Pentoxifylline, dexamethasone and azithromycin demonstrate synergistic inhibition of TLR- and inflammasome

pattismith

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Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro (plos.org)


Esther M Speer 1, David J Dowling 2 3, Jianjin Xu 4, Lukasz S Ozog 1, Jaime A Mathew 1, Avinash Chander 1, Donglei Yin 4, Ofer Levy

2018

Whole newborn and adult blood was treated with PTX (50–200 μM), DEX (10−10–10−7 M), or AZI (2.5–20 μM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewe's additivity.

Results

PTX, DEX and AZI inhibited TLR- and/or inflammasome-mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation.

PTX preferentially inhibited pro-inflammatory cytokines especially TNF.

DEX inhibited IL-10 in newborn, and TNF, IL-1β, IL-6 and interferon-α in newborn and adult blood.

AZI inhibited R848-induced TNF, IL-1β, IL-6 and IL-10, and LPS-induced IL-1β and IL-10.

(PTX+DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1β, and IL-6, and R848-induced IL-1β and interferon-α,

while (PTX+AZI) synergistically decreased induction of TNF, IL-1β, and IL-6.

Synergistic inhibition of TNF production by (PTX+DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA.
 

pattismith

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Dexamethasone also inhibited interferon-α - not a positive endpoint, is it?
All the immuno-modulators have both anti-inflammatory properties and immunodepression activities/

IL-10 inhibition may not be desirable either!

For all these reason, and because I can't tolerate most of these drugs, I plan to take a combination of them at very low dose in a synergistic angle.

Naloxone TLR4 inhibitor (or PEA or ketotifen, depend on the one I can tolerate)
Azythromycin TLR2 inhibitor
methylprednisolone, (cortico downregulate TLR)
Propentoffylline (TNF alpha inhibitor)

I wish to add TLR7/9 inhibitor also


Azithromycin Suppresses Pro-Inflammatory Mediators Stimulated by a TLR2 Ligand Zymosan in Human Corneal Epithelial Cells | IOVS | ARVO Journals
 

uglevod

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Yeah, but zith is dose dependent until you overdo, it mainly resides in macrophages without much influence over TLRs.

most of the drugs are TLR inhibitors, including vitamins, etc

quercetin:
https://pubmed.ncbi.nlm.nih.gov/27665434/

vitamin a:
https://pubmed.ncbi.nlm.nih.gov/23086657/

vitamin d:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713222/

coffee:
https://www.ncbi.nlm.nih.gov/pubmed/24457123

metformin:
https://www.ncbi.nlm.nih.gov/pubmed/28791487

cannabinoids:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997072/

melatonin:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094586/

lactoferrin(as an endotoxin binder):
https://pubmed.ncbi.nlm.nih.gov/15251114/

lycopene:
https://pubmed.ncbi.nlm.nih.gov/28076559/

polyphenols:
https://www.frontiersin.org/articles/10.3389/fimmu.2019.01000/full
 
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uglevod

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I wish to add TLR7/9 inhibitor also
well, that could be dangerous, since you'd be losing resistance towards many infections including covid

https://www.frontiersin.org/articles/10.3389/fphar.2020.601685/full

https://www.news-medical.net/news/2...rove-RBD-based-COVID-19-vaccine-efficacy.aspx

Toll-Like Receptors in Antiviral Innate Immunity:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943763/

Furthermore, initiating antiviral immune responses with TLR3 agonists has been shown to provide protection from many different viruses including hepatitis B virus, influenza virus, certain human immunodeficiency virus (HIV) strains, and coronaviruses...
...
Of the TLRs characterized to date, several have been linked to antiviral immunity. Among these, TLR3, TLR7, TLR8, and TLR9 detect distinct forms of viral nucleic acids and are critical in the recognition of viral genetic materials in endolysosomal compartments and initiate antiviral responses. TLR2 and TLR4 are two additional TLR family members that have been implicated in the recognition of viral structural and nonstructural proteins leading to inflammatory cytokine production [20], [21], [22], [23]. There is also evidence that TLR13 may recognize viral infection such as that by vesicular stomatitis virus (VSV), although the exact PAMP sensed by TLR13 in this case remains unknown [24]. In this review, we summarize recent advances in the roles of TLRs and their pathways in innate antiviral immunity. We discuss examples of TLR-mediated viral recognition and describe strategies evolved by viruses to circumvent host antiviral innate immune responses triggered by TLRs.
...
In response to invading pathogens such as viruses, a powerful antiviral innate immune system is rapidly activated in the host. TLRs are important constituents of this system and recognize a wide variety of PAMPs that are conserved molecular signatures of bacteria and viruses. Of the TLRs that have been identified, six represent a subclass that recognizes viral ligands. TLRs are predominately expressed in immune cells but also found in a variety of cell types. TLR3, TLR7/TLR8, and TLR9 are intracellular receptors located in endosomal compartments in which they detect viral dsRNA, ssRNA, and unmethylated CpG DNA, respectively. TLR2 and TLR4 reside on the cell surface and are stimulated by viral glycoproteins and, in some cases, nonstructural proteins released to extracellular milieu. The signaling mechanisms leading to the induction of antiviral innate immune responses are dependent on the particular TLR activated, its stimulus, and cell type. Through MyD88-dependent and/or TRIF-dependent pathways, TLRs elicit the production of proinflammatory cytokines and/or type I and type III IFNs via activation of the essential transcription factors NF-κB and IRF family members, tailoring the innate immune responses and shaping the subsequent, antigen-specific adaptive immunity. These immune responses often contribute to viral clearance and disease resolution but sometimes can be harmful to the host. In the past decade and a half, much has been learned concerning TLR structures, ligand recognition, signaling mechanisms, and viral countermeasures of TLR signaling, but our knowledge of the precise roles TLRs play in antiviral immunity and viral disease pathogenesis in vivo falls short. Clearly, progresses in these areas using animal infection models that recapitulate viral diseases in humans are urgently needed and will unequivocally help develop novel therapeutic and preventive approaches against viral infections.
 

nerd

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TLR inhibition from a macro perspective isn't necessarily bad. It depends which metabolites of the TLR pathways are modulated. But IFN-alpha, I think, is one of the metabolites which might not be worth messing around. It's always wise to check antiviral and antibiotic potential as well. You might find drugs that downregulate a TLR but have antiviral or antibiotic efficacy at the same time, because they don't regulate TLR directly but one of the metabolites that are dysregulated by the pathogen.

TLR2/4 pathways are different stories because they are very likely dysregulated already. So it's more like a lottery.
 

pattismith

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@uglevod, thank you for the suggestions, it may be very useful to me if I failed with others.

I plan to take only low dose of TLR9 inhibitors (maybe hydroxychloroquine), I'm not able to tolerate full dose of any drug or supplement anyway, except methylphenidate that I started some months ago.

So far I am on ultra low dose Naltrexone for 8 days (I switched for naloxone just because it's easier to dose),

and I notice all my skin acne (face and scalp) is suddenly gone!!:)

It means to me that TLR4 is highly involved in my skin problems.

Azitromycin (TLR2 inhibitor and TNF alpha inhibitor) has already helped me with spine pain so I added low dose yesterday, together with low dose propentoffylline (12.5 mg twice a day), and methylprednisolone 4 mg morning (MP has already helped me with muscle pain and enthesitis).

I keep Methylphenidate, (otherwise I can't tolerate the hyperalgesia and headache induced by naloxone), and .... so far, I haven't feel so well for months.

This afternoon, I was able to clean a room, I am just puzzled by the result, I hope I am on something.:woot: