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Immunosuppression verbiage in follica patent


#1

Going to stick this here for reference…
Pimecromilus, Rampycin, tacrolimus are all in cream forms…but I dont know if that is how they’d be delivered. One is used for eczema…

Imm unosuppressants

In certain embodiments, a nonsteroidal immunosuppressant can be used in the compositions, methods, and kits of the invention. Suitable immunosuppressants include cyclosporine, tacrolimus, rapamycin, everolimus, and pimecrolimus.

Cyclosporines

The cyclosporines are fungal metabolites that comprise a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporine A is a hydrophobic cyclic polypeptide consisting of eleven amino acids. It binds and forms a complex with the intracellular receptor cyclophilin. The cyclosporine/cyclophilin complex binds to and inhibits calcineurin, a Ca2± calmodulin-dependent serine-threonine-specifϊc protein phosphatase. Calcineurin mediates signal transduction events required for T-cell activation (reviewed in Schreiber et al., Cell 70:365-368, 1991). Cyclosporines and their functional and structural analogs suppress the T cell-dependent immune response by inhibiting antigen-triggered signal transduction. This inhibition decreases the expression of proinflammatory cytokines, such as IL-2. Many different cyclosporines (e.g., cyclosporine A, B, C, D, E, F, G, H, and I) are produced by fungi. Cyclosporine A is a commercially available under the trade name NEORAL from Novartis. Cyclosporine A structural and functional analogs include cyclosporines having one or more fluorinated amino acids (described, e.g., in U.S. Patent No. 5,227,467); cyclosporines having

modified amino acids (described, e.g., in U.S. Patent Nos. 5,122,511 and 4,798,823); and deuterated cyclosporines, such as ISAtx247 (described in U.S. Patent Application Publication No. 2002/0132763 Al). Additional cyclosporine analogs are described in U.S. Patent Nos. 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporine analogs include, but are not limited to, D-Sar (α-SMe)3 Val2-DH-Cs (209-825), Allo-Thr-2-Cs, Norvaline-2-Cs, D- Ala(3-acetylamino)-8-Cs, Thr-2-Cs, and D-MeSer-3-Cs, D-SeI-(O-CH2CH2- OH)-8-Cs, and D-Ser-8-Cs, which are described in Cruz et al., Antimicrob. Agents Chemother. 44: 143 (2000).

Tacrolimus

Tacrolimus and tacrolimus analogs are described by Tanaka et al. (J. Am. Chem. Soc, 109:5031 (1987)) and in U.S. Patent Nos. 4,894,366, 4,929,611, and 4,956,352. FK506-related compounds, including FR-900520, FR-900523, and FR-900525, are described in U.S. Patent No. 5,254,562; O- aryl, O-alkyl, O-alkenyl, and O-alkynylmacrolides are described in U.S. Patent Nos. 5,250,678, 532,248, 5,693,648; amino O-aryl macrolides are described in U.S. Patent No. 5,262,533; alkylidene macrolides are described in U.S. Patent No. 5,284,840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, and N- alkynylheteroaryl macrolides are described in U.S. Patent No. 5,208,241 ; aminomacrolides and derivatives thereof are described in U.S. Patent No. 5,208,228; fluoromacrolides are described in U.S. Patent No. 5,189,042; amino O-alkyl, O-alkenyl, and O-alkynylmacrolides are described in U.S. Patent No. 5,162,334; and halomacrolides are described in U.S. Patent No. 5,143,918. Tacrolimus is extensively metabolized by the mixed-function oxidase system, in particular, by the cytochrome P-450 system. The primary mechanism of metabolism is demethylation and hydroxylation. While various tacrolimus metabolites are likely to exhibit immunosuppressive biological

activity, the 13-demethyl metabolite is reported to have the same activity as tacrolimus.

Pimecrolimns Pimecrolimus is the 33-epi-chloro derivative of the macrolactam ascomyin. Pimecrolimus structural and functional analogs are described in U.S. Patent No. 6,384,073.

Rapamycin Rapamycin structural and functional analogs include mono- and diacylated rapamycin derivatives (U.S. Patent No. 4,316,885); rapamycin water-soluble prodrugs (U.S. Patent No. 4,650,803); carboxylic acid esters (PCT Publication No. WO 92/05179); carbamates (U.S. Patent No. 5,118,678); amide esters (U.S. Patent No. 5,118,678); biotin esters (U.S. Patent No. 5,504,091); fluorinated esters (U.S. Patent No. 5,100,883); acetals (U.S. Patent No. 5,151,413); silyl ethers (U.S. Patent No. 5,120,842); bicyclic derivatives (U.S. Patent No. 5,120,725); rapamycin dimers (U.S. Patent No. 5,120,727); O- aryl, O-alkyl, O-alkyenyl and O-alkynyl derivatives (U.S. Patent No. 5,258,389); and deuterated rapamycin (U.S. Patent No. 6,503,921). Additional rapamycin analogs are described in U.S. Patent Nos. 5,202,332 and 5,169,851.


#2

Hair growth-stimulating effects of cyclosporin A and FK506, potent immunosuppressants.

Tacrolimus = FK-506


#3

» Hair growth-stimulating effects of cyclosporin A and FK506, potent
» immunosuppressants.
»
» http://www.ncbi.nlm.nih.gov/pubmed/7528050
»
» Tacrolimus = FK-506

But … Tacrolimus & Hair Loss

http://66.102.9.104/search?q=cache:T9tzoRmO-dcJ:www.transplantbuddies.org/tbx/messages/5/8290.html%3F1176333812+tacrolimus+hair&hl=es&ct=clnk&cd=7&gl=es&client=firefox-a

" … the surgeon who performed my operation confirmed that tacrolimus causes hair loss … "


#4

I still think the focal point is the EGF inhibition but I have a new personal theory about it.

The patent seems to push forward the notion of waiting until epithelization is complete until EGF inhibition is begun. Yet in one part of the patent, it rather furtively mentions EGF inhibition at the same time as the wounding. This is only mentioned once. The rest of the patent centralises on the idea of inhibition AFTER epithelization.
My theory (and it is only a theory) is that it’s deliberate misdirection yet managing to keep their bases covered. It puts the ‘waiting until epithelization is complete’ at centre stage whilst the ‘true’ sequence of operation lurks backstage. Every medical paper that I read on epidermal growth factor stipulated it’s importance DURING epithelization. It basically tells the cells to ‘get your arse in order and make skin’. Why would you inhibit EGF after differentiation is complete?

I submit that the procedure Follica will adopt is to inhibit EGF before or at least at the same time as initiating the wounding. That way, epithelization would take longer in the absence of EGF and the cells have time to differentiate into more complex structures such as the follicles and the pilosebaceous glands.

I view things in terms of engineering and that’s how I see it. I will follow this procedure when I get my damned tannic acid. It was delivered to the wrong address and has been shipped back to Germany.


#5

»
Yet in one part
» of the patent, it rather furtively mentions EGF inhibition at the same time
» as the wounding. This is only mentioned once. The rest of the patent
» centralises on the idea of inhibition AFTER epithelization.
» My theory (and it is only a theory) is that it’s deliberate misdirection
» yet managing to keep their bases covered. It puts the ‘waiting until
» epithelization is complete’ at centre stage whilst the ‘true’ sequence of
» operation lurks backstage. Every medical paper that I read on epidermal
» growth factor stipulated it’s importance DURING epithelization. It
» basically tells the cells to ‘get your arse in order and make skin’. Why
» would you inhibit EGF after differentiation is complete?

I have wondered about this myself Baccy. The patent speaks of “time-released” topicals administered the same time as the wounding. How in the world a topical could be time released to be active exactly three days post wounding is rather perplexing. Thats some advanced chemistry happening if they could make a topical “wait” for three days before “becoming active”. I understand “time-released” medicines exist, but for an indication to just sit there for three days and --THEN-- become active with no absorption whatsoever beforehand sounds really extravagant. Of course I could be wholly wrong about this and it be perfectly logical.

I have considered Baccy, however, that follica KNOWS that there are a lot of bald doctors (and nurses) out there who could get their paws on the correct immunosuppressant CREAM and egf-antagonist. Them wanting to do a little misdirection in this patent or burying their true intended procedure in the details makes perfect sense. Everything in the patent is obtainable to the right people-----and dermabrasion can be done with sandpaper.
»
».
»
» .


#6

I’m also ready to buy the idea that the entire EGF-R waiting period was a red herring. Makes more sense, explains why we’re having trouble making their patents work at home so far, and it fits the Gentifib regrowth patient’s story better than anything else.

So . . .

Let’s talk immunosuppressants, shall we?
What are we gonna do about getting something to try at home for this?


#7

»
» Let’s talk immunosuppressants, shall we?
» What are we gonna do about getting something to try at home for this?

Maybe the only immune response we are concerned with is inflammation. If that is the case, there are any number of safe topical treatments to treat any inflammatory response. I’m also considering using benadryl cream as the anti-histamine. This has diphenhydramine and zinc oxide in it.

Looking over a version of the patent, diphenhydramine is actually mentioned in the anti-histamine section.


#8

»
»
» So . . .
»
» Let’s talk immunosuppressants, shall we?
» What are we gonna do about getting something to try at home for this?
I sent you a email at HLT at your pm account there about where you could obtain this…dont print it here though as I dont want that website shut down.


#9

Thanks a lot, Benji. I’ll take a look at it later tonight.

Baccy, you might be onto something about the inflammation response only. Folica slapped patents on a lot of scenarios with a lot of inflammation-fighting substances included in the deal.

. . . Or this might be another red herring (like the waiting period on the EGF-R inhibition probably is), for all we know.

It might be done for the purpose of getting all the competitors & home experimenters trying another batch of non-working scenarios for several months. These inflammation drugs are an easy & low-risk thing to get and try, so it would be particularly tempting for us to wear ourselves out trying them all.

Whatever it is, we just gotta keep systematically trying these patents until we hit something. There aren’t THAT many variations of the really meaningful factors.