Probenecid, any pharmacists answer my question?

[heapsreal]

Probenecid increases the blood levels and half lives of many drugs.
What i want to know is more specifically by how much??

What im wanting to know is more about famvir, how much longer does it increase the half life and is there some way of knowing what dose of a combo of probenecid/famvir is compared to just famvir, eg probenecid and 250mg famvir equal to 500mg famvir alone?

This combo can make antivirals more economical.

I had a month or maybe a bit longer off antivirals before viral symptoms returned. For 2 days i used 500mg twice a day and one of those doses was with probenecid. This seemed to help alot and stopped the rot in its tracks. Then i went back on my normal dose of 250mg twice a day, this doesnt seem to be cutting of late, probably need 500mg twice a day which costs $200 a month at this dose.

I have 2 theories on possible dosing schedules i will talk over with my doc. One is the 250mg twice a day with probenecid on one of those doses or maybe both. The other is just 1x 500mg dose of famvir with probenecid.

The second schedule i would prefer as i think the 500mg dose will have a higher blood level but it depends on how much probenecid increases half life. If its only a couple of hours it may not be worth it, if its 8hrs then i think it would work well.

Currently the half life is only 2-3hrs and i have read the intracellular half life is 16hrs? not sure what the difference is really?? But dosing compared to other avs seems less often with famvir.

Just thought of another question, how would probenecid work with immunovir, as they would seem to counteract one another. Probenecid lowers uric acid and immunovir can increase uric acid, i wonder if this effects the immune stimulating effects of immunovir????

cheers!!

 

[pattismith]

Probenecid is getting some attention to fight covid:


1 Probenecid Inhibits SARS-CoV-2 Replication In Vivo and In Vitro | bioRxiv

2 Consideration of Pannexin 1 channels in COVID-19 pathology and treatment | American Journal of Physiology-Lung Cellular and Molecular Physiology

3 The potential involvement of P2X7 receptor in COVID‐19 pathogenesis: A new therapeutic target? - Pacheco - 2021 - Scandinavian Journal of Immunology - Wiley Online Library

1

Abstract...
We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.

2


REPURPOSED FDA-APPROVED DRUGS THAT BLOCK PANX1 FOR COVID-19 TREATMENT?

Probenecid (commercially known as Probalan, Benemid, or Benuryl) is an FDA-approved treatment for gout that is also a well-established PANX1 inhibitor (61). Influenza A viral infection and lung viral load were attenuated following probenecid treatment both in vitro and in vivo (43). Probenecid also decreased inflammasome-dependent IL-1β secretion from macrophages in vitro (15), reduced the inflammatory response in sepsis (55), and suppressed hyperinflammation resulting from severe influenza A infection in mice (48). Additionally, probenecid treatment lowered the required dose of another antiviral medication, oseltamivir (43), likely due to probenecid’s ability to increase plasma levels of the antiviral drug (47). Note that probenecid also inhibits P2X7 receptors (3), which is also likely to contribute to the antiviral and anti-inflammatory activity. Probenecid has also been shown to have a protective effect in ischemia/reperfusion injury by inhibiting secretion of the lysosomal cathepsin proteases (60).

3

....., we believe that the P2X7/NLRP3 inflammasome pathway offers a possibility for therapeutic intervention, reducing or preventing severe lung pathology. Evidently, it would be necessary further basic and clinical studies to verify the effectiveness of this type of intervention in the outcome of SARS-CoV-2 infection.

Once this hypothesis has been confirmed, some pharmacological tools currently available could assist in the treatment of COVID-19 patients, in order to control the progress of the inflammatory response, avoiding excessive tissue damage and allowing the appropriate restoration of pulmonary homeostasis.

Two examples are the inhibitors AZ11645373 and probenecid that already have been shown beneficial effects in experimental models of ARDS induced by pandemic Influenza H1N1.39 Regarding to clinical usage of these drugs, probenecid is already being evaluated in clinical trials (phase I) about toxicity (NCT01428284, NCT03296800, NCT01937026) and pharmacokinetics (NCT03138759, NCT00000706).

Another probable advantage of using P2X7R inhibitors for COVID-19 treatment is modulation of CD147 expression. This glycoprotein was recently identified as a second receptor for SARS-CoV-2 invasion on host cells, becoming a new molecular target.86, 87 Pretreatment with A-438079, a P2X7R antagonist, reduced CD147 and MMP9 expression in phorbol 12‑myristate 13‑acetate (PMA)‑induced macrophages through 5'-AMP-activated protein kinase (AMPK) and MAPK signalling.88