Dr Dake Interview:
Blocked Veins MS Research Group:
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The study was small, with 81 participants. Though its primary endpoint (designed to evaluate MS progression in people following their first attack) was not met, the researchers found over the 12-month course that about 55 percent of participants did not develop new brain lesions when administered statins compared with about 27 percent of the placebo group.
Study findings were presented by University of California, San Francisco (UCSF) researchers during the recent annual American Academy of Neurology scientific meeting in Toronto.
The trial was a phase II, multi-center, randomized, placebo-controlled follow up to a landmark study published by principal investigator Scott S. Zamvil, M.D., PhD, associate professor of neurology at UCSF. His laboratory first observed that statins cause T cell immune modulation that could be beneficial in MS and other autoimmune diseases. That study tested whether the drug could be used to prevent conversion to definite MS in individuals who have had a first attack.
The new treatment for curbing these unwanted crying and laughing episodes uses two drugs, dextromethorphan and low-dose quinidine. Early indications are that the two drugs do reduce the incidence and severity of these episodes and improve quality of life.
"There's no FDA-approved therapy for pseudobulbar affect," notes study lead author Erik P. Pioro, M.D., director of the section for ALS and related disorders at the Cleveland Clinic in Ohio, and a member of the American Academy of Neurology (AAN). "The off-label medications that are being used have their own set of side effects and problems. So from a medical and patient care point of view, it would be very worthwhile to have an approved medication that is both safe and effective," he says.
The study results were presented at the recent AAN annual meeting in Toronto.
The study authors note that PBA typically manifests in people with an underlying neurological illness, including those with MS. Dr. Pioro says that conservative estimates put the number of Americans with PBA at close to 2 million, although he said the figure might actually be as high as 6 million to 7 million.
In the study, Dr. Pioro and his colleagues enlisted 283 people with PBA in an initial drug trial, during which some participants received one of two dosage levels of the two medications, while others received placebos.
After a two-week break, this was followed by a second phase involving 253 of the original study participants. During the study's second part, participants were exposed to daily doses of the two-drug regimen for 12 weeks.
Dr. Pioro and his colleagues observed "significant improvement" among all the participants — particularly among those who had not been exposed to the drug combo until the second part of the study.
1. Expert Rev Neurother. 2010 May;10(5):791-809. Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Buttmann M. Department of Neurology, Julius Maximilian University, Josef-Schneider-Str. 11, Würzburg, Germany. email@example.com Treating multiple sclerosis (MS) with monoclonal antibodies (mAbs) has been marked by both progress and setbacks in the past 2 years, which are reviewed here.The natalizumab section of the article centers around progressive multifocal leukoencephalopathy (PML), and discusses PML risk in relation to treatment duration, bioassays for individual risk prediction, the concept of drug holidays, clinical course and treatment of PML, as well as safety-related regulatory actions.The rituximab section critically analyzes recent clinical trial results, discusses the clinical relevance of anti-idiotypic mAbs and makes a short excursion to neuromyelitis optica. Following this, the newer anti-CD20 mAbs ocrelizumab and ofatumumab, which are currently being tested in Phase II for MS, are reviewed and compared.The alemtuzumab section highlights novel data on mechanisms of action, potentially allowing individual risk prediction, and new results from the CAMMS223 trial, as well as the current status of the pivotal MS studies.The daclizumab section summarizes new open-label data, shedding more light on the adverse-effect profile of the drug in MS patients, and reports on its Phase III status.Subsequently, a failed ustekinumab trial and LY2127399 are reviewed. Taking into account late Phase II and III data on novel oral agents, the final section attempts to provide a detailed perspective on disease-modifying MS therapy in the medium term. PMID: 20420497 [PubMed - in process]
PMID: 20420497 [PubMed - in process]
Kappos L ; Radue EW ; O'Connor P ; Polman C ; Hohlfeld R ; Calabresi P ; Selmaj K ; Agoropoulou C ; Leyk M ; Zhang-Auberson L ; Burtin P ;
Department of Neurology, University Hospital, University of Basel, Switzerland. firstname.lastname@example.org
BACKGROUND: Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis.
METHODS: In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point).
RESULTS: A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P 0.001 p="0.02">
The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001>
Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension.
CONCLUSIONS: As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)
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“Urological Implications on MS”
Brian Steingo, MD – Neurology
To Discuss: The importance of staying on your MS Therapy
Bill Pintauro, MD – Urology
To Discuss: Neurologic Issues concerning the bladder
Where: The Signature Grand Catering Center
When: Tuesday, May 11th, 2010
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Using extremely fine-grained analytical tools, scientists compared genetic information in three sets of identical twins. One of each pair had MS, and the other didn’t — yet their genes proved essentially identical.
“We find no smoking gun on the genetic level,” said National Center for Genome Resources geneticist Stephen Kingsmore, co-author of the study published April 28 in Nature.
The research cost $1.5 million, and the scientists took 18 months to sequence 2.8 billion DNA units in each twin, and determine whether they came from the mother or father. Most genomic comparisons look for differences in a just handful of suspect genes, and even whole-genome approaches don’t differentiate between parental contributions.
The researchers also analyzed the twins’ CD4 cells, a type of white blood cell that plays a central role in the development of MS. In these cells, the researchers sequenced epigenomes — chemical instructions that turn genes on and off — and transcriptomes, or a chemical record of genes that are actively coding proteins.
These multiple layers of information represent the cutting edge of genomic analysis, and are expected to reveal what rougher tools cannot. “This was a technical tour de force, and potentially represents a new way of looking at disease states,” said Kingsmore. Nevertheless, they found no differences.
The absence of genetic differences doesn’t mean that genetics are irrelevant to multiple sclerosis. Identical twins, who are descended from the same egg, are six times more likely to develop MS than non-identical twins, who come from two different eggs.
It’s still possible that some as-yet-unknown genetic factor, undetectable by even the most advanced tools, may explain the discordance in the study. However, Kingsmore thinks the culprit is probably an unknown environmental influence. “There must be a nongenetic factor, probably environmental,” that combines with known genetic and environmental risks, he said.
The researchers would like to look at more twins, and other types of cells. Even so, the study “was a pioneering effort on a scale that hasn’t been done before,” said Kingsmore. “We’re left with this mystery.”Read More