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Orexin/hypocretin Agonists?


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#1 ironhands

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Posted 14 August 2013 - 11:09 AM

I was curious if anyone knew anything about these.  I'd read that some are/were being developed.  Having a very low REM latency, depression, and an insanely high appetite, I would certainly think my hypocretin is low.  How long until these hti the market? :)



#2 Ferret

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Posted 15 August 2013 - 10:31 AM

I don't get it. It is my understanding that Narcoleptics do not have any of the neurons that produce orexin/hypocretin because they have all been destroyed in an auto-immune process. What's the point of having an orexin/hypocretin agonist is there's none of those neurons left for it to act on?

#3 sk8aplexy

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Posted 15 August 2013 - 10:48 AM

Last year I attended a 'group discussion' with Stanfords Director, I will attempt to describe, more or less, some of what he discussed.

He talked about how they'd injected orexin/hypocretin into the brains of mice, directly.  It worked great and symptoms were gone, but it only lasted a brief time, before the orexin/hypocretin ran out and symptoms promptly returned.  He followed that up by, there is still no sure way to pass directly the blood-brain barrier in humans and to inject something directly into the brain is too risky, especially if it doesn't last or has to be done repetitively.  Following up with, it's a matter of figuring out how to pass safely, the blood-brain barrier, so that one could regularly re-up their orexin/hypocretin level/s and remain symptom free, without having shots directly to the brain...

He mentioned also, that he wasn't so interested in stem cells, but that perhaps someday down the road (mentioning, like 20 years), they will perhaps find/create some option(?).

The main focus they were working on though, was trying to figure out the T-cell/s mutation/s in blood samples, to perhaps come up with an alternative testing method, over or along with the spinal tap orexin/hypocretin level/s test..



#4 Ferret

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Posted 15 August 2013 - 01:10 PM

Thanks Sk8aplexy...that makes more sense

#5 DeathRabbit

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Posted 15 August 2013 - 02:36 PM

Well there's that nasal spray they have that works as an Orexin antagonist. And they were supposed to be working on a spray agonist. But then, nothing.



#6 sk8aplexy

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Posted 15 August 2013 - 04:27 PM

The spray, I believe, was briefly mentioned in the talk around when he mentioned the blood brain barrier needing to be better penetrate-able. 

Something was said like, that it was not as effective, in the same manner as the direct shot into the brain...

As was said, there's not enough current interest in the market for it to be produced widespread, for Narcolepsy at least; again, this was last year, prior to many articles discussing hypocretin as the 'depression' neurotransmitter, or whatever...



#7 DeathRabbit

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Posted 15 August 2013 - 10:14 PM

Are people really trying to assert that orexin causes depression? Well gee, us Narcoleptics should be a *BEEP*ing bubbly bunch then lol.



#8 sk8aplexy

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Posted 15 August 2013 - 10:34 PM

Maybe not the cause, but some relation.  These are a few articles, of what, I was referring to:

http://www.ncbi.nlm....pubmed/23398442

http://newsroom.ucla...ess-244002.aspx

http://thebolus.org/...d-mood-changes/

http://well.blogs.ny...happiness/?_r=0



#9 ironhands

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Posted 16 August 2013 - 09:45 AM

Are people really trying to assert that orexin causes depression? Well gee, us Narcoleptics should be a *BEEP*ing bubbly bunch then lol.

 

The lack of orexin, similar to the lack of serotonin, not that having orexin causes it. 

 

Low orexin is associated with depression, appetite, and narcolepsy. from what I've read so far.

 

The only way it'll ever be pushed as an economically viable treatment for N is if they can also push it as a new type of general anti-depressant.  That's unfortunate for me, since I've had no luck with most SSRIs for my depression, and they only make me even more tired during the day.  My worst daytime sleepiness was on citalopram, even with ritalin I literally fell asleep at my desk daily. 

 

Going to discuss everything with my sleep doc on Tuesday and hopefully get some answers, though I expect he'll just push me off to a neurologist.  Hoping I can at least get some stims from him, my GP says I'm tired because my B12 is low.   Yeah doc, that makes sense, I eat a 4000 calorie meal at 6, and go to bed at 8, wake up 12 hours later exhausted.  Waking up every 10-20 mins from dreaming the past few days.  Fun stuff.



#10 DeathRabbit

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Posted 16 August 2013 - 09:57 AM

Oh okay, I see. From that previous post, I thought they were saying having too much orexin causes depression.



#11 ironhands

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Posted 16 August 2013 - 10:11 AM

Sadly, no, it's the opposite.  Unfortunately it's impossible to check those levels without a spinal tap, and with the blood/brain barrier it can't be taken as a supplement, so, unless they can do some sort of re-uptake inhibitor or something, not a lot of options. 

 

It might be great for general depression though as well, especially when obesity is an issue. 

 

Is a spinal tap commonly done with suspected narcolepsy?  I really don't wanna have one done, that freaks me out.  I'd rather do an MLST even though I know I'll likely punch someone :P



#12 DeathRabbit

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Posted 16 August 2013 - 10:33 AM

It's not common. MSLT is the usual criterion. Spinal tap and the genetic testing are usually done at the behest of patients that want absolutely definitive proof. Doctor's don't like spinal taps because of the liability, as there's always a small chance of infectious or chemical meningitis.



#13 DeathRabbit

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Posted 16 August 2013 - 10:36 AM

Well if they have an antagonist developed that can go around the BBB, it shouldn't be a complex matter of finding an agonist that will do the same. It's just a matter of finding a chemical that can make it through BBB and have significant orexin receptor affinity.



#14 ironhands

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Posted 16 August 2013 - 10:45 AM

That's a relief.  I was dreading that.  In my case I don't think there's a point to ordering an MSLT since my epworth score is low, but then again, I don't really trust that as an effective diagnostic tool.  I *could* nap, but I can keep myself awake most of the time at work.  A lot of questions about cars - I haven't been in a car in a year, and only taken a bus once, I bike or walk. 

 

Though, I would happily volunteer a lumbar puncture if it were part of clinical trials or research, if it'll result in finding effective treatment.



#15 sk8aplexy

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Posted 16 August 2013 - 10:56 AM

DeathRabbit, I believe that's it, the nasal spray is getting closer to the BBB, but still not quite as effective as a direct shot.

 

ironhands, spinal taps I think tend to be an option of persons who experience Cataplexy, as it is most often found to be low or close to nonexistent in persons with Cataplexy (that may be clear cut, more severe, Cataplexy?)...



#16 ironhands

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Posted 16 August 2013 - 11:10 AM

My tested latency was pretty high during my regular sleep study, 40 minutes, but I'm not sure when they started timing it from.  I was laying with my eyes closed for 30 minutes while they tried to fix eh wire harness, so maybe they though I was asleep and backtracked it.  It was really tough to fall asleep at that place, new environment, and having to sleep on my back which I'm not used to, same with a 2 hour wake time in the middle when they came back to fix the harness SIX times in 30 minutes, and someone snoring through the wall next door.  I really don't think I got a proper sleep latency score as a result, however, the SOREM was 6 minutes, repeatedly, and the REM sleep was very very brief.  I only entered REM sleep for one 15 minute chunk, which then bounced down to N2 and back to REM every 2 minutes over a 20 minute period.  Only about 12 minutes of SWS too.  It looks really strange compared to a "normal" hypnogram.

 

No cataplexy for me, at all, so I really don't know what to make of it yet, other than something is going on.  Only reason I'm assuming N at this point is the low SOREM, and suspected orexin deficiency because of the depression and massive appetite.



#17 IdiopathicHypersomniac

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Posted 16 August 2013 - 07:47 PM

www.orexinal.com



#18 Ferret

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Posted 16 August 2013 - 08:44 PM

Wow...that stuff is expensive.



#19 IdiopathicHypersomniac

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Posted 16 August 2013 - 11:11 PM

Not as much as Xyrem!  Xyrem is paying thousands of dollars each month to flirt with death.  It costs $500 per bottle up here in Canada.  How many bottles are needed in a month in case I have to go that route?



#20 Ferret

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Posted 17 August 2013 - 07:36 AM

Sorry don't know the answer to that but Hank might...where is he anyway?
As a Canadian living in Mexico, my Canadian health care is void. I'm taking a half of a 200 mg. tab of Provigil daily. In Mexico, Provigil is called Modiodal and a prescription is NOT required. 14x200 mg. costs 543 pesos...at 12 pesos to the Canadian dollar, I'm covered for a month for around $45.00....I'm not complaining.
I'm interested to know what it would cost in the U.S. or Canada?
What a conundrum!...need a full time job to have insurance that pay for your meds so you can function? If that doesn't add to the stress of having N, I don't know what would.
P.S. I don't remember prescriptions being covered in Canada until you are 65.