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The importance of p-glycoprotein inhibition

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Manuone
(@manuone)
Joined: 5 years ago
Posts: 157
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Dear friends,

For a long time I have been thinking about using small doses of some cytotoxic drugs like lomustine but in relatively low doses. The established dose of lomustine is 100 mg / m2, in my mother's case it would be 130 mg every 6 weeks. My idea is to use only 60 mg and to improve this dose I would like to use high doses of DHA as reflected in this article:
https://www.ncbi.nlm.nih.gov/pubmed/25526274
For this I believe that it is essential to try to improve the extrusion of drugs by acting on the glycoprotein. Third generation inhibitors would be the best bet like elacridar and tariquidar but they don't seem accessible. There is some discrepancy with some others that I am not sure if they are inducers, substrates or inhibitors, such as:
azithromycin, tamoxifen, reserpine, quercetin, sertraline, lansoprazole, and atorvastatin (there are many more)
This is a good article where they talk about natural glycoprotein inhibitors: https://www.tandfonline.com/doi/full/10.3109/14756366.2016.1149476
Many natural molecules could fulfill the function of p-glycoprotein inhibitors. I would highlight some that we already know as tetrandin, silymarin, kaempferol, baicalein, cepharanthine, pyrrolidine, glaucine, biocanine, etc.
If tetrandin is used given its low bioavailability, the best option would be intravenous or liposomal.
I think I remember that Daniel commented that tetrandin iv had been used in patients in doses of 150 mg in 500 ml of saline.
Going back to lomustine my idea is to dilute it into empty liposomes. In theory this should improve its absorption and distribution. It is well known that nanoparticles are a way to prevent drug extrusion by the glycoprotein.
Summary:
- A previous pro-oxidant treatment with taurolidine iv, vitamin c iv, salinomycin and 2 Dg metronomic. Combined with some drugs and supplements
- Use an accessible p glycoprotein inhibitor such as tetrandin IV or liposomal, combined with tamoxifen that could improve the modulating effect on p glycoprotein.
- A relatively low dose of lomustine diluted in liposomes that supposedly will also improve its passage through BBB and p-glycoprotein too.
My accesible options  are being reduced to keep the pulse of the brain tumor, but ... I never give up!

kind regards


   
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Daniel
(@daniel)
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Joined: 7 years ago
Posts: 1156
 

Dear friend Manuel,

Regarding liposomes I think you need to be aware of something that is important:

- efficient liposome uptake by the macrophages and their consequent removal from circulation is one of the main disadvantages for possible use of liposomes as drug delivery systems; in other words, liposomas are usually eaten up by macrophages;
- one trick to try overcome the above is saturation of the macrophages with a previous administration of “empty” liposomes 
- the other option is to use PEG-coated liposomes
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2426795/

Ketokonazol is a strong MDR1 inhibitor, but it has some liver toxicity - I would use it on short term only.

Kind regards,
Daniel

 


   
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Manuone
(@manuone)
Joined: 5 years ago
Posts: 157
Topic starter  

@daniel

Thanks Daniel for the reply,
Ketoconazole is quite tough on the liver, although you might consider it in small cycles.
Pedro Gonzalez is "almost" convinced to write about his liposomes. He seems to keep some "professional secret" and makes him suspicious ...
I think I will use tetrandin, liposomes and tamoxifen


   
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Daniel
(@daniel)
Admin
Joined: 7 years ago
Posts: 1156
 

@manuone

HI Manuel,

That is great! He does not have to disclose his manufacturing procedure, but I trust his expertise in liposomal manufacturing and giving us a perspective on that would be great.

This will help us to better understand the liposomal world and will help him with the exposure since this website is also visited by professionals that may find his capabilities useful.

Btw, do you know any supplement on the market that sells empty liposomes?

Kind regards,
Daniel

 

 


   
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Manuone
(@manuone)
Joined: 5 years ago
Posts: 157
Topic starter  

@daniel

Hi Daniel,

If it would be a good article and an opportunity for him to present his work of 40 years dedicated to liposomal technology.
Regarding the empty liposomes I use Pedro's. These empty liposomes will allow me to encapsulate lomustine and tetrandin. Using a mini blender shaking the empty liposomes together the estimated amount of molecule. Some molecules will encapsulate better than others depending on their hydrophilicity and lipophilicity, but it is certain that they will win in bioavailability and will be therapeutically more effective. I am very confident in Pedro's work and this can and should compensate for many difficulties in delivering the encapsulated compound.
Everything would be advantages, greater bioavailability, better distribution, fewer side effects, etc.


   
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