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BH4 and the Genetics of ME/CFS

nandixon

Senior Member
Messages
1,092
I'm going to try to make a post later today, probably on @Mimi's other thread (http://forums.phoenixrising.me/index.php?threads/bh4-gch1-question.35140/), showing the major and minor alleles for all 38* SNPs that 23andMe gives data for on the GCH1 gene, and how to research them. (It'll be at least several hours before I can do this, and possibly tomorrow.)

*The newest testing platform may have fewer than 38.

Edit: I made the post here:
http://forums.phoenixrising.me/index.php?threads/bh4-gch1-question.35140/#post-550201
 
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Mimi

Senior Member
Messages
203
Location
Medford, OR
Hi kell88 - I sent you a message. Look in your Inbox and you should find it.

@nandixon - thanks for the link to the MTHFR study. I don't know if you noticed this, but in the end, they determined that MTHFR was a weak peroxynitrite scavenger, but it was highly effective at lowering peroxynitrite because it boosted BH4.

the peroxynitrite scavengers i've seen mentioned most often are vitamin C (which also recharges BH4), gamma tocopheral e and glutathione. inosine was mentioned in a parkinson's study as being very effective, and it's also supposed to be an immune modulator. idebenone is supposed to be 30-100x more powerful than vitamin E (alpha tocopherols) and i'm a big fan of idebenone personally because it brought back my memory.

i am thinking that a BH4 study should include Kuvan and L-5MTHF plus at least one antioxidant. vitamin c is cheapest but my vote would probably go to idebenone for best effect. or maybe s-acetyl glutathione.
 

Mimi

Senior Member
Messages
203
Location
Medford, OR
forgot to mention agmatine. body builders take it for a huge NO boost since it's more bioavailable than arginine. it's decarboxylated arginine, which is one step closer to NO. my sense is that combining agmatine with BH4 could be a real kick in the pants. moreover, agmatine is supposed to be a great antidepressant, as well as a strong analgesic, an LH and GH booster and a few other cool things. it's an interesting profile, and it's cheap - $10.99 on SmartPowders.com.

if i get good results i'll post them here. if i get great results, i'll start a new thread and post the link.
 

nandixon

Senior Member
Messages
1,092
@nandixon - thanks for the link to the MTHFR study. I don't know if you noticed this, but in the end, they determined that MTHFR was a weak peroxynitrite scavenger, but it was highly effective at lowering peroxynitrite because it boosted BH4.
They were saying it's a weak superoxide scavenger.
 
Messages
1
Hi,
Please excuse my shaky genetics knowledge, but I wanted to ask anyone who could chime in-- I know from Promeathease that I have the "double CAT" mutations. I have severe cfs and am planning to make an appointment with the genetic center at the nearby Cleveland Clinic. I'm not sure if it will be worth while and if I will be taken seriously... If they'll test my BH4 levels or not. Has anyone worked with a Dr. on this issue? Nevertheless, in the meantime I'm considering trying to supplementation on my own.
 

mariovitali

Senior Member
Messages
1,214
@Mimi

Congrats for the post. Supporting BH4 was a major component of my recovery i believe. Just wanted to ask about another mutation for TH (Tyrosine Hydroxylase) Gene aka Rs10840491. Promethease tells me i am (A;G). I also have the GCH-1 Mutation (One Copy) and Homozygous MTHFR Mutation (C677T).
 

Mimi

Senior Member
Messages
203
Location
Medford, OR
Hi mariovitali,

So glad to hear of your recovery! Yay!! Glad to hear supporting BH4 was so helpful to you. And thanks for sharing your Regimen. Did you take resveratrol because it's an estrogen receptor stimulator and BH4 synthesis inducer? Also, what brand did you take? How cool that you have the same genetic signature. I feel that these snps are just so critical. But I don't know anything about the tyrosine snp. If it's causing a deficiency, of course that would impact your dopamine and all the NTs that follow. I tried to surf it up but my connection speed is abysmally slow today. But your Regimen just loaded so I see why you took the resveratrol. I wanted to see if you took Longevinex which is made in a vacuum. And wow, TUDCA looks like it's exactly what I need. I think my bile got thick after 8 months on Valcyte. Thanks a lot!!

Mimi
 

Gondwanaland

Senior Member
Messages
5,092
Did you take resveratrol because it's an estrogen receptor stimulator and BH4 synthesis inducer
Ha, no wonder my estrogen levels are undetectable. And perhaps this is why I can't tolerate resveratrol/grape seed extract. Thanks for putting the things this way!
 
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mariovitali

Senior Member
Messages
1,214
Hi @Mimi

I really don't know what happens with Resveratrol (RSV). I feel great when i take it but 3 days later i am not sure. I believe i read that RSV downregulates E2. And low E2 could also affect BH4 in a negative way. However, i also saw PubMed articles stating that RSV boosts BH4...!

Go figure ;-)
 

kel88

Senior Member
Messages
125
*** offtopic if someone will try BH4/Kuvan, i have it for sale. It did nothing for me ... (Its a shame).
But i have to pay my own risk at insurance! I have used 6 tablets of it. The rest i have it at home so if someone is looking for buying it... You can contact me :)
 

JPV

ɹǝqɯǝɯ ɹoıuǝs
Messages
858
However, this BH4 orphan drug status is due to expire in June 2015, ending the exclusivity, so thereafter we can expect the price of BH4 to drop, and the general availability and dosage amounts of BH4 to increase.
It still may be a few more years before we see a generic Kuvan, thanks to convoluted generic drug laws. And even once the generic is approved and tested, the new manufacturers will have a period of exclusivity that keeps prices inflated...
BioMarin faces challenge from generic rare disease treatment

BioMarin Pharmaceutical Inc. is facing a generic challenger to its rare disease drug Kuvan, which since its approval seven years ago has rung up sales of more than $700 million.

The name of the challenger that submitted a patent challenge with the Food and Drug Administration wasn't identified. The so-called Paragraph IV notice allows San Rafael-based BioMarin (NASDAQ: BMRN) 45 days to file a patent infringement complaint against the company, which would stop the Food and Drug Administration from approving the generic until early 2017.

The Hatch-Waxman Act--25 Years Later: Keeping the Pharmaceutical Scales Balanced

Hatch-Waxman established the abbreviated new drug application (ANDA) process that requires generic manufacturers to demonstrate that the generic is “bioequivalent” to an approved brand drug. Additionally, the generic manufacturer must file a certification regarding patents listed in the Orange Book (also known as Approved Drug Products with Therapeutic Equivalence Evaluations). A paragraph IV certification states that the patent is invalid or will not be infringed and begins a process by which that question may be answered by the courts prior to expiration of the patent. Under Hatch-Waxman, FDA approval of an ANDA is automatically stayed for 30 months when a patent owner files a patent infringement lawsuit within 45 days of receiving a paragraph IV notification. During the stay, the FDA is prohibited from approving another ANDA. Additionally, the first ANDA is granted a 180-day exclusivity period, as an incentive whereby the generic company does not have competition from other generic companies and can both establish market share and charge a higher price.

-----

Today, bringing generics to market involves more than copying, and time from initial product selection to market can take between 5 and 7 years, including paragraph IV litigation.
If I read this correctly, it may not be until 2020, or later, before we see an expensive generic version of Kuvan available.
 
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Hip

Senior Member
Messages
17,824
If I read this correctly, it may not be until 2020, or later, before we see an expensive generic version of Kuvan available.

I have not been able to find any clear statements about when BH4 (Kuvan) orphan drug status is due to end.

BH4 was given orphan drug status in 2002. Biomarin and Merck Serono are the only companies that can sell BH4 under this orphan drug marketing exclusivity deal. I understand that in the US, orphan drug market exclusivity is given for 7 years, and in the EU it is given for 10 years.


I read about the FDA giving an extension to BH4's orphan drug marketing exclusivity until June 2015 here:
The FDA action extends KUVAN's market exclusivity to June 2015

So from that statement, I thought that BH4 orphan drug status would end in June 2015, but I can find no clear written indication that this is the case.
 

JPV

ɹǝqɯǝɯ ɹoıuǝs
Messages
858
So from that statement, I thought that BH4 orphan drug status would end in June 2015, but I can find no clear written indication that this is the case.
Yeah but laws such as The Hatch-Waxman Act seem to create some sort of stumbling block in the timeline for competitors to able to make generics versions. Like I said in my original post, it all seems very convoluted and a bit hard to understand.

In addition to what I quoted above, I found a BioMarin press release saying that 2017 may be the earliest date that they expect a generic version to appear on the market...
BioMarin's pipeline success should allow it to turn a profit in 2017.

We think Naglazyme sales could peak at $500 million as patients receive higher doses of drug and live longer, and that U.S. Kuvan sales could approach $300 million prior to the entry of generic competition (which could come as early as 2017).
 

Hip

Senior Member
Messages
17,824
BioMarin press release saying that 2017 may be the earliest date that they expect a generic version to appear on the market

Oh well, so that's another two year's wait for (hopefully) cheaper BH4.

Still, it might be that some small-scale companies like the Swiss lab (Schircks Laboratories) start selling BH4 prescription-free after June 2015.
 

JPV

ɹǝqɯǝɯ ɹoıuǝs
Messages
858
Still, it might be that some small-scale companies like the Swiss lab (Schircks Laboratories) start selling BH4 prescription-free after June 2015.
I hope you're right. It's certainly something on my list of things to try but not at the current prices.

From what I understand, Kuvan is a synthetic form of Tetrahydrobiopterin. I'm not quite sure but it seems that they somehow managed to block other forms of Tetrahydrobiopterin, that have nothing to do with their synthetic version, from distribution. The pharmaceutical industry and governments are so corrupt that it doesn't surprise me to see how laws are set up to stifle competition.
 

Hip

Senior Member
Messages
17,824
I don't think we can necessarily assume it's corrupt or stifles competition, unless you know specifically otherwise. The idea of an orphan drug is a good one:
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease.

In the US and EU it is easier to gain marketing approval for an orphan drug, and there may be other financial incentives, such as extended exclusivity periods, all intended to encourage the development of drugs which might otherwise lack a sufficient profit motive. The assignment of orphan status to a disease and to any drugs developed to treat it, is a matter of public policy in many countries, and has resulted in medical breakthroughs that may not have otherwise been achieved due to the economics of drug research and development.
 
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JPV

ɹǝqɯǝɯ ɹoıuǝs
Messages
858
I don't think you can necessarily assume it's corrupt or to stifle competition, unless you know specifically otherwise. The idea of an orphan drug is a good one:
Maybe I don't fully understand it but Didn't the Orphan Drug Law allow BioMarin to take something that should be an affordable OTC supplement and to turn it into a prescription pharmaceutical costing $40 a tablet? Maybe the idea is a good one but the real world implementation leaves much to be desired...
Corrupting the Common Cure
The FDA's 'orphan drug' efforts are warping the incentives for pharmaceutical research.


I am a big fan of the spirit of the Orphan Drug Act. Unfortunately, it has become corrupted recently, in great part due to the difficulty in obtaining FDA approval and dealing with the agency during the development and review process. Couple that with the mega-premium pricing orphan drugs command, and you see how this strategy leads to great profitability because of the negligible marketing and sales spending required to penetrate most orphan disease claims. Because of the incentives (including seven years of market exclusivity from competitors and exemption from the Affordable Care Act’s branded prescription drug fee), every major pharmaceutical company is pursuing orphan diseases aggressively.