Ive went through the follica patent a good deal in the past few months.
Experiment 7, whereby hair follicle “placodes” were noticed in HUMAN skin grafted onto SCID mice has been the experiment (or example) that Ive focused on.
In humans, skin-re-epilithialization usually happens faster than it does in mice. For what reason I dont know, but I even found one study showing cold dressings following wounding got one subset of human skin to fully re-epilithialize by day 4.6 on average. Ive seen it be described as 7.9 days on average.
Then again Ive seen it average 10-12 days with other types of wounding using various laser and whatnot.
So I personally only used things that would have inhibited wnt for the first three days after wounding myself for fear of the risk of inhibiting it for too long. I have a bad feeling I screwed up my own experiment as I feel I re-epilithialized way too slowly this time, and frankly ran out of cyclosporin too soon. I also got my head wet on day 8.5, at a very crucial time.
To make this work for someone, I wanted to use the exact things follica used in the patent that are known to work in vivo in human beings running no risk of using any “anti-infective, ointment, or dressing normally administered to a wound” that is talked about in the patent. I figure soap is an anti-infective. This is the patent verbiage that left this impression upon me:
"Optionally, the skin, following the epidermal disruption, is not contacted for a period of time with any substance (e.g., ointment, a bandage, or a device) that is normally administered to an abrasion or wound to prevent infection.
Here the skin is not contacted with any substance until, for example, the ■ •■ - epidermal disruption -has healed (e.g., any time between 2 days and 3 weeks). Alternatively, the skin can be contacted with a cast or bandage (e.g., resulting in increased blood flow to the disrupted skin or decreased transdermal water loss or decreased mass transfer of gases into the skin and from the skin (e.g. oxygen, carbon dioxide, water vapor), decreased heat transfer from the skin (e.g. resulting in an increased temperature of the skin surface) or increased pressure on the skin.
Prior to disruption, the skin can depilated or epilated. The depilation or epilation can be accomplished through, for example, waxing, plucking, an abrasive material, a laser, electrolosis, a mechanical device, or thioglycolic acid.
The disruption of the epidermis can be induced between 3-12 days (e.g., 4-12, 5-12, 4-11, 6-11, 6-10, 6-9, 7-8, 5-11, 5-10, or 7-10 days) prior to the addition of the compositions of the invention."
TO make a long story short, every incidence of new growth associated with human skin was either on a SCID mouse (no immune system) or humans who had been in extensive chemotherapy (decimated immune status). The mice in experiment 7 didn’t even have egf-inhibitors used on them, injected in them, or placed in their chow. They simply were abraded and allowed to heal with human skin on their backs. EGF-antagonism merely made “more” hair with the little creatures. This is why I think (and wish I was wrong about it) that immunosuppression may be the key for the whole thing to work. I probably didn’t have enough cyclo myself anyway to be honest, as Im going to “guess” that one will need about 4-500 mgs of cyclo a day to get immunity compromised enough for t-cells not to use cytokines and all the other weapons at their disposal to inflame the wound sites. Harlodo once posted a study that showed in neo-natal mice, no new hair forms if inflammation is present. They get born hairless. The immune system inflames wounds, thats part of what it does, so that the inflammation and heat kill would-be invaders until the wound heals. I think we probably have to “scotch” it. As Ive said earlier, I’d like to be wrong about that, but five different immunosuppressants are mentioned as “adjuvants” in the patent. One is internal cyclosporin. They are discussed at some length. Why would follica even bother?
Here is the patent verbaige on immunosuppressants (note how much longer this entry is than the entry for potassium channel openers, retinoids, anti-histamines, anti-androgens, etc.:
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.
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 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.