Published Research - Pharmaceutical

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New drug being developedbased on gabapentin


Gabapentin enacarbil, a gabapentin prodrug for the treatment of the neurological symptoms associated with disorders such as restless legs syndrome.

MERLINO G, SERAFINI A, YOUNG JJ, ROBIONY F, GIGLI GL, VALENTE M.
Curr Opin Investig Drugs 2009;10(1):91-102.
DPMSC, University of Udine, Via Palladio, 8 Palazzo Florio 33100, Udine, Italy. gigli@uniud.it

Abstract:


Restless Legs Syndrome (RLS) is a sleep-related movement disorder characterized by an urge to move the legs accompanied by unpleasant symptoms. Dopaminergic agents currently represent the first-line therapy for RLS. However, some patients are unable to continue with this pharmacological approach in the long term because of augmentation or other adverse events.

Limited studies with the anticonvulsant/analgesic agent gabapentin have demonstrated that this drug might be useful in the treatment of primary and uremic RLS. Unfortunately, gabapentin has an unfavorable pharmacokinetic profile characterized by a dose-dependent bioavailability. Gabapentin enacarbil, a prodrug of gabapentin, is currently being developed by XenoPort Inc/Astellas Pharma Inc/GlaxoSmithKline plc in order to overcome this limitation. In vitro and in vivo studies have demonstrated that gabapentin enacarbil provides a dose-proportional exposure to gabapentin when orally administered. Gabapentin enacarbil has proved to be beneficial in treating RLS symptoms in several phase II and III clinical trials. In addition, these trials have demonstrated that gabapentin enacarbil is safe and well tolerated, causing transient and mild or moderate adverse events.

Gabapentin enacarbil is an interesting compound, which is potentially useful in treating RLS patients who report severe adverse events under dopaminergic agents. The author concludes that additional studies are required in order to better assess the efficacy and safety of gabapentin enacarbil on RLS.

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Update on Xenoport's gabapentin drug

http://www.docguide.com/news/content.ns ... 5100598148

XP13512 Shows Promising Results in Restless Legs Syndrome: Presented at AAPM

By Emma Hitt, PhD

HONOLULU -- February 2, 2009 -- An experimental treatment for restless legs syndrome (RLS), XP13512, was found to improve symptoms in all patients and reduced pain associated with RLS compared with placebo, according to results of a study presented here at the American Academy of Pain Medicine (AAPM) 25th Annual Meeting.

"Pain is not a criterion for diagnosis of RLS, but many patients report pain with RLS, and about 1 in 5 say it is their most troublesome symptom," said lead author Ron Barrett, PhD, XenoPort, Inc., Santa Clara, California, in a presentation on January 30.

XP13512 is a novel transported prodrug of gabapentin in development for the treatment of RLS, postherpetic neuralgia, painful diabetic neuropathy, and migraine prophylaxis. The current study included 222 patients with moderate to severe RLS, who were randomised to receive once-daily XP13512 at a dose of 1,200 mg, or placebo, taken with food.

Treatment response was defined as a response of "much improved" or "very much improved" according to the Clinical Global Impression-Improvement (CGI-I) scale.

Results showed that XP13512 improved significantly the mean International Restless Legs Scale (IRLS) total score compared with placebo at week 12 (P = .0003) and significantly more patients were responders according to the CGI-I scale (76.1% vs 38.9%; P < .0001).

In addition, among patients with a baseline pain score of 4 or greater, more patients treated with XP13512 reported at least a 50% pain reduction versus placebo (75% vs 33%; P < .0001), indicating that the magnitude of the treatment effect is greater among patients with more severe pain at baseline.

The most common treatment-related adverse events included somnolence (26% vs 8%) and dizziness (21% vs 5%) for XP13512 vs placebo, respectively. No clinically significant changes in vital signs, electrocardiogram, or laboratory parameters were observed.

"These findings suggest that XP13512 is effective in this setting and that if approved, it will represent another useful treatment option for patients with RLS," Dr. Barrett said.

Funding for the study was provided by XenoPort, Inc.

[Presentation title: XP13512/GSK1838262 Treats the Pain Associated With Restless Legs Syndrome. Abstract 210]

[Polar Bear]

thanks, Ann

[ViewsAskew]

Huh, it says there was a low risk of augmentation with rotigotine (the patch). I wonder how long of a period is included in the data?

Rotigotine transdermal patch: in restless legs syndrome.

BALDWIN CM, KEATING GM.
CNS Drugs 2008;22(10):797-806.
Wolters Kluwer Health | Adis, Auckland, New Zealand. demail@adis.co.nz

Abstract:


Rotigotine is a non-ergolinic dopamine receptor agonist, formulated as a silicone-based transdermal patch, which has been evaluated for use in the treatment of adults with moderate to severe restless legs syndrome (RLS).

Transdermal rotigotine improved the symptoms of RLS in two well designed 6-month trials in adults with idiopathic, moderate to severe RLS. Rotigotine (1-3 mg/24 h in one study and 2 or 3 mg/24 h in the other) decreased the International RLS Study Group Severity Rating Scale (IRLS) sum score and the Clinical Global Impression (CGI) item-1 assessment (severity of symptoms) from baseline (co-primary endpoints) to a significantly greater extent than placebo. Over half of rotigotine recipients were classified as treatment responders according to the IRLS sum score and CGI item-1 and item-2 ratings.

Improvements in RLS symptoms have been maintained in the long term with rotigotine, according to the 3-year results of an open-label extension trial. Transdermal rotigotine was generally well tolerated in clinical trials and long-term extension studies in patients with moderate to severe RLS.

There was a low risk of augmentation (i.e. intensification of RLS symptoms) with rotigotine, although further evaluations are required to ascertain if continuous dopaminergic stimulation has the effect of limiting or preventing augmentation.

[ViewsAskew]

Not sure if this is the [u]same study[/u] Susan found earlier...my only concern is that it's such a small sample. The good news is that there were 0 with reboxetine, the one Susan is trying now.

Restless legs syndrome as side effect of second generation antidepressants.

ROTTACH KG, SCHANER BM, KIRCH MH, ZIVOTOFSKY AZ, TEUFEL LM, GALLWITZ T, MESSER T.
J Psychiatr Res 2008;43(1):70-5.
Hafenmarkt 12, 87600 Kaufbeuren, Germany. Klaus.Rottach@t-online.de

Abstract:


Although of clinical interest, the question is still not fully answered whether antidepressants (AD) can cause or exacerbate restless legs syndrome (RLS). The literature provides contradictory information. This study addresses this problem for the class of second generation AD.

In four neurological offices, all patients treated for the first time with an AD were prospectively observed with regard to the question of whether RLS occurred or pre-existing RLS worsened as a result of the medication. Because initial treatment in the participating offices is mainly executed with "modern" selective AD, the study was restricted to these drugs (fluoxetine, paroxetine, citalopram, sertraline, escitalopram, venlafaxine, duloxetine, reboxetine, and mirtazapine).

In 9% of patients, RLS was recorded as a side effect related to the administration of AD. The frequency of this side effect varied among the drugs. The problem is most pronounced with mirtazapine provoking or deteriorating RLS in 28% of patients. By contrast, no case occurred during use of reboxetine. As for the other AD, the rate of newly occurred and deteriorated RLS, ranged from 5% to 10%. Typically, RLS occurred during the initial days of treatment.

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Here's somethingfor a fibro sufferers.

Text copied below:

Low Doses of Drug for Alcoholics Helps Reduce Fibromyalgia Pain, New Research Finds

Taking low doses of a drug commonly given to alcoholics and drug addicts reduces pain and fatigue in some people battling the chronic-pain condition fibromyalgia, Stanford University researchers say.

In preliminary research, the drug, naltrexone, reduced the pain and fatigue in fibromyalgia patients by an average of 30 percent, researchers said. The findings are an encouraging development for millions of Americans who suffer from fibromyalgia, a somewhat mysterious disorder for which there is no reliable cure or treatment.

However, larger and more detailed studies are needed before naltrexone can be recommended for treating fibromyalgia, researchers said.
Study Finds Benefits for Fibromyalgia Sufferers

The Stanford University study focused on 10 fibromyalgia patients. Some of the patients received low doses of the drug at bedtime while some were given placebos. Those taking naltrexone reported significant drops in daily pain, highest pain, stress, fatigue, and improved pain thresholds, according to the study. On average, patients given naltrexone had their fibromyalgia symptoms reduced by 32.5 percent, compared to improvement of 2.3 percent in patients given placebo treatments.
Few Side Effects, Relatively Inexpensive

Naltrexone treatments resulted in few side effects, although some participants reported experiencing vivid dreams after taking the drug. Researchers are excited about the prospects of naltrexone as a fibromyalgia treatment because there currently are few treatment options for such patients and the drug is relatively inexpensive, costing about $40 a month.

A second, longer-term study of the effects of naltrexone on fibromyalgia symptoms and including 30 patients tested over a period of four months is set to begin soon, Stanford researchers said.

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And, a studythat shows Lyrica (pregabalin) helps some RLS patients.

Copied below in case link doesn't work:

Fibromyalgia and Epilepsy Drug Lyrica Helps Restless Leg Sufferers, Researchers Say

Lyrica, the Pfizer drug for treatment of the chronic pain disorder fibromyalgia and preventing epileptic seizures, also appears to benefit people who cannot get to sleep because of restless legs syndrome, new findings suggest.

A recently completed clinical trial found that pregabalin, the active ingredient in Lyrica, is “a promising alternative to current treatments” in terms of helping people with restless legs syndrome get more quality sleep, according to research unveiled this week at a meeting of the American Academy of Neurology.
Lyrica for Fibromyalgia Pain

In 2007, Lyrica became the first FDA-approved treatment for fibromyalgia, a debilitating condition which affects as many as six million Americans, mostly adult women. Fibromyalgia victims tend to experience chronic or long-lasting pain as well as muscle stiffness and tenderness, the FDA said.

Restless legs syndrome is a neurological disorder which causes burning or tugging sensation in the legs, sometimes called parethesias or dysethesias, particularly when the person is lying down at rest. The sensations can range from uncomfortable to extremely painful.
Study of Restless Legs Sufferers

Researchers from the Sleep Research Institute in Madrid, Spain studied 58 patients who suffered from restless legs syndrome. The patients were given placebo pills for two weeks then half were given 150 to 600 milligrams daily doses of Lyrica, while half continued to receive placebos for another 12 weeks.

The researchers monitored the severity of restless legs syndrome and sleeping habits of both groups and found that those taking Lyrica experienced less severe symptoms of the syndrome.
Less Symptoms, More Sleep

Using the International Restless Legs Syndrome Rating Scale, people on Lyrica saw their scores on the disease severity index decline from 19.8 to 6.8, while scores for participants on placebo treatments declined from 21.5 to 11.2, the researchers said.

Also, people in the study who were taking Lyrica spent significantly more time sound asleep in what is called deep slow wave Stage 3 sleep and less time in light sleep, called state 1 or 2 sleep, compared to people not taking the drug, the researchers said.

[ViewsAskew]

Huh, hope those patches get approved again soon. Not that augmentation didn't happen at all, but this studyshowed that it was much lower with the patches than with other dopamine drugs. That's good news.

[ViewsAskew]

Another drug to try: oxcarbazepine. I've not heard of anyone using it; in the Clinical Mgmt of RLS book, it's listed as having only one research study related to it - one person was successfully treated with it.

Guess there are two studies now!

[ViewsAskew]

Well, we've talked about it sometimes, but here's proof that tramadol CAN become addictive....it's only two cases, fortunately.

[ViewsAskew]

And, Neupro (the transdermal patch) is back in Europe as of July, 2009. I hope it's back in the US soon. It was very effective more many.

[Neco]

I've had these concerns about tramadol for a long time, so I've always cautioned people it can be addictive.. And though I never commented on it until recently, my 400 - 800mg a day intake was pretty telling.

[ViewsAskew]

Fascinating story about dopamine and how it works in the brain.

[cornelia]

I am too tired to comment on the article, but it is certainly very frightening and interesting! Thanks Ann for posting it.
Corrie

[Polar Bear]

This shows just how powerful drugs can be.