Im getting off getfitinib------SIDE EFFECTS

Stem cell; cell based hair therapy
41

.
»
» Since the window opens after re-epithelialization, and since the juicy
» part of the window is very short, one area that we need to focus on (in
» terms of home experimentation) is recognizing the point of
» re-epithelialization in a wound.

Then I ought to have hair beginning to grow all over the place, because I had the ultimate shiny layer of keratinocytes covering my hairline and temples while on getfitinib. I have detected absolutely no new growth though. I got on it 3 days post wounding and stayed on it until 9 days post wounding. I would think I’d have hair all over the place. When I tried minox (day 4 post wounding), it burned like all hell. I mean badly. I put water on it to cool it off. Perhaps this was the big screw up for me. I still have a feeling that one might find that they shouldn’t put anything on the injured dermis (including chlorinated water) for the first seven-eight days when the follicles are forming.

TAGHOL, when you think about it, when the epidermal stem cells “decide” to make a hair follicle…this is probably the point of almost no return. Unless some blatant chemical disruption takes place, that is probably precisely what they will do from there on until the new hairs are made.

42

Day 11 in mice is about like day 6 in us as the human skin experiment had hair on day 7…So perhaps days 6-10 or so is the important time?

If you think about it, it all depends on your wound and if your wound depth was right. Too deep, and the window will be later, not enough…and you dont induce reepilithialization.

Five Days?

Example 11: Inhibition of EDIHN by epidermal growth factor injection.

21 day-old mice were wounded as described in previous Examples. Starting from day 11 after wounding, a time point corresponding to the point at which the wound had recently re-epithelialized, 10 mL of 1 mg/ml EGF was injected into the wound bed. EGF was injected once per day after this point for a total of 5 days. Three days later, the skin was collected, and whole-mount EDIHN assays were performed. EGF prevented HF formation as assessed by gross morphology . In addition, whole mounts of control and treated skin were analyzed with anti-K17 antibody immunostaining. All mice injected with EGF (n=4) exhibited no new HF formation (Figures 25 A-B), while control mice (n=2) had many new HF, as expected. (Figures 25 C-D).

In an additional experiment, recombinant EGF (1 microgram

(mcg)/microliter (mcl)) was injected at days 11, 13 and 15 after wounding.

Skin was collected at 18 days after wounding and stained for K17 and alkaline phosphotase. Once again, administration of EGF inhibited EDIHN.

The findings of this Example show that EGF inhibits HF formation. Thus, inhibiting EGF, EGFR, or one of the pathways in which they participate increases EDIHN- induced HF formation.

Example 12: Enhancement of EDIHN by inhibition of EGF receptor.

To determine the effect of administration of EGF receptor inhibitors on DIHN, the inhibitor AG1478 (150 μM in 10 μL volume) was administered as a single injection 11 days after incisional wounding (1 cm2) to the middle of the wound near the skin surface. EGF receptor inhibitor administration led to generation of more and larger hair follicles compared with control mice that were wounded only (Figure 26A). As shown in Figure 26B, large hair follicles developed in the wounded area in the AG1478-injected mice. Left panel: epidermis stained for K 17, with three large hair follicles next to each other. Right panel: dermis stained for AP with large coalescing dermal papilla areas.

The findings of this Example confirm the results of the previous Example, and show that more and larger HF can be generated when EDIHN comprises, or is followed by, administration of EGFR inhibitors, or with compounds with a similar mechanism of action; e.g., Hedgehog protein and androgen antagonists

43

Frozen Human Epidermal Allogeneic Cultures Promote Rapid Healing of Facial Dermabrasion Wounds
Héctor Arámbula, MD,* Eduardo Sierra-Martínez, MD,* Nastia Eunice González-Aguirre, MD,* Adrían Rodríguez-Pérez, MD,* Enrique Juarez-Aguilar, PhD, † Meytha Marsch-Moreno, BCE, † and Walid Kuri-Harcuch, PhD † ‡
*Plastic and Reconstructive Surgery Service, Hospital de Traumatología Magdalena de Las Salinas, † Department of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN, and
‡ Unit of Epidermal Technology, Department of Cell Biology, CINVESTAV-IPN, Mexico City, Mexico
Address correspondence and reprint requests to: Walid Kuri-Harcuch, Department of Cell Biology, CINVESTAV-IPN, Apdo. Postal 14-740, Col. San Pedro Zacatenco, Mexico City 07000, Mexico. Email: walid@cell.cinvestav.mx
Copyright 1999 American Society for Dermatologic Surgery
ABSTRACT
Background. Clinical studies have shown that cultured human epidermal allogenic sheets promote faster reepithelization of skin donor sites and deep partial-thickness wounds.

Objective. We describe the results of a controlled, clinical study of facial dermabrasion sites treated with a single application of frozen cultured human allogenic epidermal sheets that were thawed for 5–10 minutes at room temperature before application.

Methods. Ten patients with scars from acne or of other etiology underwent facial dermabrasion. One side of the face was treated with the frozen and thawed cultures, the other side was treated with standard dry dressing.

Results. The epidermal cultures promoted faster reepithelization of the wounds, with complete reepithelization in an average time of 4.6 days, whereas controls healed in an average of 7.9 days. The reduction in healing time was 42% (P = 4.82 × 10−7). Pain was reduced in sites treated with the thawed cultures.

Conclusion. Epidermal allogenic cultures, preserved by freezing, promoted significantly faster reepithelization and reduced pain intensity of dermabraded facial wounds, suggesting that they could be used routinely to improve the recovery from dermabrasion.

The follica experiments had hair placodes by day 7 in human skin, so I guess most people will probably be going too deep and delaying the embryonic window. The more I read about this…the more I think that people wont get success “at home” but will have to have this process professionally performed. There are just too many variables we dont know about to be honest. I hope Im wrong about that.

44

»
» I am basing the 7 day window figure on the Nature study. Specifically, a
» WNT inhibitor (Dkk1) was tested in four intervals in mice: days 0-10, days
» 0-17, days 11-14, and days 12-15. With days 0-10 of inhibition only, you get
» a full complement of new hair follicles (97 follicles in this experiment).
» With days 0-17 inhibited, you get zero hair follicles. With days 11-14, you
» get several follicles (3 in the experiment), and days 12-15, you get just a
» couple of follicles (2 in the actual experiment).
»
» What this experiment shows is the following: days 11-17 are clearly where
» all the magic takes place (it’s the embryonic window), and almost all of
» the magic takes place in the first few days of the window.

I am totally confused about the part with days 0-10 of inhibition only, you get a full complement of new hair follicles (97 follicles in this experiment). So the mice had WNT inhibited for days 0-10 and you would start egf-r 3 days post wounding. You inhibit WNT? If you do, then with what? I’m totally confused here. When will WNT be boosted?

45

» The follica experiments had hair placodes by day 7 in human skin, so I
» guess most people will probably be going too deep and delaying the
» embryonic window. The more I read about this…the more I
» think that people wont get success “at home” but will have to have this
» process professionally performed. There are just too many variables we dont
» know about to be honest. I hope Im wrong about that.

I can definitely understand why Follica is starting their human trials with wounding only. You need to get the wounding process down pat before you can do anything else. You need to figure out the proper wound size and depth needed to invoke the window, what to expect when you actually do this on live scalps (this is important, if nothing else, to let patients plan downtime…time off from work, social engagements, etc.), how long it takes to re-epithelialize given the wound technique you’re using, etc. If you don’t hit the window right, forget the drugs and everything else…the procedure is compromised.

46

» »
» »» I am totally confused about the part with days 0-10 of inhibition only,
» you get a full complement of new hair follicles (97 follicles in this
» experiment). So the mice had WNT inhibited for days 0-10 and you would
» start egf-r 3 days post wounding. You inhibit WNT? If you do, then with
» what? I’m totally confused here. When will WNT be boosted?

Human skin and mice skin reepilithialize after abrasion at different rates. It takes about 10 full days for mice skin to reepilihtialize, while human skin can reepilhtialize (if one abrades it just right) in as little as three days.

WNT can be inhibited to produce dark hairs in mice skin before reepilithialization, but not after it. If they inhibit wnt on days 11-17 in mice, they dont get any hair, but if they inhibit wnt on days 1-10 they get a bunch of hair. This shows that the crucial time is days 11-17 in the mice.

In humans, it depends on the persons wound depth and their own personal healing characteristics might move the ‘window’ for a day or so. We can supposedly heal in as little as three days…but it can take a great deal longer if you abrade just a little too deep, so its hard to say. EGF inhibition and all that jazz probably only have to really take place for 2 or 3 days post re-epilithialization. We may find that the inflammation or immuno response might have to be controlled in real people also. Follica doesn’t know yet. I think Follica will work, but they are going to have to formulate topicals that will not interefere with this process, find out if they need an immunosuppressant or increased EDAR signalling, find a means of controlling wound depth to ensure reepilthialization is complete by day x, etc.

47

» Human skin and mice skin reepilithialize after abrasion at different
» rates. It takes about 10 full days for mice skin to reepilihtialize, while
» human skin can reepilhtialize (if one abrades it just right) in as little
» as three days.
»
»
» WNT can be inhibited to produce dark hairs in mice skin before
» reepilithialization, but not after it. If they inhibit wnt on days 11-17 in
» mice, they dont get any hair, but if they inhibit wnt on days 1-10 they get
» a bunch of hair. This shows that the crucial time is days 11-17 in the
» mice.
»

So is the above example just to give us clues of when the embryonic windows open? How does that transpires into humans? Do you think it is necessary to inhibit wnt the first 10 days? At this point I don’t care if the hair is white, I just want to see good growth. What if you don’t inhibit wnt at all? – Increase WNT before and after wounding and up until the point you are done applying the egf-r? Would this contradict anything the patent says.

48

» » The follica experiments had hair placodes by day 7 in human skin, so I
» » guess most people will probably be going too deep and delaying the
» » embryonic window. The more I read about this…the more
» I
» » think that people wont get success “at home” but will have to have this
» » process professionally performed. There are just too many variables we
» dont
» » know about to be honest. I hope Im wrong about that.
»
» I can definitely understand why Follica is starting their human trials
» with wounding only. You need to get the wounding process down pat before
» you can do anything else. You need to figure out the proper wound size and
» depth needed to invoke the window, what to expect when you actually do this
» on live scalps (this is important, if nothing else, to let patients plan
» downtime…time off from work, social engagements, etc.), how long it takes
» to re-epithelialize given the wound technique you’re using, etc. If you
» don’t hit the window right, forget the drugs and everything else…the
» procedure is compromised.

It would be logical for them to start trials using dermabration alone first, but In a recent articel Zohar described the recent trial as “more of an investigator-sponsored trial.”

Then I found the IND Wiki (because we all know how reliable wikipedia is :-P) :
“There are two main categories of IND: Investigator-initiated, and Sponsor-initiated. Investigator-initiated INDs are used when a physician wishes to perform a clinical trial to study an unapproved drug treatment, for example a new indication for an existing drug.”

They can dermabrade all day long, but if they wan’t to legally use a drug that is already approved for something else (even if it is reformulated as a topical) as part of their human trial they will need to be granted IND status from the FDA.
Getting an IND usually involves doing pre-clinical animal studies to show what they will be doing should be relitively safe for humans phase I-III trials, which follica have already done.

I think that if follica indeed do need an IND, they will already have it or be very close to getting it.

49

» It would be logical for them to start trials using dermabration alone
» first, but In a recent articel Zohar described the recent trial as “more of
» an investigator-sponsored trial.”

Follica has already confirmed that the first trial will be abrasion only – no drugs will be used. He’s a direct qoute from Zohar on the purpose of the trial:

“At this point we are looking at the human response to disruption and the timing of the human ‘embryonic window’ post disruption,” she said.

Like I said earlier, you need to get the wounding down pat first. Then, you can start tweaking the wounding process to create hair.

» They can dermabrade all day long, but if they wan’t to legally use a drug
» that is already approved for something else (even if it is reformulated as
» a topical) as part of their human trial they will need to be granted
» IND status from the FDA.

From a pure technical standpoint, they can use approved drugs off-label without FDA approval. Any doctor can. Follica may seek official approval, anyway, just to make sure they are on completely solid ground. But we really don’t know what their exact plans are.

50

» » It would be logical for them to start trials using dermabration alone
» » first, but In a recent articel Zohar described the recent trial as “more
» of
» » an investigator-sponsored trial.”
»
» Follica has already confirmed that the first trial will be abrasion only
» – no drugs will be used. He’s a direct qoute from Zohar on the purpose of
» the trial:
»
» “At this point we are looking at the human response to disruption and the
» timing of the human ‘embryonic window’ post disruption,” she said.
»
» Like I said earlier, you need to get the wounding down pat first. Then,
» you can start tweaking the wounding process to create hair.

Yes I know, I didn’t dispute that.
What I was saying was if they want to move forward after the disruption (and its not nescesarily abrasion) study and use drugs at a later stage, which they inevitably will, they will need an IND .

I even wrote a ‘direct’ quote from zohar in my post where she describes the trial as an investigator-sponsored trial, which is part of the IND process;

“There are two main categories of IND: Investigator-initiated, and Sponsor-initiated. Investigator-initiated INDs are used when a physician wishes to perform a clinical trial to study an unapproved drug treatment, for example a new indication for an existing drug. Sponsor-initiated INDs are filed by pharmaceutical companies studying new drugs or new uses for existing drugs. Both of these types of studies require approval by an institutional review board (IRB), an independent body constituted of medical, scientific, and nonscientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial. The IRB must review, approve, and provide continuing review of the trials, protocols and amendments, and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.”

» » They can dermabrade all day long, but if they wan’t to legally use a
» drug
» » that is already approved for something else (even if it is reformulated
» as
» » a topical) as part of their human trial they will need to be
» granted
» » IND status from the FDA.
»
» From a pure technical standpoint, they can use approved drugs off-label
» without FDA approval. Any doctor can. Follica may seek official approval,
» anyway, just to make sure they are on completely solid ground. But we
» really don’t know what their exact plans are.

Well thats not stricly true, a doctor can prescribe a drug to use off lable but as follica wont be prescribing anything they will be selling a product and it is unlawful to market, advertise or otherwise promote the off-label use of drugs.

Also it is illegal to use a previously approved drug in the USA for a human clinical trial unless they have been previously granted an IND from the FDA based on the results of pre-clinical animal studies.

I think an unlikely loop-hole could be if Dr Cotsarelis tried this at home on himself (not under a clinical trial of any sort) and cracked it first time, he could start prescribing all the drugs or formulation of drugs to people to use at home off label the same day.
Of course he wouldn’t make any money that way and miss out on the millions of dollars he could make if it went through trials and officially sold as a ‘kit’ or whatever.

51

the patent didn’t say anything about inhibiting wnt in humans, but if you were going to do that somewhat (quercetin or things that contain it), you might want to stop about three days post wounding because you dont want to inhibit wnt after post-reepilithialization. I dont know if inhibiting wnt will enhance results or not, but its neat to think that.

52

» the patent didn’t say anything about inhibiting wnt in humans, but if you
» were going to do that somewhat (quercetin or things that contain it), you
» might want to stop about three days post wounding because you dont want to
» inhibit wnt after post-reepilithialization. I dont know if inhibiting wnt
» will enhance results or not, but its neat to think that.

Neat??? I think it just makes it all the complicated, especially with the timing issues.

53

» Well thats not stricly true, a doctor can prescribe a drug
» to use off lable but as follica wont be prescribing anything they will be
» selling a product and it is unlawful to market, advertise or otherwise
» promote the off-label use of drugs.

I’m not going to get into this same old argument. Look in the archives where this topic has been debated to death. Follica doesn’t make EGFR inhibitors, and they won’t be marketing EGFR inibitors for treating hair loss.

54

» » Well thats not stricly true, a doctor can prescribe a drug
» » to use off lable but as follica wont be prescribing anything they will
» be
» » selling a product and it is unlawful to market, advertise or otherwise
» » promote the off-label use of drugs.
»
» I’m not going to get into this same old argument. Look in the archives
» where this topic has been debated to death. Follica doesn’t make EGFR
» inhibitors, and they won’t be marketing EGFR inibitors for treating hair
» loss.

No I never said they will be making an EGFR inhibitor, they will be reformulating an existing one into a topical.
So it is likely they will be selling Gefitnib reformulated into a topical as part of their kit.
Therefore they will be marketing an EGFR inhibitor for hair loss as an EGFR inhibitor will be used in the kit and then will be marketed for regrowing hair.

They can not just say they will use Gefitnib for its original approved use, as its original use was to fight cancer, not as a stand alone EGFr inhibitor.
Drugs gain there approval not for their method of action but for what they will be used to treat, and follical will be using an EGFr inhibitor to grow hair, not fight cancer.

It would be illegal for them to sell gefitnib or whatever reformulated EGFR inhibitor they use off label.
They can not use them off label because, drugs can only be prescribed for off label use not sold.
Also it is illegal to use a previously approved drug for a new use in a human clinical trial without first obtaining an IND.

I think you need to re read what I wrote to gain a better understanding.

I’m not trying to argue with you, I know what I’m saying and I’m very aware of what has previously been discussed thank you.
Just because something has been ‘debated to death’ doesn’t mean the correct conclusion has been drawn and it obviously haven’t if you think follica will not be selling their kit with an EGFR inhibitor used as part of the formulation.

Its irrelevant anyway, we should know straight from the horses mouth pretty soon hopefully, with regards to what need to do.

I can’t be bothered to think about it anymore, they are obviosly pretty certain they will have something soon so ill just get on with waiting patiently, watching the results of the home testers in the mean time.

The people trying this at home could get great results soon, which could render Follica obsolete, then it wouldn’t matter what Follica need to do or not.

Lets keep those fingers crossed. :ok: Good luck all who are trying this them selves.

55

Believe me, there’s a lot of crossed fingers out there right now.

It probably won’t hurt Folica much in the long-run if we do nail this stuff down early.

It’s like downloading free movies. It’s technically possible to do it without waiting or paying. But the majority of the market just wants a reliable, top-quality, convenient, and safe product. Most of them will still wait a little while and pay for the legit way to get it rather than get into the complex & unreliable process of doing it under the table.

Likewise, even if we figure out Folica’s deal years early, it still shouldn’t take any significant bite out of their ultimate business.

56

» Believe me, there’s a lot of crossed fingers out there right now.
»
»
»
» It probably won’t hurt Folica much in the long-run if we do nail this
» stuff down early.
»
»
» It’s like downloading free movies. It’s technically possible to do it
» without waiting or paying. But the majority of the market just wants a
» reliable, top-quality, convenient, and safe product. Most of them will
» still wait a little while and pay for the legit way to get it rather than
» get into the complex & unreliable process of doing it under the table.
»
» Likewise, even if we figure out Folica’s deal years early, it still
» shouldn’t take any significant bite out of their ultimate business.

Good point, I agree.