Now for some really GOOD news... a better drug for Narcolepsy on the horizon


May 7, 2014, 7:00 a.m. EDT

Sleep Researchers at SRI International Identify Promising New Treatment for Narcolepsy

New Model May Also Explain How Narcolepsy Develops in Humans

MENLO PARK, Calif., May 7, 2014 /PRNewswire/ -- Neuroscientists at SRI International have found that a form of baclofen, a drug used to treat muscle spasticity, works better at treating narcolepsy than the best drug currently available when tested in mice.

According to the National Institute of Neurological Disorders and Stroke ( NINDS ), narcolepsy, a chronic neurologic disorder characterized by excessive daytime sleepiness, is not a rare condition, but is under-recognized and under-diagnosed. It is estimated to impact 1 in 2,000 people worldwide.

In back-to-back papers published in the May 7 issue of The Journal of Neuroscience, Thomas Kilduff, Ph.D., who directs the Center for Neuroscience within SRI Biosciences, Sarah Wurts Black, Ph.D., a research scientist in the Center for Neuroscience, and colleagues present a mouse model of narcolepsy that mimics the human disorder better than other models currently in use. Kilduff, Black and the SRI team then used the new narcolepsy model alongside a standard model to investigate a novel therapeutic pathway and to identify a promising way of treating narcolepsy.

"Our work is an example of how basic research can lead to a potential new therapy for a disease," said Kilduff. His team found that a form of baclofen, R-baclofen, works in both mouse models much better than the leading FDA-approved therapeutic for narcolepsy. (Baclofen, which has been available for more than 50 years, is a chemical compound that exists as a mixture of two isomers, designated R and S.) "The next step would be to perform a study in narcoleptic patients to determine its potential for treatment of human narcolepsy."

In humans, narcolepsy onset is typically during adolescence or later, but diagnosis may take more than a decade, making it difficult to study the progression of the disease. The lack of definitive mechanisms to explain what goes awry in the brain's ability to regulate sleep-wake cycles has consequently yielded drugs that only address the symptoms, rather than the underlying causes, of narcolepsy.

In the first of the two papers, "Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function," Kilduff and Black teamed with colleagues at five institutions in Japan to generate a model of narcolepsy that better mimics the human disorder. The existing model, called "Ataxin mice," has been available for over 10 years. Although Ataxin mice have enabled researchers to study narcolepsy, an important limitation is that these mice are born with the deficiency of the neurotransmitter hypocretin that has been implicated in causing narcolepsy, whereas the onset of human narcolepsy typically occurs after puberty.

"The mouse model developed by Dr. Kilduff and his colleagues offers a new approach to study narcolepsy and to explore potential therapies for this devastating sleep disorder. This new model allows more precise control of the timing and extent of hypocretin/orexin neuron loss, and thus may better mimic human narcolepsy," said Janet He, Ph.D., program director at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

In collaboration with Professor Akihiro Yamanaka of Nagoya University in Japan, formerly an SRI International Fellow in Dr. Kilduff's laboratory, the research team genetically engineered a mouse in which the hypocretin neurons could be selectively eliminated at any age simply by removal of an antibiotic in the mouse food. In the new "DTA" model, degeneration of hypocretin neurons can be initiated after puberty, causing the mice to exhibit the two major symptoms of narcolepsy: excessive daytime sleepiness and cataplexy, the brief loss of muscle tone experienced by most narcoleptics.

In the second paper, "GABAB Agonism Promotes Sleep and Reduces Cataplexy in Murine Narcolepsy," Black, Kilduff and colleagues used the new DTA model and the Ataxin model to compare R-baclofen against gamma-hydroxybutyrate (GHB). Sodium oxybate, the sodium salt of GHB, was approved by the FDA in 2002 as the only therapeutic for narcolepsy that simultaneously alleviates cataplexy, excessive daytime sleepiness and nocturnal sleep disruption. However, it remains unclear how this drug exerts its beneficial effects.

It was suspected that GHB works by affecting brain cells that respond to a neurotransmitter known as gamma-aminobutyric acid (GABA), which primarily functions to inhibit excitability and regulate muscle tone. To study the mechanism of action of GHB, SRI Biosciences' researchers tested R-baclofen, which blocks the GABA receptors suspected to be the target of GHB.

The research team found that R-baclofen promoted sleep time and longer bouts of wakefulness during the appropriate times for mice and also suppressed cataplexy. GHB modestly reduced cataplexy and increased sleep intensity, but did not improve other symptoms of narcolepsy to the extent that R-baclofen did. "The improvement in wakefulness that we observed after R-baclofen was a particularly unexpected and important finding," said Black.

"R-Baclofen works better than GHB in these two mouse models, but it remains to be determined whether it will work better in humans," cautioned Kilduff. "Although baclofen is already known to be safe for use in humans, the dose that is effective for spasticity may be different than the dose of R-baclofen that has the potential to treat narcolepsy."

In addition to Kilduff and Black, other SRI Biosciences researchers who participated in this study included Stephen Morairty, Tsui-Ming Chen, Andrew Leung and Jonathan Wisor.

The research was supported by the National Institute of Neurological Diseases and Stroke. Professor Yamanaka is supported by the Japan Science and Technology Agency.

Even with all the usual caveats that sounds really promising doesn’t it. It’s always so good to see research happening and money being spent to solve the mysteries of rare diseases and find a cure.

That’s so exciting the scientists probably had their sleep disturbed, too.

This would be great! I am allergic to Provigil and due to other conditions and medications I have to take, I have never been able to take Xyrem. I have friends who take Xyrem though and to be honest it sounds like it is always more work than it is worth any way. I would sign up for this program in a heart beat to help see if it works!

Kristin can you say more about Xyrem please. StrikerKing was asking about it yesterday and I couldn’t answer.

Xyrem- sodium oxibate is a form of GHB and a Schedule 3 controlled substance in the US. It is only produced by one pharmaceutical company and cannot be obtained in a generic form. When you start Xyrem, you register in this program so they can monitor you closely and also so you have someone to ask questions if you need to. They obviously want to keep track of individuals with this medication due to its class.

From what they have shared with me, it is a liquid that you take your first dose when you are ready to get into bed, make sure you are absolutely ready for bed as it can take effect very quickly. Then later in the night (4 hours after 1st dose I think) you take a second dose. This is supposed to produce restorative sleep with no constant waking and does something for your REM cycle, they are just not sure how it does it, that counteracts daytime sleepiness. Dosing seems to be a tricky thing to get right, as most of my friends on it are constantly going back to their doctors to fix the dose, but apparently when they get it right, THEY GET IT RIGHT! Like any medication and illness, things can interfere, like stress and other substances, with the quality effect of the medication. Narcolepsy its self is made worse by stress any how, so you are fighting a losing battle there.

There are many dangerous medication/substance interactions with this medicine though and I would definitely speak with your health care provider and make sure it is right for you. I cannot take this medication due to these risks. I also personally am scared of it as I have always thought of GHB as a "date rape drug" but the people I know who take it swear by it. You also cannot take stimulants from what I understand, if you are taking Xyrem.

I hope this helps

Thanks Kristin. Anybody taking Xyrem care to comment? We would love to hear your experience with it.

I had a depressive reaction to Xyrem, so I discontinued use. I hope that’s a rare side effect.

It can be a side effect of so many drugs. I came home from hospital so happy to be “out” and spent the next four weeks dissolving into tears. I thought it was situation I was in and it took that long for me to realise that one of the medications was responsible for my personality change whereupon I ditched it. Within two days I was myself again. Better the pain than the depression.

It has happened to me with a couple of drugs, Entex back in the 80s and more recently Flonase. It feels like someone putting a wet blanket of grief on you, and you don't know why. I'm glad you both figured it out and ditched the depressive meds, Carol and Nel.

Carol, Nel and Dancermom; I have experienced this as well. It is not a good feeling and definitely a sign to immediately discontinue (under doctor's supervision of course) a medication. Our bodies are strange how they react to things sometimes. I also get am adverse reaction called Extrapyramidal Symptoms (EPS) to a lot of meds. This one is defo not any fun either!

Dancermom that describes it exactly. I didn’t get much sympathy either because it looked as if I was just sorry for myself:(
I looked up EPS and that is really scary Kristin. Our bodies are strange full stop!

I completely agree Nel, not fun at all! Thank you for having the interest to look into it! :)

Nel said:

Dancermom that describes it exactly. I didn't get much sympathy either because it looked as if I was just sorry for myself:(
I looked up EPS and that is really scary Kristin. Our bodies are strange full stop!