Pentoxifylline: shows amazing results but it's a potent immunesupresive agent: your opinion?

serg1942

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Hi guys,

I recently learned about pentoxifylline because it was prescribed to a friend of mine with ME/CFS by an immunologist, who said that 50% of his ME/CFS patients improved on it.

She was reassured that it was mainly an immune-modulator agent, so she had nothing to worry about.

She is doing amazingly well on this drug after about 2 months on it, to the point where she is feeling almost normal.

I have been doing a thorough research on the drug (because I was considering trying it, as I am bedridden, so is my mom and my partner!). And I found that it actually is a powerful immunesupresive agent. Most available studies are done in vitro, and they show that it strongly decreases NK cells cytotoxicity, inhibits fagocytic activity of the PBMCs, inhibits T and B cell activation, inhibits expression of adhesion molecules on the surface of CD4+ and CD8+ lymphocytes, lowers total count of leukocytes, decreases neutrophil functions, reactivates CMV, and a long etc. (links to the studies below). It's been also shown that pentoxifylline is as immune supressive as dexamethasone.

I have only found 2 studies in vivo where immune system status was assessed. In this respect, one study in humans confirmed what the studies in vitro had found repeatedly: after 1 year or more on pentoxifylline, patients showed a 38% and a 41% reduction in NK cytotoxicity compared with patients or with healthy controls, respectively.

The second study I found in humans showed an 11% reduction in leukocyte count after just one month on the treatment, when given to diabetic patients.

I can understand how this drug can work amazingly for some patients. It lowers TNF-alpha, which is a key cytokine in the feeling of fatigue. It also inhibits the T and B polyclonal proliferation, and also quenches autoimmune processes that might play a role in the pathogenesis of the disease. Moreover, it inhibits the translation of the inflammatory complex NF-kappa B, which we know is also key in ME/CFS pathophysiology. It even increases reduced glutathione (what is to be expected when lowering inflammation) and improves microcirculation.

Now, all this might come at a price, and it is my intention to figure out what exactly this price may be.

A 40% reduction in vivo of NK cell function is just a lot. The relationship between low NKs and cancer is certain. For example, there was a 23.6% higher survival rate of gastric cancer patients in 5 years follow-up, if NK functionality was more conserved:
https://pubmed.ncbi.nlm.nih.gov/11232710

In this regard I've done some research on the cancer-induced rate of immune suppressive drugs when taken as a single treatment for autoimmune conditions. Thus, a review on the subject explains how, for example, for multiple sclerosis patients taking azathioprine, there's a 30% increase of cancer in less than 5 years, a 100% increase in 5-10 years and a 440% increase in more than 10 years. Similarly, a mean of 8 years follow-up of patients with Wegener’s granulomatosis taking cyclophosphamide showed a 2.4-fold overall increase in malignancies per year. In the same vein, patients with psoriasis treated with cyclophosphamide had a 2.1-fold increase of cancer in a 5 years follow-up.

A drug that could be compared to some extent to pentoxifylline is the anti TNF-alpha Infliximab, given that pentoxifylline is known for its capacity to lower TNF-alpha levels. In this case there are mixed results. For example, some studies do not show more cancer rates in Crohn’s disease patients taking Infliximab, but other trials demonstrated a 2-3 fold increase in the risk of non-Hodgkin lymphomas, in patients with reumathoid arthritis taking Infliximab (although to be fair, this comparison is not completely adequate given that Infliximab is a single targeted drug, versus pentoxifylline which shows immunesupresive properties in numerous branches of the immune system):

https://pubmed.ncbi.nlm.nih.gov/12581698

https://pubmed.ncbi.nlm.nih.gov/1739240/

In summary, what I'm asking is not whether it would be worth taking the risk to take immune suppressants in ME/CFS, as, of course, the answer is: it depends! .

What I'd like is for you to help me figure out the real risks in terms of future cancer that might entail the chronic use of pentoxifylline. Unfortunately this is a pretty cheap drug which have not been properly studied.

Thank you so much in advance for your insights and opinions,

Best!
Sergio
******

Bibliography:

- Pentoxifylline given to patients for more than a year showed a 38% and a 41% less cytotoxicity compared to patients and controls, respectively:

https://link.springer.com/article/10.1007/PL00005346

- Pentoxifylline strongly suppressed NK cell function in vitro:

https://pubmed.ncbi.nlm.nih.gov/1593221/

- Pentoxifylline inhibits granzyme B and perforin expression following T-lymphocyte activation by anti-CD3 antibody, in mice:

https://www.sciencedirect.com/science/article/abs/pii/S0192056196000690

- Pentoxifylline reduces pro-inflammatory cytokines and inhibits adhesion between leukocytes and endothelial or epithelial cells. There may also be inhibitory effects on neutrophil, T and B lymphocytes and NK cell activity:

https://www.sciencedirect.com/science/article/pii/B9780702028588500142

- Pentoxyfilline may inhibit HIV expression indirectly by diminishing TNF production and directly, by decreasing activity of NF-kappa B:

https://pubmed.ncbi.nlm.nih.gov/8699854/

- Pentoxifylline decreases neutrophil function, decreases leukocyte response and proliferation, inhibits B and T cells and decreases Th1 cytokines and increases Th2 cytokines:

https://onlinelibrary.wiley.com/doi/full/10.1002/vms3.204

- Pentoxifylline, after one month given to type-2 diabetes patients: decreases 11.1% of total leukocyte count, decreases CRP and ESR, and increases reduced glutathione:

https://pubmed.ncbi.nlm.nih.gov/17613279

- Pentoxifylline inhibits binder and killer cell generation, cytotoxicity, proliferation, regulation of surface antigen expression, and induction of cell surface receptors:

https://link.springer.com/article/10.1007/BF01541173

- Pentoxifylline increases fibroblast collagenases and decreases collagen, fibronectin and glycosaminoglycan production (...) Pentoxifylline is an inhibitor of production of IL-1 and IL-6, an inhibitor of T and B cell activation, and a suppressor of neutrophil degranulation:

https://escholarship.org/uc/item/6270c6vm

- Pentoxifylline Promotes Replication of Human Cytomegalovirus In Vivo and In Vitro:

https://ashpublications.org/blood/a.../Pentoxifylline-Promotes-Replication-of-Human

- Pentoxifylline inhibits natural cytotoxicity as effectively as dexamethasone:

https://www.researchgate.net/public...forin-dependent_natural_cytotoxicity_in_vitro

- Pentoxifylline strongly reduces total number of monocytes capable of fagocytizing latex particles in vitro:

https://pubmed.ncbi.nlm.nih.gov/3023514/

- Pentoxifylline suppressed expression of adhesion molecules LFA-1 and VLA-4, in CD4+ and CD8+ lymphocytes:

https://www.jni-journal.com/article/S0165-5728(96)00198-1/fulltext
 

leokitten

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It’s definitely not considered nearly as immunosuppressive as steroids as it doesn’t affect numbers of circulating lymphocytes. Also it doesn’t have the horrible side effects of steroids limiting their use for more than a few days at a time.

I read too that pentoxifylline also improves red blood cell deformability and blood viscosity. Ron Davis’s lab wrote a paper showing reduced deformability in ME/CFS

Red blood cell deformability is diminished in patients with Chronic Fatigue Syndrome
 
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In our country, pentoxifylline is often prescribed to people with osteochondrosis. But I drank without a prescription, we have it without a prescription. It had a very good effect on performance, on eyesight, on hair loss, the skin on my face became pink, healthy. But it caused some nervous excitement and intensification of my neuralgia. So sorry. The effect was excellent, I did a lot of things. But to endure severe pain is beyond my strength ..
 

serg1942

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Thank you @bensmith! I really appreciate your comment!

Hi @leokitten, yes, pentoxyfylline does improve RBCs deformability, and this is one of the reasons why it might be helpful in ME/CFS.

When I say that it is considered as powerful as corticosteroids, it is because an in vitro study shows a similar degree of immunesupression as does dexamethasone, but this is just an in vitro assay:

"(...) pentoxifylline inhibits natural cytotoxicity as effectively as dexamethasone. However, the result of PTX inhibitory influence is observed much earlier than that of dexamethason (...)"

https://www.researchgate.net/public...forin-dependent_natural_cytotoxicity_in_vitro

And as far as not lowering circulating leukocytes, well it does lower in vivo an 11.1% the total count of lymphocytes in just 1 month (as shown in a study I posted above). However, what is more concerning to me is that this drug seems to halter the functionality of white blood cells much more than their numbers. Thus, It reduced a 40% the cytotoxicity of NKs in vivo. And also over a 40% the Phagocytic capacity of monocytes in vitro...

But this is exactly the reason of my post: why doctors say that it is not immunesupresive despite of what the literature says?

Thank you for your opinion!
Best
Sergio
 

serg1942

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Hi @Nat kea,

Thank you for you answer. I am so sorry that you had to stop it when you were seeing so good results! It must have been frustrating! Thank you for letting me know your experience!

Sergio
 

leokitten

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But this is exactly the reason of my post: why doctors say that it is not immunesupresive despite of what the literature says?
Probably because they do not see increased risk of infections from patients taking it long-term, whereas with steroids this is not the case. People take pentoxifylline every day long-term for peripheral artery disease.
 

JES

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Lots of medication inhibit TNF-alpha indirectly, the antidepressant bupropion is one example, but millions of people take bupropion without any correlation drawn to cancer as far as I know. Fish oil is another one, I have read studies that high-dose especially lowers it quite a bit.

So yeah, this is more of an opinion, but based on the above two examples I wouldn't be super concerned.
 

serg1942

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Thank you guys for your inputs!

@leokitten, you might be right (I hope you are for the sake of my fiend and of those who choose to take it!). However, in ME/CFS, we have usually low NKs and we barely show infections. Still, it's been shown that we have more chances of getting cancer than general population. This is relatively easy to explain, given that we lack a powerful Th1 and Th17 response (mainly CD8+) to mount a proper response to infections. So, not showing infections doesn't necessarily mean that pentoxifilie cannot entail greater chances of developing cancer. Also, we don't know if pentoxyfylline is actually immune suppressing patients taking it, because there haven't been proper studies conducted (and patients taking it are usually elderly people with chronic diseases, so it would be hard to discern a greater occurrence of cancer) . However the in vitro and limited in vivo evidence still seems concerning to me.

Hi @pattismith, actually she usually has very low NKs, I think normal neutrophils and I don't think she's measured TNF-alpha. But it is my gues that she must have had high TNF-alpha because she did show high perforin levels, meaning that macrophages are trying to stimulate NKs!

@crypt0cu1t, I agree with you. There are many immune-suppressive drugs on the market yet to be explored for ME/CFS, which will show great benefits.

Hi @JES, thank you for yor reply! Well, one thing is lowering excessive inflammation (this is known as immune modulation, and as you say it can be achieved by many molecules, including fish oil, turmeric, vit C, quercitine, LDN, etc.), and a very different one is immune-supression. Normally, immune modulation lowers inflammation when high while increasing the immune system when low.

So, those of you who think that there's nothing to worry about with pentoxyfilline, how do you explain the literature I have listed above? I mean, if reproduced by other studies, a 40% decrease in in vivo NK function wouldn't be acceptable for any medication on the market...

Thank you all again for sharing your opinions!

Sergio
 
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well perhaps it could be used as a research tool to explore the mechanics of me/cfs if it is not suitable for long term consumption. Its interesting to reconsider about rituximab responders.... being in the UK I have not had any tests done via the NHS that would rule out being in the subgroup which respond to rituximab. Does nobody find it remarkable that there are drugs now which have been confirmed to be effective in some way ?
 

Hip

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Some years ago I tried a related compound called propentofylline, and there is some discussion about both propentofylline and pentoxifylline in this short thread.

(I experimented with propentofylline because it increases expression of brain glutamate transporters, which remove glutamate from the brain; there's some speculation that the "wired" feeling of ME/CFS may involve high brain glutamate; propentofylline may have sharpened my mind and reduced my brain fog, but I did not take it for long enough to fully evaluate the drug).



This is a report of an ME/CFS patient who tried pentoxifylline for one month, but noticed no benefits.
 

mitoMAN

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I recently learned about pentoxifylline because it was prescribed to a friend of mine with ME/CFS by an immunologist, who said that 50% of his ME/CFS patients improved on it.
I doubt about these statements, similiar to another CFS doctor quoted recently that claimed 90% Success Rate.

Rituximab trial ended up having less successrate then the Placebo group.
 

serg1942

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I doubt about these statements, similiar to another CFS doctor quoted recently that claimed 90% Success Rate.

Rituximab trial ended up having less successrate then the Placebo group.
Well, yes, who knows... I only know a friend of mine to whom it is working really well. But, judging by its profile I wouldn't be surprised if it worked for many fellows...
 

serg1942

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Hi @Hip, thank you for your message. I didn't know about propentofylline. Is it also an antiinflammatory as pentoxifilline?. Yes, I think there is some evidence on the high glutamatergic synapses in ME/CFS, and I think this is the reason why clonazepam works for some of us, when no benzo works.

Thank you for sharing the link. I'm going to read it. (It is interesting though that pentoxifilie took 2 months to work for my friend).

Take care,

Sergio
 

Learner1

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@serg1942 I am a stage 3 cancer survivor and have spent quite a bit of time in the cancer world in the past 6 years. I have met a number of people who hit various cancers, typically lymphoma or leukemia, from being in immunosuppressive drugs.

I think you are very wise to be concerned about the effects of pentoxyfilline. Many cancer treatments rely on NK cells functioning to work, so anything that diminishes their function could be scary - in fact, my low NK cell function has been a worry in case I experience a recurrence.

It might be prudent to dig through the various effects it has on the immune system, and maybe get tested for the problems that pentoxyfilline seems to solve, and then figure out what's driving those - hidden infections, some sort of toxicity (myctoxins?) or more likely, some sort of autoimmunity and then treat those.

I know I've gotten a long way with antivirals, antibiotics, LDN, IVIG and Rituximab to unwind the several serious problems we identified and ME/CFS that I developed as a result of my cancer treatment.

If you use pentoxyfilline without any more in depth investigation, I'm not sure you'd know what caused the problems in the first place and there may be unexpected side effects or unwanted other problems that develop, like cancer or sepsis, another common problem with immunosuppressants.

Best wishes....
 

Hip

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I would think that unless you have an active cancer, the concern over reduced NK function from pentoxifylline should not be an issue in a short term test, to see whether this drug might improve your ME/CFS.

If pentoxifylline did substantially improve ME/CFS, and you thus wanted to take it indefinitely as an ME/CFS treatment, that's when further investigation into the consequences of reduced NK function might be warranted.

ME/CFS patients have reduced NK functioning anyway, and there's no evidence to suggest this leads to a greater incidence of cancers in the ME/CFS patient population.

In any case, there are a number of drugs and supplement which can boost NK function, so these might be taken alongside pentoxifylline to counter the NK suppression. For example, the supplement MGN3 Biobran increases NK activity by 300%.


Interestingly enough, "pentoxifylline has been found to sensitize some cancer cell lines to chemo- and radiotherapy". Ref: here.

And this study gave pentoxifylline 400 mg three times daily for 12 months to breast cancer patients after radiotherapy treatment, and the study concluded " the combination of pentoxifylline and vitamin E was safe and may be used for the prevention of some radiation-induced side-effects".
 

leokitten

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There are many papers that show the potential anticancer sensitizing effects of pentoxifylline when combined with other cancer therapies.
 

Learner1

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