Published Research - Pharmaceutical

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Published Research - Pharmaceutical

Postby ViewsAskew » Sat May 13, 2006 5:43 am

Today I read about safinamide, a new drug in Phase II trials that "resulted in a significant improvement in all efficacy parameters studied when administered to patients with Restless Legs Syndrome (RLS). Safinamide was also found to be well tolerated and did not exhibit any clinically relevant side-effects."

"We found that treatment with safinamide improved RLS symptoms. Sleep
architecture was not modified; conversely sleep fragmentation was positively influenced, as this is often the most distressing aspect of the disorder. The treatment was very well tolerated and did not result in any clinically relevant side effects,"

http://www.prnewswire.com/cgi-bin/stori ... 639&EDATE=
Last edited by ViewsAskew on Sat Jan 10, 2009 9:42 pm, edited 1 time in total.
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Postby Rubyslipper » Thu May 18, 2006 1:25 am

Thanks for the info Views, and for staying on top of things for us! Is this a medication that can be used yet like Mirapex (soon to be FDA approved for RLS) or just in the testing phase?
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Postby ViewsAskew » Thu May 18, 2006 2:21 am

Sadly, this is just going into Phase III testing. It will need a bit more testing - this can take at least 2 to 5 years, I would think. It takes longer to approve drugs that are experimental than those already used for other things. I think this is an experiemental drug, not already in use, but I'm not sure.

Here's some info I found on the approval process (I didn't know any of this until I just looked it up)

"Phase I trials test the safety of new drugs for humans. These trials record the side effects that occur at different dosages of the drug. Everyone in a Phase I trial receives the new drug, but different participants may get different dosages. The trials usually study less than 100 people, and take less than a year. In Phase I trials, new drugs are given to humans for the first time. People who participate in Phase I trials face the highest risks compared to possible benefits.

Phase II trials can enroll several hundred people and take 1 to 2 years. They study how well the drug works in relation to the disease/disorder. They also collect more information about side effects. Only about 1 drug candidate in 3 makes it through Phase II trials.

These trials are usually randomized. This means that trial participants are divided into two groups that are similar in terms of age, sex, and health. One group receives the study drug. The other group is the reference or control group. People in the control group get standard treatment (called "standard of care.") If there is no standard treatment, they may get a dummy medication (called a placebo).

Trial participants and their doctors usually do not know who is getting the study drug or the placebo. This is called a blinded study. Studies are blinded so that the doctors will be totally objective when they evaluate the health of patients in the study.

Phase III trials collect more data on a drug's effectiveness and side effects. These trials can study up to a few thousand people and often last for a year or more.

Phase III trials are normally randomized and blinded. Participants might not receive the study drug. With good results in Phase III trials, a manufacturer can apply for FDA approval to sell the new drug.

Phase IV trials are called "post-marketing studies". The regulations for Phase IV trials are not very clear, and they are not conducted very often. Phase IV trials can monitor a new drug' s long-term effectiveness and side effects, or how cost-effective it is. They can also compare the new drug to other drugs approved for the same condition."

And here is a visual chart if that makes more sense: http://www.fda.gov/cder/handbook/develop.htm
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Postby ViewsAskew » Wed Jul 05, 2006 3:32 am

I saw this fascinating article tonight in Pub-Med:

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_docsum

Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding.

Cervenka S, Palhagen SE, Comley RA, Panagiotidis G, Cselenyi Z, Matthews JC, Lai RY, Halldin C, Farde L.

Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.

Clinical observations support a central role of the dopamine system in restless legs syndrome (RLS) but previous imaging studies of striatal dopamine D2-receptors have yielded inconclusive results. Extrastriatal dopaminergic function has hitherto not been investigated. Sixteen RLS patients naive to dopaminergic drugs and sixteen matched control subjects were examined with PET. [(11)C]Raclopride and [(11)C]FLB 457 were used to estimate D2-receptor availability in striatum and extrastriatal regions, respectively. Examinations were performed both in the morning (starting between 10:00 and 12:00 h) and evening (starting at 18:00 h). Measures were taken to monitor and control for head movement during data acquisition. In the striatum, patients had significantly higher [(11)C]raclopride binding potential (BP) values than controls. In extrastriatal regions, [(11)C]FLB 457 BP was higher in patients than controls, and in the regional analysis the difference was statistically significant in subregions of thalamus and the anterior cingulate cortex. The diurnal variability in BP with [(11)C]FLB 457 and [(11)C]raclopride was within the previously reported test-retest reproducibility for both radioligands. The study supports involvement of the dopamine system in both striatal and extrastriatal brain regions in the pathophysiology of RLS. The brain regions where differences in D2-receptor binding were shown are implicated in the regulation of affective and motivational aspects of sensory processing, suggesting a possible pathway for sensory symptoms in RLS. Increased D2-receptor availability in RLS may correspond to higher receptor densities or lower levels of endogenous dopamine. Both interpretations are consistent with the hypothesis of hypoactive dopaminergic neurotransmission in RLS, as increased receptor levels can be owing to receptor upregulation in response to low levels of endogenous dopamine. The results do not support variations in dopamine D2-receptor availability as a correlate to the diurnal rhythm of RLS symptoms.
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Postby ViewsAskew » Wed Jul 05, 2006 3:50 am

More evidence supporting iron as a primary issue in causing RLS:

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_docsum

Is ferroportin-hepcidin signaling altered in restless legs syndrome?

Clardy SL, Wang X, Boyer PJ, Earley CJ, Allen RP, Connor JR.

Department of Neurosurgery, M.S. Hershey Medical Center, 500 University Drive, H110, Hershey, PA 17033, USA.

Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs. Sufferers of RLS often experience chronic sleep deprivation, due to the characteristic worsening of symptoms both when at rest and during the night. MRI data, autopsy studies, and a consistent decrease in CSF ferritin all suggest that early-onset RLS is associated with insufficient iron in the brain. In this study, we examined the relationship between the iron regulatory hormone hepcidin and RLS. Hepcidin serves as a hormone that signals iron release from cells by interacting with ferroportin. We measured the expression and concentration of pro-hepcidin in the brain and cerebrospinal fluid of both RLS patients and control individuals. In CSF, we found that pro-hepcidin levels were significantly decreased in early-onset RLS patient samples, but not in late-onset RLS patients, when compared to controls. Conversely, in neuromelanin cells, substantia nigra, and putamen, the concentration of pro-hepcidin in RLS samples is significantly increased compared to controls. Functionally, hepcidin binds to ferroportin to limit iron movement from cells. Therefore, we provide immunocytochemical evidence that ferroportin is expressed by the epithelial cells of the choroid plexus and the ependymal cells lining the ventricles. These data suggest that sites of action for hepcidin include signaling the ventricular system for movement between brain and CSF. At this time, it cannot be determined if the lower levels of pro-hepcidin in the CSF represent a compensatory response to the decreased levels of iron in the brain or a defective signaling mechanism in RLS. Nonetheless, these data support the mounting evidence that there is a biological basis for RLS and the underlying mechanism involves iron management.
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Postby ViewsAskew » Wed Jul 05, 2006 4:01 am

This is a continuation of the one posted above. Interesting that the low brain iron is ONLY an issue in early onset RLS, not late onset. Iron may still be involved, but not in the same way.

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_docsum

MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome.

Earley CJ, B Barker P, Horska A, Allen RP.

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA.

OBJECTIVE: Cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and autopsy studies have suggested that brain iron may be reduced in restless legs syndrome (RLS). Further analysis of the data also suggests that diminished brain iron may selectively be for early-onset RLS. This study was designed to replicate and extend our previous findings, specifically with regard to early-onset RLS. In this study our primary hypothesis was that substantia nigra (SN) iron index would be decreased in early-onset RLS compared to controls. METHODS: The iron concentration or 'iron index' in 10 brain regions was determined using MRI in 39 controls and in 22 early-onset and 19 late-onset RLS subjects. The Johns Hopkins RLS severity (JHRLSS) scale was used to define disease severity. RESULTS: The mean iron index from the SN was significantly lower in the early-onset RLS compared to controls (t=2.5, P=0.016), while late-onset RLS and controls did not differ. There was a significant negative Spearman rank correlation between SN iron index and JHRLSS scale for the control-early-onset-RLS cohort (rho=-0.32, P=0.016). CONCLUSIONS: The current MRI results in combination with previous autopsy data support the role of low brain iron in the SN in at least those with early-onset RLS symptoms.
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Postby ViewsAskew » Wed Jul 05, 2006 4:02 am

Anyone remember EECP being discussed as a possible solution? There was no abstract for this, but this is the title:

Enhanced external counter pulsation (EECP) for restless legs syndrome (RLS): Preliminary negative results in a parallel double-blind study.

Rajaram SS, Rudzinskiy P, Walters AS.


Hmmm, sounds like EECP did not work in this study.
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Postby ViewsAskew » Wed Jul 05, 2006 4:16 am

This is an interesting method to determine if someone has RLS if only three or the four criteria are met:

Validation of the "L-DOPA test" for diagnosis of restless legs syndrome.

Stiasny-Kolster K, Kohnen R, Carsten Moller J, Trenkwalder C, Oertel WH.

Department of Neurology, Center of Nervous Diseases, Philipps-University, Marburg, Germany.

We developed and validated a standardized test procedure to evaluate the accuracy of the supportive diagnostic criterion "response to dopaminergic treatment" in restless legs syndrome (RLS). Forty-eight patients who fulfilled at least three of the four essential criteria for RLS, thus including uncertain clinical cases for a nonexpert, were recruited. Patients received a preliminary diagnosis of RLS or non-RLS. All patients underwent a polysomnography (PSG) and were then asked to perform the diagnostic L-DOPA test at home, which consisted in the application of one single dose of 100/25 mg L-DOPA/benserazide and a subsequent observational period of 2 hours. Before, and in 15-minute intervals after, drug intake, the patients rated the severity of the "symptoms in the legs" and the "urge to move the legs" using a 100-mm visual analogue scale. Considering a 50% improvement as a positive test result, we found a sensitivity of 88% ("symptoms in the legs") and 80% ("urge to move the legs") with a specificity of 100% for both test items. A rate of 90% or 83% of all patients could be correctly diagnosed by the L-DOPA test. Both scales were able to predict the response to dopaminergic agents in the subsequent course of the treatment by 100%. The periodic leg movements arousal index as assessed by polysomnography was less appropriate for the prediction of the correct diagnosis. We recommend the L-DOPA test for diagnostic decision making in all patients with an unclear RLS diagnosis according to the essential diagnostic criteria of the International RLS Study Group. (c) 2006 Movement Disorder Society.
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Postby ViewsAskew » Wed Jul 05, 2006 4:22 am

Wow, this is not what I wanted to read! This means there are no closer to determining the genetic cause of RLS.


http://www.ncbi.nlm.nih.gov/entrez/quer ... med_DocSum


Restless legs syndrome: Epidemiological and clinicogenetic study in a South Tyrolean population isolate.

Vogl FD, Pichler I, Adel S, Pinggera GK, Bracco S, De Grandi A, Volpato CB, Aridon P, Mayer T, Meitinger T, Klein C, Casari G, Pramstaller PP.

Institute of Genetic Medicine, European Academy, Bolzano, Italy.

Genetic contributions to restless legs syndrome (RLS) have been consistently recognized from population and family studies. To determine the clinical and genetic features of RLS in a population isolate and explore linkage to three previously described susceptibility loci on chromosomes 12q, 14q, and 9p, respectively, an isolated population in the South Tyrolean Alps was identified and 530 adults participated in the study. Using a two-step strategy, 47 patients with idiopathic RLS were ascertained. The prevalence in the population was 8.9%. Twenty-eight patients (59.6%) had at least one affected first-degree relative and were classified as hereditary cases. In a single extended pedigree, linkage to known RLS loci was investigated specifying autosomal dominant and recessive models; parametric and nonparametric multipoint linkage scores were computed. None of the calculated linkage scores was suggestive of linkage between RLS and any of the three investigated loci. This study was conducted in a population isolate providing for a homogeneous genetic and environmental background. The absence of a suggestive linkage signal at the three known RLS susceptibility loci is indicative of further locus heterogeneity of this frequent disorder and encourages further studies to unveil the genetic causes of RLS. (c) 2006 Movement Disorder Society
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Postby ViewsAskew » Wed Jul 05, 2006 4:36 am

Here is a possible new med we might see/hear more about in the future for treating RLS. It is another dopamine agonist - an iso-ergoline. It is being studied in the US for treating PD.

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_DocSum

Lisuride treatment of Restless Legs Syndrome: first studies with monotherapy in de novo patients and in combination with levodopa in advanced disease.

Benes H, Deissler A, Rodenbeck A, Engfer A, Kohnen R.

Somni bene Institute for Medical Research and Sleep Medicine, Schwerin, Germany.

In two 4-week polysomnography pilot studies with 10 patients each, we investigated the efficacy of oral lisuride as monotherapy in de novo RLS patients as well as in combination with levodopa in advanced RLS. Daily doses at study end were 0.3 mg lisuride, plus 150 mg levodopa in the combination study. Marked improvements occurred in both studies in different PLM indexes and in the CGI. Levodopa dose could be decreased by 27%. Lisuride might be an efficacious treatment for RLS in general, and in combination with levodopa in advanced stage.
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Postby ViewsAskew » Wed Jul 05, 2006 4:42 am

This could be helpful to anyone who also has essential tremor. This study suggests that ET and RLS may share genetic similarities.

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_DocSum

Association between restless legs syndrome and essential tremor.

Ondo WG, Lai D.

Baylor College of Medicine, Houston, Texas, USA.

After observing that several families with essential tremor (ET) clinically cosegregated with restless legs syndrome (RLS), we prospectively evaluated for the presence of RLS in 100 patients presenting to the Baylor College of Medicine with ET and prospectively examined all patients presenting with RLS for the presence of tremor during the same time frame. Of 100 consecutive ET patients (60 women and 75 with a family history of ET) seen over 19 weeks (current age, 65.2 +/- 16.3 years; age at tremor onset, 37.8 +/- 19.9 years) 33 met all criteria for RLS, of which 25 had never been diagnosed previously. A family history of RLS was reported in 57.6% of these 33 patients and was the only significant predictor of RLS in the ET population. Their International Restless Legs Syndrome Rating Scale score was 16.6 +/- 8.1. Over 19 weeks, we also examined 68 consecutive RLS patients (63.2% women and 54.4% with a family history of RLS) for the presence of tremor. Their current age was 55.8 +/- 14.4 years, and age at RLS onset was 33.7 +/- 19.5 years. Overtly pathological tremor was rare, but trace tremor was very common. Overall, we found a very high rate of undiagnosed RLS in patients presenting for tremor, but unlike other "secondary" forms of RLS, this finding was also associated with a high familial history of RLS, suggesting that they share some genetic similarities. Copyright 2005 Movement Disorder Society.
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Postby ViewsAskew » Wed Jul 05, 2006 4:53 am

Here is more information about PLMW - periodic movements while awake.

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_DocSum

Propriospinal myoclonus: a motor phenomenon found in restless legs syndrome different from periodic limb movements during sleep.

Vetrugno R, Provini F, Plazzi G, Cortelli P, Montagna P.

Department of Neurological Sciences, University of Bologna, Bologna, Italy. vetrugno@neuro.unibo.it

Three patients presented with a 25-, 15-, and 5-year history of restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS). For 1, 4, and 5 years, they reported additional involuntary trunk and limbs jerks preceding falling asleep and occasionally during intrasleep wakefulness. Videopolysomnography revealed jerks during relaxed wakefulness arising in axial muscles with a caudal and rostral propagation at a slow conduction velocity, characteristic of propriospinal myoclonus (PSM). Jerk-related EEG-EMG back-averaging did not disclose any preceding cortical potential. During relaxed wakefulness preceding falling asleep and during intrasleep wakefulness, PSM coexisted with motor restlessness and sensory discomfort in the limbs. PSM disappeared when spindles and K-complexes appeared on the EEG. At this time, typical PLMS appeared every 20 to 40 seconds, especially during light sleep stages. PLMS EMG activity was limited to leg, especially tibialis anterior muscles, and did not show propriospinal propagation. In one patient, alternating leg muscle activation was also present. Jerks with a PSM pattern represent another motor phenomenon associated with RLS and different from the more usual PLMS. Copyright (c) 2005 Movement Disorder Society.
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Postby ViewsAskew » Tue Oct 31, 2006 4:20 pm

I came across this news today:

http://www.earthtimes.org/articles/show ... 2388.shtml

Now, it is a press release, so not sure that the amount are true - but that there are three new drugs coming out soon IS true. These drugs are in various stages of clinical trials, but should help many people. The Rotigitine patch's method of delivery may prevent augmentation.

Restless Legs Syndrome Drug Market Will Exceed $1 Billion in 2015
Posted on : Mon, 30 Oct 2006 13:12:00 GMT | Author : Decision Resources
News Category : PressRelease


WALTHAM, Mass., Oct. 30 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, forecasts that the restless legs syndrome drug market will exceed $1 billion in 2015 up from $200 million in 2005.

According to the new Pharmacor report entitled Restless Legs Syndrome, the market will be driven by increases in the diagnosed population and the launch of three new drugs from Schwarz, XenoPort, and Serono. Each of the three new agents will launch successfully for restless legs syndrome on the strength of product differentiation: Schwarz's rotigotine CDS (Neupro) will boast a transdermal formulation; XenoPort's XP-13512 will possess improved pharmacokinetics; and Serono's safinamide will offer new mechanisms of action.

"The approval of Schwarz's rotigotine CDS, and XenoPort's XP-13512 will drive a four-fold increase in the drug-treated population and a six-fold increase in total market sales by 2015," said Julie Kerner, Ph.D., analyst at Decision Resources. "The most successful emerging agent in the restless legs syndrome market will be rotigotine CDS, sales for which will account for 46% of the total restless legs syndrome market growth by 2015."
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Postby cornelia » Wed Nov 01, 2006 8:48 am

I hope these new meds Safinamide, Rotigotine and Lisuride are not more of the same things.

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Postby ViewsAskew » Wed Nov 01, 2006 3:56 pm

They basically are :-(, except for one. Rotigatine is a new DA - it's also being tested for PD. It is a patch, though, and supposed to resolve augmentation issues.

The XP one is a new formulation of Neurontin - it supposedly will work differently. The Safinamide is formulated for epilepsy and has a new mechanixm of action.
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