain, I think only propentofylline will work.

I did come across this report of an ME/CFS patient who tried pentoxifylline for one month, but noticed no benefits.

The TNF-alpha inhibiting effects of pentoxifylline might be useful however. Cat's claw supplement might be the one to try for this, though, since one study found that cat's claw was a "a remarkably potent inhibitor of TNFalpha production".


But I will soon go ahead and try Rocephin injections, as Rocephin appears to be the most potent booster of EAAT2 glutamate transporter expression.

 

[Hip]

Regarding adenosine: I was thinking that this might actually be helpful for ME/CFS, in order to prevent insomnia, regulate the circadian rhythm, and perhaps get better sleep. It's thought that it is the build up of adenosine during the day that leads us to get that nice healthy sleepy feeling near bedtime, when we sense it's the right to to go to sleep.

I don't get that sleepy feeling just before bed anymore since getting ME/CFS; rather I tend feel wide awake and "wired" mentally last thing at night, which makes it hard to get to sleep.

So perhaps taking some adenosine just before bedtime might rectify this problem.

You can buy adenosine monophosphate as a supplement called "My-B Tabs".

An explanation of why adenosine monophosphate works for inducing sleep is here.

Yet another medication on my "to do" list!

 

[Ema]

Regarding adenosine: I was thinking that this might actually be helpful for ME/CFS, in order to prevent insomnia, regulate the circadian rhythm, and perhaps get better sleep. It's thought that it is the build up of adenosine during the day that leads us to get that nice healthy sleepy feeling near bedtime, when we sense it's the right to to go to sleep.

I don't get that sleepy feeling just before bed anymore since getting ME/CFS; rather I tend feel wide awake and "wired" mentally last thing at night, which makes it hard to get to sleep.

So perhaps taking some adenosine just before bedtime might rectify this problem.

You can buy adenosine monophosphate as a supplement called "My-B Tabs".

An explanation of why adenosine monophosphate works for inducing sleep is here.

Yet another medication on my "to do" list!

It's probably a matter of the amount.

Too much adenosine causes hibernation syndrome in mammals with all the attendant metabolic issues and immune issues like we see in ME/CFS. Too little is probably bad as well.

Mine was over range on the methylation pathways panel and RichvanK mentioned that was not an unusual finding (though he was unsure of the significance). Purine metabolism dysregulation has also been a fairly common area of study.

I started a thread about low levels of adenosine deaminase causing high adenosine levels here:

http://forums.phoenixrising.me/inde...y-adagen-for-ad-deficiency.26971/#post-411539

 

[Ema]

Another wrinkle concerning pentoxifylline:

http://m.bloodjournal.org/content/89/10/3682.full.pdf

It says that (especially in the presence of high TNF-a), pentoxifylline promotes replication of cytomegalovirus. It says that all drugs that increase cAMP (which I thought was a good thing?) can have this effect so I wonder if this also applies to propentofylline as well?

It says that alone pentoxifylline only had marginal stimulatory activities on CMV. It apparently has synergistic effects on CMV when in the presence of high TNF-a.

Finally, I'm just not sure how relevant this study is to our population anyway. It was a tiny sample size (7 patients) who were immunosuppressed already and I've not seen any follow up research.

However, it is concerning given I already have high titers to CMV.

 

[Ema]

Here is an interesting article from the late 90s.

Mol Chem Neuropathol. 1996 May-Aug;28(1-3):185-90.
Modulation of glial cell signaling by adenosine and pharmacological reinforcement. A neuroprotective strategy?
Schubert P1, Ogata T, Ferroni S, McRae A, Nakamura Y, Rudolphi K.
Author information

Abstract
In view of the increasing evidence that a pathological glial activation plays a significant role in the development of neurodegenerative diseases, we investigated the underlying molecular signaling as a possible target for the pharmacological therapy.

Here, we are particularly focusing on the endogenous modulation of the CA2+ and cyclic nucleotide-dependent signaling by the nucleoside adenosine and its reinforcement by the xanthine derivative propentofylline (PPF).

As an experimental model, we used cultured rat microglial cells and astrocytes that are immature, show a high proliferation rate, and resemble in several aspects pathologically activated glial cells. A prolonged increase of the cellular cAMP level favored the differentiation of cultured astrocytes and associated properties required for the physiological nerve cell function.

On the other hand a strengthening of the cyclic nucleotide-dependent signaling inhibited potentially neurotoxic properties of cultured microglial cells. Similar effects were obtained by treatment with propentofylline, which mimicked modulatory adenosine effects and increased the intracellular level of cAMP and cGMP.

Such a pharmacological glial cell conditioning, obtained by modifying the strength and the timing of these second messengers, may provide a therapy of neurodegenerative diseases in which a pathological activation of microglial cells and astrocytes is discussed to playa pathogenic role.

 

[Hip]

So propentofylline may inhibit the neurotoxic effects of microglial cells.

 

[xrayspex]

So propentofylline may inhibit the neurotoxic effects of microglial cells.

I am researching this med right now, am curious, is that a good thing? it sounds like it, but when I read about microglial cells they help prevent infections from getting to spine and brain, is that right? sounds like they are only line of defense. so when do they become neurotoxic?

edit--oh, I see, should have finished reading at wiki, sounds like this is what my "neurogenic" pain is about.....like in AI illnesses, a good thing (the glial cells) turn into bad thing.....basically?

so according to the study trying pentoxifylline might be worth a shot to calm that sh*t down?

http://www.ebay.com/itm/Pentoxifyll...668198?hash=item2caef22e66:g:tEUAAOSwkl5XejPd

 

[Hip]

@xrayspex I don't think anyone knows whether inhibiting the neurodestructive mode of microglia is a good thing or not in any given disease. Microglia do fight and protect against infections in the brain, but there is also collateral damage involved.

Microglia also have a neuroprotective mode, where they heal the damage caused by their neurodestructive mode.

There is a large list of drugs and supplements in this post that inhibit microglial activation.

 

[pattismith]

I did look at pentoxifylline, but I does not seem to increase EAAT2 glutamate transporter expression like propentofylline does. So for the purpose of clearing excess extracellular glutamate from the brain, I think only propentofylline will work.

Did you do another trial with propentofylline?

My 15 years old dog is doing fine with it!

I start today a trial with LDN + propentofylline, I will update your thread if you wish?

500 mg to 1000 mg seems a lot! Is there a way to improve bioavailability?

 

[Hip]

Did you do another trial with propentofylline?

If have tried courses of propentofylline a few times on and off, but I can't say I noticed much from it.

 

[pattismith]

@Hip
I read that 4% bioavalibility is for rabbits, did you really find 4% for humans?

For the dogs:


"5.2 Pharmacokinetic particulars


After oral administration propentofylline is fast and completely absorbed and quickly distributed in the tissues. Given orally to dogs, maximum plasma levels are reached already after 15 minutes.

The half-time is about 30 minutes and the bioavailability for the mother substance amounts to about 30%. There are a number of effective metabolites and the biotransformation takes place mainly in the liver. Propentofylline is excreted in form of its metabolites in 80-90% via the kidneys. The rest is eliminated with the faeces. There is no accumulation. "

http://www.vmd.defra.gov.uk/productinformationdatabase/SPC_Documents/SPC_359463.DOC

 

[Hip]

I read that 4% bioavalibility is for rabbits, did you really find 4% for humans?

I based it on the rabbit bioavailability figure found here, as that's the only one I could find. But the dog bioavailability looks better.

 

[pattismith]

I based it on the rabbit bioavailability figure found here, as that's the only one I could find. But the dog bioavailability looks better.

it may be that we are more dogs than rabbits... but it depends of who ...

 

[pattismith]

If have tried courses of propentofylline a few times on and off, but I can't say I noticed much from it.

how much were you taking ?

According to studies in monkies and human, Propentofylline increases brain blood flow (vasodilation, but i still don't know if it is an arterial or a venous effect), brain glucose metabolism, and may benefit to Vascular Dementia and Alzheimer.

I am interesting in the vascular effect, so i am currently doing a new trial, at 100 mg x 3 times per day.

The dose tested in Alzheimer patients was 300 mg x 3 times per day.

https://www.ncbi.nlm.nih.gov/pubmed/2135708/

https://www.infona.pl/resource/bwmeta1.element.elsevier-1c1c9d4c-be6a-3aa3-b591-8439d41d2210

https://www.ncbi.nlm.nih.gov/pubmed/8880694?dopt=Abstract

https://onlinelibrary.wiley.com/doi/abs/10.1002/ddr.430050203

 

[Hip]

how much were you taking ?

300 mg once daily.

 

[Gingergrrl]

My 15 years old dog is doing fine with it!

Patti, Can I ask why your dog was prescribed Pentoxyfilline? My dog (who is 13.5 yrs old) was prescribed it for autoimmune vaccine induced vasculitis (from the rabies vaccine). It is to try to increase the blood flow to the small vessels in her ears. Was your dog prescribed it for a similar reason? Thanks!

 

[pattismith]

Patti, Can I ask why your dog was prescribed Pentoxyfilline? My dog (who is 13.5 yrs old) was prescribed it for autoimmune vaccine induced vasculitis (from the rabies vaccine). It is to try to increase the blood flow to the small vessels in her ears. Was your dog prescribed it for a similar reason? Thanks!

my dog was taking Propentofylline to improve aging brain blood flow.

 

[Gingergrrl]

my dog was taking Propentofylline to improve aging brain blood flow.

Thank you for the info and I had been curious if it was vasculitis (or similar to my dog's autoimmune reaction to a vaccine) but it sounds very different.