RxPG News : Demyelinating Diseases

Smoking associated with rapid progression of multiple sclerosis

Mon, 13 Jul 2009 15:31:39 PST

( from http://www.rxpgnews.com ) Patients with multiple sclerosis who smoke appear to experience a more rapid progression of their disease, according to a report in the July issue of Archives of Neurology, one of the JAMA/Archives journals.

Cigarette smokers are at higher risk of developing multiple sclerosis (MS), according to background information in the article. However, the effect of smoking on the progression of MS remains uncertain.

Brian C. Healy, Ph.D., of Brigham and Women's Hospital, Harvard Medical School and Massachusetts General Hospital, Boston, and colleagues studied 1,465 patients with MS who visited a referral center between February 2006 and August 2007. Participants had an average age of 42 and had MS for an average of 9.4 years. Their progression was assessed by clinical characteristics as well as by magnetic resonance imaging (MRI) over an average of 3.29 years.

A total of 780 (53.2 percent) of the patients had never smoked, 428 (29.2 percent) had smoked in the past and 257 (17.5 percent) were current smokers. During follow-up, seven never-smokers began smoking and 57 current smokers quit. Current smokers had significantly more severe disease at the beginning of the study in terms of scores on disability scales and also in the analysis of MRI factors. Current smokers were also more likely to have primary progressive MS, characterized by a steady decline, rather than relapsing-remitting MS (involving alternating periods of attacks and symptom-free periods).

A group of 891 patients was assessed over time to evaluate the rate of conversion from relapsing-remitting MS to secondary progressive MS (steady decline that develops after a period of relapsing-remitting symptoms). During an average of 3.34 years, 72 patients (20 of 154 smokers, 20 of 237 ex-smokers, and 32 of 500 never-smokers) experienced this progression. "The conversion from relapsing-remitting MS to secondary progressive MS occurred faster in current smokers compared with never-smokers but was similar in ex-smokers and never-smokers," the authors write.

An adverse effect of smoking on the progression of MS would be consistent with previous research, the authors note. Components of cigarette smoke are known to have toxic effects on brain and neural tissue; for example, cyanides, which have been associated with the destruction of nerve cells' myelin coating (a characteristic feature of MS) in animals. "Other chemicals in smoke (e.g., nicotine) can compromise the blood-brain barrier or have immunomodulatory effects," the authors write. "Cigarette smoke increases the frequency and duration of respiratory infections, which have been linked to risk of MS and to the occurrence of MS relapses."

"In conclusion, the results of this large and in part prospective investigation support the hypothesis that cigarette smoking has an adverse effect on progression of MS as measured by clinical and MRI outcomes," they conclude. "Although causality remains to be proved, these findings suggest that patients with MS who quit smoking may not only reduce their risk of smoking-related diseases but also delay the progression of MS."

Testosterone may help men with multiple sclerosis

Mon, 14 May 2007 20:42:54 PST

( from http://www.rxpgnews.com ) A small pilot study suggests that testosterone treatment is safe, well tolerated and may reduce symptoms, slow brain degeneration and increase muscle mass in men with relapsing-remitting multiple sclerosis, the most common form of the disease, according to a report in the May issue of Archives of Neurology, one of the JAMA/Archives journals.

Multiple sclerosis is a progressive disease involving the immune and central nervous systems. MS and many other autoimmune diseases (in which the body attacks its own systems or tissues) are less common in men than in women, according to background information in the article. This is especially true during reproductive years. Sex hormones, including testosterone and estrogen, may be responsible for the difference. Testosterone has been shown to protect against an MSâlike condition and other autoimmune diseases in animals.

Nancy L. Sicotte, M.D., of the David Geffen School of Medicine at UCLA, Los Angeles, and colleagues conducted a study of testosterone treatment in 10 men with relapsing-remitting MS, characterized by periods of neurologic symptoms (such as numbness or difficulty walking) followed by periods of remission. The men, who had an average age of 46, were enrolled in the study and then entered a six-month pre-treatment phase, during which symptoms were monitored but no therapies were administered. Then, each man applied 10 grams of a gel containing 100 milligrams of testosterone to his upper arms once daily for 12 months.

"One year of treatment with testosterone gel was associated with improvement in cognitive performance and a slowing of brain atrophy [deterioration]," the authors write. During the first nine months of the studyâthe period of time before the men began taking testosterone, plus the first three months of treatment, before it had time to take effectâbrain volume decreased an average of -0.81 percent per year. In the second nine months, this decline slowed by 67 percent to an annual rate of -0.25 percent. "Because the protective effect of testosterone treatment on brain atrophy was observed in the absence of an appreciable anti-inflammatory effect, this protection may not be limited to MS, but may be applicable to those with non-inflammatory neurodegenerative diseases," including amyotrophic lateral sclerosis or Lou Gehrig's disease, the authors write.

In addition, lean body mass (muscle mass) increased an average of 1.7 kilograms (about 3.74 pounds) during the treatment phase. Participants did not report any adverse effects, there were no abnormalities in blood tests taken during the trial and the men's prostate examination results remained stable.

"Overall, in this first trial of testosterone treatment in men with relapsing-remitting MS, the treatment was shown to be safe and well tolerated," the authors conclude. "In addition, exploratory findings reported herein suggest a possible neuroprotective effect of testosterone treatment in men, which warrants further investigation."

Age of onset but not severity of Multiple Sclerosis inherited from parents

Mon, 29 Jan 2007 15:32:16 PST

( from http://www.rxpgnews.com ) When more than one member of a family is affected by multiple sclerosis (MS), their ages at disease onset are likely to be similar, but disease severity may not be. These new findings have important implications for counseling patients, according to a study published in the January 30, 2007, issue of Neurology®, the scientific journal of the American Academy of Neurology.

"Weve known for some time that family influence plays a role in whether you are susceptible to MS, but it has not been clear whether your family influence affects the course of the disease," according to lead study author Alastair Compston, PhD, of the University of Cambridge Clinical School in Cambridge, United Kingdom.

To address the question of family influence on the course of the disease, researchers examined data on 2,310 individuals from over 1,000 families in which at least two members had MS. They examined age at onset, disability, disease severity, and other features of the disease.

The researchers found that age at onset of the disease was similar among family members, whether comparing parents to children or siblings with each other. They also found that siblings tended to have the same pattern of disease progression, while there was no correlation between the pattern in parents and children.

The study also showed there was no correlation between the severity of the disease in one family member and severity in another member, whether siblings or parent and child. "Disease progression is often considered the indicator of severity," said Compston. "But, we found no evidence that disease severity is more likely to be similar between two family members with MS than two unrelated people with MS."

The causes of the similarities in onset and progression pattern are largely unknown, as are the causes of MS itself. It is possible that genetic factors are responsible, but environmental factors shared by family members may also play a role.

Compston says the studys findings have significant implications for counseling patients. "People should not draw personal conclusions for their own MS prognosis and expected disease severity from observing the condition of their relatives with MS," he said.

Cause of nerve fiber damage in multiple sclerosis identified

Tue, 17 Oct 2006 02:37:37 PST

( from http://www.rxpgnews.com ) Researchers have identified how the bodys own immune system contributes to the nerve fiber damage caused by multiple sclerosis, a finding that can potentially aid earlier diagnosis and improved treatment for this chronic disease.

The study reveals how immune system B-cells damage axons during MS attacks by inhibiting energy production in these nerve fiber cells, ultimately causing them to degenerate and die. Study results appear in the Oct. 15 issue of the Journal of Immunology.

B-cell-axon activity is an emerging area of MS research, one that is changing how scientists and clinicians can look at this disease. In this study, Dr. Yufen Qin and fellow researchers from UC Irvines School of Medicine analyzed spinal fluid and tissue samples from MS patients to identify substances that stimulate a B-cell immune response. They noted an increased level of B-cell antibodies on lesions and in spinal fluid bound to two specific enzymes GAPDH and TPI.

These two enzymes are essential for efficient energy production. The researchers believe that the binding of these antibodies to these enzymes GAPDH, in particular may lower the amounts of ATP the chemical fuel for cells available in cells, which eventually can lead to axon cell degeneration and death. In addition to the energy-production function, GAPDH is involved with a number of genetic activities, such as RNA translocation, DNA replication and DNA repair.

Other recent studies have shown that binding of inhibitors to GAPDH and TPI causes decreased ATP production in neurons, followed by progressive neuronal degeneration and death. Moreover, patients with TPI deficiency can develop progressive neurological disorders.

This research is exciting and potentially important for future treatments because it identifies new antibodies associated with MS that can be targeted with emerging therapies, said Qin, an assistant professor of neurology. Significantly, these are the first antibodies to be identified with axon activity, which is a new area researchers are exploring in the pathology of MS.

MS is a chronic central nervous system disease that can cause blurred vision, poor coordination, slurred speech, numbness, acute fatigue and, in its most extreme form, blindness and paralysis. Some 400,000 Americans have this disease. Its causes are unknown, and symptoms are unpredictable and vary greatly in severity.

Much MS research is focused on an autoimmune process in which T-cells attack and damage myelin, the fatty insulating tissue of axons. These T-cells do not attack axons themselves; the process of demyelination interrupts electrical impulses that run through these nerve fibers, thus causing MS symptoms. Demyelination has been considered the central feature of MS.

Recently, however, Qin has been among a group of researchers who have discovered that B-cells too are involved with the autoimmune response to MS. Instead of targeting myelin, these B-cells attack axons directly. Axons are the long, slender fibers of a neuron that serve as the primary transmission lines of the nervous system, and as bundles they help make up nerves.

Research at UCI and elsewhere has shown that myelin grows back if the T-cell autoimmune response is turned off, and drugs exist or are in development to block demyelination. Axons, in turn, repair very slowly, which implies that B-cell attacks on axons may have a significant impact on the chronic central nervous system damage caused by MS.

Since this area of research is in its early stage, its important to understand the process by which these B-cell responses happen, Qin said. Hopefully, by identifying these two crucial enzymes, it will lead to a greater understanding of MS and lead to more effective treatments for people who live with this disease.

Fampridine may hold promise for treating Multiple Sclerosis

Tue, 26 Sep 2006 18:49:37 PST

( from http://www.rxpgnews.com ) Acorda Therapeutics, Inc. (Nasdaq: ACOR) today announced positive results from its Phase 3 clinical trial of Fampridine-SR on walking in people with multiple sclerosis (MS). Statistical significance was achieved on all three efficacy criteria defined in the Special Protocol Assessment (SPA) by the Food and Drug Administration (FDA). A significantly greater proportion of people taking Fampridine-SR had a consistent improvement in walking speed, the study's primary outcome, compared to people taking placebo (34.8 percent vs. 8.3 percent) as measured by the Timed 25-Foot Walk (p less than 0.001). In addition, the effect was maintained in this study throughout the 14-week treatment period (p less than 0.001) and there was a statistically significant improvement in the 12-Item MS Walking Scale (MSWS-12) for walking responders vs. non-responders (p less than 0.001).

The average increase in walking speed over the treatment period compared to baseline was 25.2 percent for the drug group vs. 4.7 percent for the placebo group. Increased response rate on the Timed 25-Foot Walk was seen across all four major types of MS. In addition, statistically significant increases in leg strength were seen in both the Fampridine-SR Timed Walk responders (p less than 0.001) and the Fampridine-SR Timed Walk non-responders (p=0.046) compared to placebo. The Company intends to present comprehensive data at an upcoming medical meeting.

"We are delighted with the results from this trial, which are consistent with Acorda's prior Phase 2 study in people with MS. We will request a meeting with the FDA as soon as possible to discuss next steps for the Fampridine-SR program," said Ron Cohen, M.D., President and CEO. "Acorda is committed to the development of therapies that will improve the function and lives of people with MS, and we wish to thank the physicians and people with MS who participated in this trial."

"Many people with MS experience nerve damage that eventually impairs walking. Currently, no therapies are indicated to improve neurological function, such as loss of mobility, in MS," said Andrew Goodman, M.D., Director of the Multiple Sclerosis Center at the University of Rochester. "Based on the results of this trial, Fampridine-SR could represent a new way to treat people with MS. In this study, a significantly higher proportion of subjects experienced a consistent improvement in walking speed with Fampridine-SR than with placebo, and this was accompanied by a reduction in the degree of disability that the subjects reported in their daily activities related to mobility."

Special Protocol Assessment (SPA)

This clinical trial was conducted under an SPA from the FDA. The efficacy criteria set forth in the SPA included three elements:

To show that there were significantly more responders in the Fampridine-SR treated group than in the placebo group, as measured by the Timed 25-Foot Walk, a standard neurological test. A responder was defined as someone whose walking speed on the Timed 25-Foot Walk was consistently greater during at least three of four on-drug visits than the person's fastest speed on any of the five off-drug visits.
To demonstrate statistically significant improvement in walking speed on the last on-drug visit for the Fampridine-SR-treated responders compared to the placebo group.
To show that responders reported a significantly greater improvement than non-responders on the MSWS-12, a self-rated assessment of walking disability. This step was meant to validate the clinical meaningfulness of consistent improvement on the Timed 25-Foot Walk.

Study Design

The double-blind, placebo-controlled trial was designed to evaluate the safety and efficacy of Fampridine-SR in improving walking ability in people with MS. The trial, which enrolled 301 individuals at 33 MS centers in the United States and Canada, recruited patients between 18 and 70 years old with a definite diagnosis of MS and some degree of walking disability. The study was open to people with all types of MS, including primary-progressive, secondary-progressive, relapsing-remitting and progressive-relapsing. Participants were permitted to remain on a stable regimen of their current medications, including interferons. Secondary endpoints for the trial included measurements of leg strength. Subjects were randomized to 14 weeks of treatment with Fampridine-SR (n=229) or placebo (n=72), a 3:1 ratio of drug to placebo.

Safety Statement

In this study, adverse events were largely consistent with the safety profile observed in previous studies of Fampridine-SR in people with MS, including an increased risk of seizures that appears to be dose related. Following is a list of the most common adverse events reported in the study, with percentages representing the Fampridine-SR treatment group vs. the placebo group: falls (15.8 percent vs.15.3 percent), urinary tract infection (13.6 percent vs.13.9 percent), dizziness (8.3 percent vs. 5.6 percent), insomnia (8.3 percent vs. 4.2 percent), fatigue (6.1 percent vs. 2.8 percent), nausea (6.1 percent vs. 4.2 percent), upper respiratory tract infection (6.1 percent vs. 9.7 percent), asthenia (5.7 percent vs. 6.9 percent), back pain (5.7 percent vs. 0 percent), balance disorder (5.7 percent vs. 2.8 percent) and headache (5.7 percent vs. 5.6 percent).

Two serious adverse events that were judged potentially related to treatment and led to discontinuation were anxiety in one subject and a seizure in another subject that was observed during an occurrence of sepsis associated with a urinary tract infection. No deaths occurred during the study. One death was reported for a subject five weeks after the last on-drug study visit. This death occurred outside of the protocol time window for reporting adverse reactions and the cause of death is not known at this time.

About MS

Multiple sclerosis is a chronic, usually progressive disease of the central nervous system in which the immune system attacks and destroys the structure, and therefore degrades the function, of nerve cells. Approximately 400,000 Americans have MS, and every week about 200 people are newly diagnosed. Most are between the ages of 20 and 50, and women are affected two to three times as much as men. Worldwide, MS may affect 2.5 million individuals.

According to the National Multiple Sclerosis Society (NMSS), the direct costs of medical care for MS patients in the United States exceed $6 billion annually. Additionally, a recent NMSS analysis estimated the total cost of MS, including medical and non-medical care, production losses, and informal care, at more than $47,000 per U.S. patient per year. Complications from MS may make it harder for people to work and may interfere with their ability to perform common, daily activities.

For most people with MS, the disease slowly progresses with a series of unpredictable flare-ups, also called relapses or exacerbations. But for some, the progression of the disease is rapid. Each relapse tends to lead to increasing disabilities such as walking impairment, muscle weakness or speech or vision impairments. Approximately 80 percent of people with MS experience some form of walking disability. Within 15 years of an MS diagnosis, 50 percent of patients often require assistance walking and in later stages, about a third of patients are unable to walk.

About Fampridine-SR

Fampridine-SR is a sustained-release tablet formulation of the investigational drug fampridine (4-aminopyridine, or 4-AP). Data collected in laboratory studies found that fampridine can improve the communication between damaged nerves, which may result in increased neurological function.

Fampridine-SR Mechanism of Action

A nerve cell has one extension, called an axon, which it uses to communicate via electrical signals to other nerve cells. All but the smallest axons have a special covering of a fatty substance called myelin that acts as insulation to preserve and speed these nerve signals, much like the insulating cover of an electrical cord helps preserve the transmission of electricity.

In MS, the myelin becomes damaged and the axon cannot effectively transmit electrical impulses. Specifically, the damaged myelin exposes channels in the membrane of the axon, which allow potassium ions to leak from the axon, dissipating the electrical current. Fampridine-SR blocks these exposed channels, and helps the electrical signals to pass through areas of damage.

CNS can send out signals to invite autoimmune attacks

Fri, 16 Jun 2006 23:48:37 PST

( from http://www.rxpgnews.com ) It may sound like a case of blame the victim, but researchers at Washington University School of Medicine in St. Louis have shown that cells in the central nervous system can sometimes send out signals that invite hostile immune system attacks. In mice the researchers studied, this invitation resulted in damage to the protective covering of nerves, causing a disease resembling multiple sclerosis.

"It's been clear for quite a while that our own lymphocytes (white blood cells) have the ability to enter the central nervous system and react with the cells there," says John Russell, Ph.D., professor of molecular biology and pharmacology. "Under normal circumstances, the brain and the immune system cooperate to keep out those cells that might harm the brain. But in people with multiple sclerosis, they get in."

The researchers found that they could prevent destructive immune cells from entering nervous system tissue by eliminating a molecular switch that sends "come here" messages to immune cells. Ordinarily, flipping that switch would cause immune cells to rush to the vicinity of the cells that sent the signals and destroy whatever they consider a danger including nerve cell coatings.

But in the mice in which the switch was removed, the researchers saw that immune cells previously primed by the scientists to attack the central nervous system (CNS) did not enter the CNS, and the mice stayed healthy.

In contrast, normal mice treated with the same hostile immune cells had numerous immune cells in their CNS tissue and developed symptoms similar to multiple sclerosis.

"What allows the primed lymphocytes into the CNS are signals from the CNS asking them in," Russell says. "We determined that the astrocytes, the specialized cells that provide nutrients to neurons, are among the cells most active in sending signals to attract lymphocytes."

The molecular switch that sends the call to immune cells is termed the tumor necrosis factor receptor (TNFR). When TNFR is activated, it causes cells to send out signal molecules called chemokines that direct immune cells to the site of damage or infection. The researchers found that astrocytes in mice were producing chemokines in response to activation of their TNFR molecules.

TNFR activation also makes the astrocytes bristle with specific adhesion molecules that act like Velcro to bind to similar molecules on the surface of the immune cells. That allows the immune cells that are attracted by the chemokines to stick around and do more harm.

One of the most promising new drugs for treating multiple sclerosis, natalizumab (tradename Tysabri), works by blocking the ability of the immune cells to stick in the CNS through this Velcro mechanism, Russell notes. Natalizumab is being tested in clinical trials and appears to be much better at preventing the nerve cell destruction associated with multiple sclerosis than previous therapies.

"Experiments by others suggested that natalizumab prevented immune cells from crossing the blood-brain barrier it was thought to prevent the cells from leaving the blood stream," Russell says. "We are working on that question, and we think that it doesn't necessarily prevent them from getting out of the blood, but it does keep them from getting further into the brain. The immune cells pile up in the space around the blood vessels. This space, the perivascular space, serves as a gatekeeper to determine what gets in and what doesn't."

Next, the research team will study various regions of the brain to determine the types of signals sent to and from different areas of the CNS to the immune system.

Natalizumab Re-approved for Relapsing Multiple Sclerosis

Fri, 09 Jun 2006 00:09:37 PST

( from http://www.rxpgnews.com ) U.S. Food and Drug Administration (FDA) has approved the supplemental Biologics License Application (sBLA) for the reintroduction of Natalizumab as a monotherapy treatment for relapsing forms of multiple sclerosis (MS) to slow the progression of disability and reduce the frequency of clinical relapses. The approval for reintroduction was granted based on the review of Natalizumab clinical trial data; revised labelling with enhanced safety warnings; and a risk management plan, called TOUCH Prescribing Program, designed to inform physicians and patients of the benefits and risks of Natalizumab treatment and minimize potential risk of progressive multifocal leukoencephalopathy (PML). The reintroduction of Natalizumab offers new hope as an important therapeutic choice for patients living with this disabling disease. "Natalizumab has demonstrated compelling efficacy in MS, and we believe the TOUCH Prescribing Program, designed in collaboration with the FDA, will help patients and physicians assess the benefits and risks of Natalizumab and make informed decisions about therapy," said James C. Mullen, Chief Executive Officer, Biogen Idec.

"We are pleased with the FDA's decision to once again make Natalizumab available to patients and their families suffering from this chronic, debilitating disease, " said Kelly Martin, Chief Executive Officer, Elan. "There continues to be a significant unmet medical need where Natalizumab will be an important treatment option. "

Today's action follows a March 8, 2006 unanimous recommendation by the FDA's Peripheral and Central Nervous System Drugs Advisory Committee to allow the reintroduction of Natalizumab. TOUCH (TYSABRI® [Natalizumab] Outreach: Unified Commitment to Health) Prescribing Program was developed in conjunction with the FDA to facilitate the appropriate use of Natalizumab and to assess, on an ongoing basis, the incidence and risk factors for PML and other serious opportunistic infections associated with Natalizumab treatment. This program represents Biogen Idec and Elan's commitment to making the unique benefits of Natalizumab available in a responsible manner. Elements of the TOUCH Prescribing Program include revised labeling with a prominent boxed warning of the risk of PML; and warnings against concurrent use of Natalizumab with chronic immunosuppressant or immunomodulatory therapies, and patients who are immunocompromised due to HIV, hematological malignancies, organ transplants or immunosuppressive therapies, mandatory enrolment for all prescribers, central pharmacies, infusion centres and patients who wish to prescribe, distribute, infuse, or receive, respectively, Natalizumab; controlled, centralized distribution only to authorized infusion centers, mandatory FDA-reviewed educational tools for patients and physicians, including a patient medication guide, TOUCH enrollment form and a monthly pre-infusion checklist, ongoing assessment of PML risk and overall safety, a 5,000 patient cohort observational study over five years, the Natalizumab Global Observation Program in Safety (TYGRIS)

Natalizumab treatment also resulted in sustained and statistically significant reductions in brain lesion activity as measured by MRI. The two-year data from the SENTINEL add-on trial also demonstrated that treatment with Natalizumab in addition to AVONEX® (Interferon beta-1a) had a significant effect on disability progression, relapse rate and brain MRI disease activity compared to AVONEX alone.

Natalizumab increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Three cases of PML occurred in clinical trial patients who were concomitantly exposed to immunomodulators (interferon beta in the patients with MS) or were immunocompromised due to recent treatment with immunosuppressants (e.g., azathioprine in the patient with Crohn's disease). A third case of PML occurred among 1,043 patients with Crohn's disease after the patient received eight doses. The number of cases is too few and the number of patients treated too small to reliably conclude that the risk of PML is lower in patients treated with Natalizumab alone than in patients who are receiving other drugs that decrease immune function or who are otherwise immunocompromised. Healthcare professionals should monitor patients on Natalizumab for any new signs or symptoms that may be suggestive of PML. Natalizumab dosing should be withheld immediately at the first sign or symptom suggestive of PML.

Natalizumab is contraindicated in patients who have or have had PML or with known hypersensitivity to Natalizumab or any of its components. In Phase III placebo-controlled trials of Natalizumab in MS, the overall incidence and rate of other infections were balanced between Natalizumab-treated patients and controls. Herpes infections were slightly more common in patients treated with Natalizumab. Commonly reported infections with Natalizumab included urinary tract infections, lower respiratory tract infections, gastroenteritis and vaginitis. Serious opportunistic and other atypical infections have been observed in Natalizumab-treated patients, some of these patients were receiving concurrent immunosuppressants.

Serious events that occurred in Natalizumab-treated patients included hypersensitivity reactions (e.g., anaphylaxis), depression and gallstones. Appendicitis was more common in patients receiving Natalizumab with AVONEX. Common adverse events reported in Natalizumab-treated patients include infusion reactions, headache, fatigue, joint and limb pain, abdominal discomfort, diarrhoea and rash.

Efficacy in relapse rate reduction beyond five years shown for interferon beta 1b in Multiple Sclerosis

Wed, 05 Apr 2006 14:50:37 PST

( from http://www.rxpgnews.com ) Berlex announced today that Betaseron® (interferon beta 1b) remained consistently safe, effective and well tolerated over the long term, according to results of the Betaseron 16-Year Long-Term Follow-up (16-Year LTF) Study presented at the 58th Annual Meeting of the American Academy of Neurology. This is the longest follow-up study for any disease modifying therapy in multiple sclerosis (MS).

Patients with relapsing forms of MS taking Betaseron (known as Betaferon® outside the US) had a sustained reduction in the annual rate of relapses of up to 40 percent over 16 years.

The data also showed that patients remaining on long-term Betaseron treatment had a slower disease progression compared to patients who did not. Among the patients who reached EDSS level 6.0 (e.g., needing a cane for walking), those on long-term Betaseron treatment reached EDSS 6.0 after a median time of 13 years compared to seven years for patients on short-term treatment. Long-term treatment was defined as use of Betaseron for more than 80 percent of the time since the start of the pivotal trial (approx. 12 years or longer), while short-term treatment was defined as use for less than 10 percent of the time (approx. 1.6 years or less). The impact of long-term treatment on disease progression is being studied further using historical control groups.

"This study has comprehensively re-evaluated patients after 16 years," said Professor George Ebers, lead investigator of the study, Department of Clinical Neurology, Radcliffe Infirmary, University of Oxford. "The evidence for relapse rate reduction, combined with further support for long-term safety of Betaseron, is convincing. More studies are being done to further analyze the impact of treatment on disease progression."

The long-term use of Betaseron over 16 years revealed no new or unexpected adverse events. Betaseron was well accepted by patients in this long-term study. The median treatment duration with Betaseron of the analyzed trial participants was almost 10 years, while the longest duration on therapy is 17.1 years.

"The 16-year LTF is ground-breaking in that it is the longest follow-up study of patients on disease modifying MS therapy," said Richard Nieman, MD, Vice President, Head of Medical Affairs at Berlex. "These results show that first-line and long-term use of Betaseron for relapsing MS patients is safe, effective and well-tolerated. These data are very reassuring given the chronic nature of relapsing forms of MS, and the need for long-term therapy."

Sixteen Years of Betaseron Use in Patients with MS
The 16-Year LTF Study provides clinical assessment of patients who first enrolled in the Betaseron pivotal trial between 1988 and 1990. Of the original 372 patients involved in the pivotal trial, 328 (88.2 percent) have been identified. It is a multicenter, open-label, observational study designed to evaluate the impact of Betaseron treatment on long-term outcomes in patients with relapsing forms of MS. The study constitutes the longest follow up for any disease-modifying therapy in MS.

The results support a previously reported trend, in that there was a lower number of deaths in patients that were initially treated with Betaseron 250 mcg during the pivotal trial. This trend needs to be further evaluated.

The Betaseron pivotal trial was the first large, randomized, placebo-controlled study of any therapy in MS. This groundbreaking study was conducted in North America and led to the approval of Betaseron, the first disease-modifying agent for MS, in 1993. Patients were randomly assigned to one of three study arms, Betaseron® 50 mcg , Betaseron 250 mcg or placebo, with a median duration of observation of 45 months. Analysis after two years demonstrated that significantly more patients receiving Betaseron were relapse-free, that those relapses that occurred were less frequent and that hospitalizations for MS were cut nearly in half. These results were confirmed at five years.

Systematic Review Questions Accuracy of MRI in Multiple Sclerosis

Fri, 24 Mar 2006 13:20:37 PST

( from http://www.rxpgnews.com ) The accuracy of magnetic resonance imaging (MRI) is not sufficient to rule in or rule out a diagnosis of MS with a high degree of certainty, finds a study published online by the BMJ today.

MRI has been adopted in England and Wales by the National Institute for Health and Clinical Excellence (NICE) as part of the recommended criteria for diagnosing multiple sclerosis. Although its accuracy has been assessed, the evidence has not previously been systematically assessed.

Researchers analysed 29 studies to assess the accuracy of magnetic resonance imaging criteria for the early diagnosis of multiple sclerosis in patients with suspected disease. Each study compared MRI criteria to a reference standard for the diagnosis of multiple sclerosis. The average duration of follow-up ranged from seven months to 14 years.

Considerable weaknesses existed in the studies included in the review, and studies with methodological flaws overestimated the diagnostic accuracy of MRI.

Only two studies followed patients for more than 10 years, and these suggested that the role of magnetic resonance imaging either in ruling in or ruling out multiple sclerosis is limited. Patients with a first attack suggestive of MS have around a 60% probability of developing MS, this is increased to between 75 and 84% in those with a positive MRI scan and decreased to between 43 and 57% in those with a negative scan over 10-14 years.

The results suggest that use of magnetic resonance imaging to confirm multiple sclerosis on the basis of a single attack of neurological dysfunction may lead to over-diagnosis and over-treatment.

"There is a real danger of giving patients a serious diagnosis which will affect their lives but may turn out to be incorrect later on," says Penny Whiting.

Dr Jonathan Sterne adds: "Neurologists should discuss potential consequences of false positive and false negative magnetic resonance imaging results with their patients."

Statins could prove useful in treating MS

Fri, 17 Mar 2006 13:55:37 PST

( from http://www.rxpgnews.com ) Scientists at the University of California, San Francisco and Stanford University Medical Center are reporting compelling new evidence that the cholesterol-lowering drug atorvastatin could prove an effective therapy for preventing the progression of, and reversing the severity of, multiple sclerosis (MS).

In the March 16 on-line edition of The Journal of Clinical Investigation, they report the results of a study that looked at the use of the drug (marketed as Lipitor) in combination with Glatiramer acetate (marketed as Copaxone), a drug already approved for treating MS.

The findings demonstrate, they say, that the drugs worked synergistically, preventing or diminishing paralysis in mice with experimental autoimmune encephalomyelitis (EAE), a model disease that closely resembles multiple sclerosis. Multiple sclerosis causes a variety of neurological symptoms including loss of motor control, visual loss or imbalance. A primary symptom is temporary, recurring paralysis in the limbs, as occurs in the mice.

Copaxone is known to boost the immune system's anti-inflammatory response, countering the release of pro-inflammatory cytokines, or chemicals, unleashed when the immune system inadvertently turns against the brain's nervous tissue in MS. The drug is approved for treatment of relapsing-remitting MS, the most common form of the disease, but is effective in only a third of cases.

Lipitor is also known to have immunomodulatory properties, and recent evidence in mice and initial clinical trials suggest that it, and possibly other statins, may be effective in treating T-cell-mediated, autoimmune diseases, such as rheumatoid arthritis, as well as other inflammatory conditions. In fact, a 2002 study of mice with EAE by the UCSF-Stanford team (Nature, Nov. 7, 2002), has led to the establishment of a fourteen-center, placebo-controlled trial, led by UCSF scientists, to determine if Lipitor prevents conversion to definite multiple sclerosis in individuals who have had a first attack, known as a "clinically isolated syndrome." 1.

In the current study, however, the researchers took a different tack. Because Lipitor and Copaxone work through different mechanisms, the team set out to investigate whether Lipitor could augment Copaxone's efficacy in mice with EAE. Because both drugs are fully effective in preventing or reversing the disease in the animals, they were administered at precisely determined suboptimal doses.

The results were dramatic, according to the researchers. In the first step of the study, 10 mice were given the combination therapy prior to their immunization with the protein that induces EAE (MBP, or myelin basic protein). Of these, only three developed paralysis, and their symptoms were very mild. In addition, the central nervous system tissue of these animals had substantially fewer destructive inflammatory lesions. Fewer pro-inflammatory cytokines were produced, while more of the beneficial, anti-inflammatory cytokines were produced. In contrast, all of the EAE "control" mice -- those that received either no drug or suboptimal doses of Lipitor or Copaxone -- developed the full-blown disease.

In the second, and more provocative step of the study, involving 10 mice with established EAE, the combination therapy dramatically lessened the clinical and histological signs of the disease. The animals were essentially free of paralysis, they had reduced inflammation in the central nervous system, and decreased destruction of the myelin sheath, which insulates the nerves and is the target of destruction in MS. In contrast, there was no reversal of the disease in mice that received either no drug or suboptimal doses of Lipitor or Copaxone.

The findings in the mice demonstrate, says co-senior and corresponding author Scott Zamvil, MD, PhD, UCSF associate professor of neurology, that agents with different mechanisms of immune modulation can combine in a synergistic manner for the treatment of central nervous system autoimmunity, and provide a rationale for testing the combination therapy in multiple sclerosis. "We hope," he says, "that the combination will prove beneficial in MS treatment."

"The combined effect of these two drugs is very impressive," says co-lead author Olaf Stüve, MD, who conducted much of his work while a UCSF postdoctoral fellow in the Zamvil lab. "As such, the therapy represents a potential new strategy for treating multiple sclerosis." Stüve is now an assistant professor of neurology at UT Southwestern Medical Center at Dallas and is affiliated with the VA North Texas Health Care System.

More broadly, notes co-lead author Sawsan Youssef, PhD, a postdoctoral fellow in the laboratory of co-senior author Lawrence Steinman, MD, professor of neurology and Director of the Program in Immunology at Stanford University, the results demonstrate that the EAE mouse model can be used to evaluate the effectiveness of various drug combinations, with an eye toward developing new strategies for treating MS.

"There is still much to learn," says co-lead author Martin S. Weber, MD, a UCSF postdoctoral fellow in the Zamvil lab, "but this is an exciting advance."

"The treatment of a complex disease like multiple sclerosis will certainly involve regimens that combine more than one drug," says Steinman. "For this approach to work we need to find drugs with complementary modes of action. Statins and glatiramer work by entirely different mechanisms, and their effects are additive. Moreover, their toxicities are modest when used alone, and they are expected to continue to show only modest side effects when used together. Finally, in an age where the costs of medical treatments are receiving more and more scrutiny, adding a relatively inexpensive drug like a statin to an already expensive regimen is likely to make consumers and health care insurers even more enthusiastic about combination therapies."

The finding is the latest step in elucidating the potential of Lipitor to treat MS. It follows a study of mouse EAE published by the same team last month (The Journal of Experimental Medicine, Feb. 20, 2006) that suggests a mechanism by which Lipitor may suppress the production of pro-inflammatory cytokines associated with central nervous system autoimmune disease. Study findings indicated that the drug's effects on the immune system occur independently of its cholesterol-reducing effects. And it builds on the team's 2002 paper that showed Lipitor significantly improved, prevented relapses or reversed paralysis in mice with two different forms of EAE, most notably preventing animals who were experiencing their first attack from progressing to the fully established disease.

Multiple sclerosis is an auto, or "self," immune disease, in which one of the immune system's key cells, the T helper (Th) cell, or CD4+ T cell, orchestrates an inflammatory attack against the central nervous system. The primary target of the attack is the myelin sheath, which coats the brain's nerve fibers, or communication wires, through which nerve cells, or neurons, communicate.

The damage to the sheath, known as demyelination, disrupts the ability of neurons to transmit signals swiftly to one another. The destruction causes fatigue, imbalance, visual loss, disrupts various motor skills and, more subtly, diminishes some cognitive abilities. In later phases of the more progressive forms of the disease, non-inflammatory toxic molecules damage some of the brain's glial tissue and kill nerve cells.

Three types of drugs are currently approved to treat multiple sclerosis. Copaxone and the beta interferons are used to treat relapsing-remitting disease, which, in half of these patients, progresses to a "secondary progressive," or chronic, form, and Novatrone, a cancer chemotherapy, is used to treat this progressive form. The drugs are effective to varying degrees in roughly a third of patients and are often limited by side effects or toxicities. A fourth type of drug, Tysabri, was removed from the market in 2004 due to severe toxicity in patients also given beta interferon, though the Food and Drug Administration is now reviewing the drug, for possible reintroduction. Statins, by contrast, are relatively well tolerated and generally safe.

Use of statins is associated with a low risk of liver toxicity, and, less frequently, with a potentially more serious medical complication that results from muscle damage. For this reason, and because the drug has not been tested in multiple sclerosis, the researchers strongly urge patients and their physicians to wait for the results of the clinical trials before considering therapy with statins for multiple sclerosis.

12.5 kda cystatin may generate first simple test for multiple sclerosis

Mon, 06 Mar 2006 16:53:37 PST

( from http://www.rxpgnews.com ) Johns Hopkins scientists report the discovery of a protein found only in cerebrospinal fluid that they say might be useful in identifying a subgroup of patients with multiple sclerosis (MS) or identifying those at risk for the debilitating autoimmune disorder.

MS strikes over 10,000 Americans each year, most of whom are women, and causes weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. It is a disorder in which the immune system destroys myelin, the covering of nerves that helps transmit signals. Cerebrospinal fluid (CSF) is the watery fluid that surrounds and cushions the brain and spinal cord.

The federally funded Hopkins research, reported in the February issue of the Annals of Neurology, is important, the researchers say, because unlike other autoimmune diseases in which the body attacks its own tissues, MS cannot be diagnosed with a simple blood or other test.

While it is recognized that there might be several forms of MS, laboratory-based tests need to be developed to diagnose these subtypes.

"There is the possibility now that the protein we identified, 12.5 kDa cystatin, can be used to diagnose MS, perhaps in its earliest stages, and also to monitor treatment by measuring its levels in CSF," says Avindra Nath, M.D., a professor in the Department of Neurology at The Johns Hopkins University School of Medicine and lead author of the study.

Working with human CSF, the Hopkins team showed that 12.5 kDa cystatin is a breakdown product of a larger protein called cystatin C or 13.4kDa, which in turn blocks activity of some enzymes, including cathepsin B. Cathepsin B has been linked to demyelination-the destruction of the nerve sheath. The term kDa refers to Kilodalton, the weight of one molecule of a substance.

"In fact, those patients who had more of the breakdown product of 12.5 kDa cystatin also seemed to have the highest cathepsin B inhibition," Nath said.

The investigators made their finding using a sophisticated technique called SELDI-time-of-flight mass spectroscopy that can find one specific protein in a complex mixture based on its weight. They used it to examine CSF samples from 29 patients with MS or pre-MS symptoms such as numbness on one side; 27 patients with transverse myelitis, a painful inflammation of spinal cord nerves; 50 infected with the AIDS virus (which can cause nerve damage); and 27 with other neurological diseases. The Hopkins scientists analyzed CSF instead of blood samples because CSF better represents local events in the brain than does blood, according to Nath. And the high concentrations of many proteins in the blood can mask proteins that might be biomarkers for MS, he added.

The team found that the 12.5kDa fragment of cystatin C occurred in CSF samples from two-thirds of patients with MS or the pre-MS conditions. Moreover, although total cystatin C levels in MS patients were not different from control patients without the disease, patients with MS had a larger proportion of the 12.5 kDa compared to 13.4 kDa cystatin C than did other patients. Thus, the presence of the 12.5 kDa fragment might identify a subgroup of MS patients.

Fatal flaw in natalizumab, multiple sclerosis drug, trial

Fri, 03 Mar 2006 12:45:37 PST

( from http://www.rxpgnews.com ) When Anita Louise Smith enrolled in an experimental drug trial in 2002 in Colorado, she had a diagnosis of multiple sclerosis but no symptoms and was looking to reduce the chances of being ravaged by the disease. Last year, she died at the age of 46 from an infection linked to the drug.

This tragedy - recounted in an article in the March 4 issue of The Lancet by two Stanford University School of Medicine neurologists - serves as a telling case study of what can go wrong in clinical trials. In their article, Annette Langer-Gould, MD, and Lawrence Steinman, MD, warn of the pitfalls of testing a drug with unknown side effects in patients who would do fine without the drug.

The drug in question is natalizumab, which has the brand name of Tysabri. In November 2004, the U.S. Food and Drug Administration fast-tracked its approval for use in multiple sclerosis patients following promising results seen early in two clinical trials. But within months of the approval, some patients taking the drug had developed a rare infection - progressive multifocal leukoencephalopathy, or PML - and Smith and one other patient had died.

Langer-Gould, a clinical instructor in neurology, treated a patient who was part of the clinical trial and developed PML after taking Tysabri; the patient survived. But that experience, coupled with an examination of Smith's case, prompted Langer-Gould to approach Steinman about writing an article that would examine the appropriateness of testing a drug on people with no evidence of the disease and who are not disabled at the time of the trial.

"We are arguing that people with no disability should probably not enter into a clinical trial or be recruited into clinical trials, because where is the potential benefit to them if nothing is wrong?" said Steinman, professor of neurology and neurological sciences and of pediatrics.

"This situation represents a systemic problem," said Langer-Gould. "It is not just one company being a rogue, doing something out in left field."

Langer-Gould and Steinman argue that if a drug has a known risk of death, it should only be used on patients who are likely to suffer severe disability from the targeted disease - and for whom there are no other options. In other words, those who have tried all the other available therapies. That is almost the reverse of what happened in the Tysabri trial, which excluded the most severely affected patients.

"A big mistake was made in these trials that, in my opinion, is easily preventable," said Langer-Gould. "All they need to do is tighten up entry criteria into multiple sclerosis clinical trials and we could avoid similar types of problems in other trials."

Multiple sclerosis results when the immune system attacks the protective myelin sheath surrounding nerve cells, causing them to misfire and leading to loss of motor control and possibly paralysis. Tysabri appeared to block this effect and, after the first year of the two-year clinical trials, did not appear to cause more infections.

Steinman was involved early on in the development of the drug, publishing on its effects in 1992. Even then, he had suspicions that the drug's mechanism of action - blocking the entry of immune cells into the nervous system - might also make patients more vulnerable to infections. Indeed, PML is an infection that usually affects people whose immune systems are compromised.

"It was a shocking development that a drug that had so much promise and so many potential benefits ended up causing two deaths and one very serious injury," said Steinman. "It is kind of a cruel Greek drama, something that may be more beneficial than anything yet developed for multiple sclerosis, but yet may be far more dangerous than those other approved drugs."

The FDA withdrew Tysabri only three months after its approval. The FDA is now considering re-approving the drug. On March 7 and 8, an FDA advisory panel is meeting about the possibility of bringing back Tysabri as a single therapy (in the trials, it was combined with another drug).

"I predict it will come back with really hellacious warnings," said Steinman. "I think the right course would be to have it undergo more testing, but I don't think that is practical or fair to patients; they ought to have the opportunity to decide with their physicians if they are willing to take the one in a thousand risk of dying."

But Steinman and Langer-Gould expressed reservations about the drug returning to the market. They noted that its effects, while impressive, are in general not much better than what is seen with other available drugs: The risk of relapse dropped from an average of two relapses every three years using other approved multiple sclerosis drugs to one every three years with Tysabri.

"Do you want to expose someone to the risk of death for eliminating one relapse every three years?" said Steinman. "I say no."

"I'm not sure if it is wise to re-approve it," added Langer-Gould. "The question is, will the FDA rise to the occasion and admit their mistake and try to prevent future mistakes or are they going to ignore it?"

Azathioprine reduces new brain inflammatory lesions in MS

Wed, 14 Dec 2005 17:21:38 PST

( from http://www.rxpgnews.com ) A medication that reduces relapse rates in patients with multiple sclerosis (MS) appears to be effective in reducing new brain inflammatory lesions and is well tolerated, according to a study in the December issue of the Archives of Neurology, one of the JAMA/Archives journals.

The drug is azathioprine, an immunosuppressive agent that is well tolerated, easy to administer and monitor, and has been used for many years in the treatment of transplant rejections and autoimmune diseases. Azathioprine reduces relapse rates in MS patients, but its effects on the frequency and accumulation of new brain inflammatory lesions has not been studied in MS, according to background information in the article. MS is a disease of the central nervous system, marked by numbness, weakness, loss of muscle coordination, and problems with vision, speech, and bladder control.

Luca Massacesi, M.D., and colleagues at the University of Florence, Italy, conducted an open-label treatment study to evaluate the effect of azathioprine therapy on new brain lesion suppression in MS. They used magnetic resonance imaging (MRI) to evaluate brain lesions of 14 patients with relapse-remitting MS (RRMS) of short duration. RRMS is a form of the disease characterized by relapses, when new symptoms can appear and old ones resurface or worsen, followed by periods of remission, when the person fully or partially recovers from the deficits acquired during the relapse. The patients were evaluated for six months before and six months during treatment with azathioprine, and new lesions were evaluated during the same periods and after an additional six months.

"The results of this study show, for the first time, that the immunosuppressive agent azathioprine suppresses new brain lesions evaluated using MRI in patients with RRMS," the authors report.

"Indeed, the treatment induces remarkable new brain lesion reduction, stable for 12 months," they write. "This activity was obtained at doses that can be well tolerated and that are associated with low circulating lymphocyte numbers."

Adverse events were observed in six patients, mainly at the beginning of the evaluation period, but they were transient or reversed after dose reduction and no patient interrupted therapy. Neurologic disability was stable, and the relapse rate decreased consistently with the new brain lesion rate.

"If considered in the context of previous clinical trials, the present study indicates that azathioprine may represent an alternative to immunomodulatory medications specifically approved for RRMS," the authors conclude.

Multiple sclerosis diagnostic guidelines (McDonald criteria) updated

Thu, 10 Nov 2005 13:21:38 PST

( from http://www.rxpgnews.com ) An international panel of neurologists has updated the current guidelines for diagnosing multiple sclerosis (MS), strengthening the role of magnetic resonance imaging (MRI). The guidelines, published online November 10, 2005 in the Annals of Neurology, update the "McDonald criteria," created five years ago and named after the chair of the previous panel, Prof W. Ian McDonald of the Institute of Neurology in London.

"We hope, and trust, that these revisions will allow an even earlier diagnosis of MS, without any loss of diagnostic accuracy," said Chris H. Polman, M.D., of the Free University Medical Center in Amsterdam, The Netherlands, and chair of the current panel.

Multiple sclerosis is an enigmatic disease of the nervous system and results in the loss of myelin, a substance that normally insulates nerve fibers and speeds electrical conduction through the fibers.

Depending on which nerve fibers are hindered, patients can experience problems ranging from weakness and clumsiness to numbness, visual disturbances, and even emotional and intellectual alterations. In some patients, MS manifests itself in cycles of relapse and remission, while in others the disease progresses steadily.

"The changes in diagnostic criteria for primary progressive multiple sclerosis is particularly helpful," said Robert P. Lisak, M.D., of Wayne State University in Detroit, Michigan, and chair of the American Neurological Association's public information committee. "The ability to make the diagnosis of multiple sclerosis early and accurately is important for both patient care and for clinical research including clinical trials of new treatments."

There is increasing evidence that MS drugs such as interferon beta and glatiramer acetate are most effective when started early in the disease course.

The original McDonald Criteria were the first to incorporate MRI testing into the traditional tool kit of neurological history and examination, along with various laboratory exams. Brain imaging can show physicians the damaged sites (termed 'lesions') in the brain and spinal cord.

"A series of studies performed during the last few years, with improved techniques for spinal cord MRI, shows that it is a powerful tool not only to demonstrate MS lesions, but also to exclude alternative diagnoses," said Polman.

The new criteria also conclude that only two separate MRI scans, rather than three, are needed to evaluate whether the disease is progressing.

Key Role Of Macrophage Migration Inhibitory Factor (MIF) In Multiple Sclerosis

Thu, 20 Oct 2005 16:08:38 PST

( from http://www.rxpgnews.com ) A new study suggests that a substance made by immune cells plays a key role in the progression of a disease in animals that closely mimics multiple sclerosis (MS). The findings further suggest that blocking the molecule, known as macrophage migration inhibitory factor (MIF) might prevent the progression of the disease.

Researchers at The Ohio State University Medical Center conducted the study using mice that develop a disease that mimics MS. They compared these animals to similar mice that lacked MIF, an immune-system signaling molecule.

The results show that the animals without MIF develop the initial, acute phase of the disease, but then show no signs of further progression.

âOur results suggest that MIF may be less important for initiating MS, but that it may be necessary for MS progression,â says principal investigator Caroline C. Whitacre, professor of molecular virology, immunology and medical genetics.

âThese findings indicate that in the future we can perhaps use MIF levels to predict the onset of a relapse. But more importantly, perhaps this study will lead to drugs that can halt the course of MS by blocking the action of MIF.â

MS is an inflammatory, autoimmune disease which primarily affects the brain and spinal cord. Autoimmune diseases occur when the body's own immune cells destroy tissues in the body. In MS, immune cells destroy the myelin sheath that surrounds nerve fibers in the brain and spinal cord. Myelin is a fatty substance that insulates nerve fibers and enables them to transmit impulses.

According to the National MS Society, about 400,000 Americans are living with MS and about 10,400 new cases are diagnosed yearly. The disease usually strikes between the ages of 20 and 40, and it is more common in women. MS symptoms vary from person to person. Some individuals experience unusual fatigue, numbness and tingling; others can have loss of balance and difficulty walking; still others develop slurred speech, double vision, tremors or bladder problems.

In about 85 percent of cases, MS shows a pattern of remission and relapse, with no warning as to when a relapse will occur.

For this study, Whitacre and a group of colleagues used mice that develop the MS-like condition known as experimental autoimmune encephalomyelitis (EAE). The mice develop the disease after being inoculated with a myelin protein. The researchers compared these mice to mice that were identical except that they lacked the gene for MIF.

After inoculation, the mice with the MIF gene showed progressive EAE. In contrast, the mice lacking the MIF gene showed signs of early disease, but after about 20 days, these mice recovered and showed no further sign of progression.

The study also gave the investigators insights into the mechanism by which MIF influences the course of disease. They found that MIF blocked the steroid hormone, corticosterone (known as cortisol, in humans). Animals missing MIF had high levels of the steroid, while those with MIF showed very low levels.

The level of the steroid hormone, in turn, caused important immune-system changes in the animals that are likely to affect the disease.

For example, the mice with MIF (and low levels of the steroid hormone) showed high levels of immune-system cytokines or products that promote inflammation. Mice that lacked MIF (and had high levels of the steroid), on the other hand, showed high levels of immune-system cytokines or products that suppress inflammation .

âOur evidence overall suggests that the inhibition of this steroid hormone by MIF has an important influence on the immune system and in determining whether the disease progresses or not,â Whitacre says.

Chromosome six gene screen confirms MS suspects

Thu, 22 Sep 2005 05:04:38 PST

( from http://www.rxpgnews.com ) A cluster of genes on chromosome six is the only one that plays a significant role in multiple sclerosis (MS), according to the most complete genetic study to date in the disorder, presented at the 130th annual meeting of the American Neurological Association in San Diego.

"Our results confirm the strong role of the major histocompatibility complex genes in MS, and provides a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics," said Jonathan Haines, Ph.D, of Vanderbilt University in Nashville, Tennessee, who presented on behalf of the International Multiple Sclerosis Genetics Consortium.

"A detailed examination of the major histocompatibility complex is critically important," said Haines, who suggests that this study may have profound implications for the future directions of MS genetics research.

The major histocompatibility complex (MHC) is a cluster of genes that play a critical role in the recognition of cells in the body as belonging to the body, i.e., not intruders such as bacteria or other pathogens.

When this system of recognition breaks down, the immune system may mistakenly launch an attack against cells, as happens in MS. Researchers believe that some genetic variations in MHC genes make people more susceptible to whatever environmental causes also contribute to MS.

Haines is one of the founders of an international team of researchers from many institutions that collected genetic data on 730 families with more than one case of MS from Australia, Scandinavia, the United Kingdom, and the United States.

Previous studies have implicated the MHC, but also regions on other chromosomes, as harboring genes that increase MS risk. Haines suggests that these studies failed to include enough subjects.

"This is the largest genetic linkage study on MS, and the first to be done using the latest technology, which provides very detailed coverage of the entire human genome," said Haines. "Other genes may still play an important role in MS, but finding them will require using new genomic techniques."

Multiple sclerosis is an enigmatic disease of the nervous system and results in the loss of myelin, a substance that normally insulates nerve fibers and speeds electrical conduction through the fibers. Patches of inflammation (known as 'plaques') occur throughout the brain and spinal cord resulting in the loss of myelin and sometimes the nerve fibers themselves.

Depending on which nerve fibers are hindered, patients can experience problems ranging from weakness and clumsiness to numbness, visual disturbances, and even emotional and intellectual alterations. In some patients, MS manifests itself in cycles of relapse and remission and patients may show little sign of the disease between attacks.

Aquaporin-4 implicated in a form of multiple sclerosis

Thu, 22 Sep 2005 04:58:38 PST

( from http://www.rxpgnews.com ) Researchers have identified a molecular suspect in a disorder similar to multiple sclerosis (MS) that attacks the optic nerve and spinal cord, according to a report presented at the 130th annual meeting of the American Neurological Association in San Diego. The protein, called aquaporin-4, is a channel protein that allows water to move in and out of cells.

"Aquaporin-4 is the first specific molecule to be defined as a target for the autoimmune response in any form of MS," said author Vanda A. Lennon, MD, PhD, of the Mayo Clinic in Rochester, Minnesota. "It is also the first example of a water channel being the target of any autoimmune disorder."

Because there are many other variants of aquaporins throughout the body, Lennon suggests that these proteins might play a role in poorly understood autoimmune disorders in other organ systems.

For some time, scientists have understood that multiple sclerosis is not so much a single disease, but a category of disorders with similar damage to different parts of the nervous system. Recently, progress has been made in teasing out a particular syndrome called neuromyelitis optica (NMO), in which the body mistakenly mounts an immune attack against the optic nerve and spinal cord.

Last year, Lennon and her colleagues at Mayo, along with collaborators in Japan, were able to detect a particular antibody that occurrs in most people with NMO, but not in patients with "classical" MS.

This is particularly important for clinicians because specific treatment recommendations to help prevent blindness and other later symptoms, including paralysis, differ for NMO and MS .

In the present study, Lennon and colleagues have identified an aquaporin as the target molecule of the NMO antibody. "This finding is a departure from mainstream thinking about MS and related disorders, where the major focus of research in the past century has been the myelin that insulates nerve fibers, and the cell that manufactures myelin, known as the oligodendrocyte," said Lennon.

The Mayo Clinic group's work reveals that the protein targeted by the NMO antibody is not a component of myelin, or of oligodendrocytes. Aquaporin-4, which is the most abundant water channel in the brain, is instead located in a different type of cell called astrocytes.

"Aquaporin-4 is concentrated in membranes in the precise site where spinal cord inflammation is found in NMO patients," said Lennon.

The next step in this research is to use this knowledge to create an animal model that can be used to confirm the relationhip between aquaporin-4 and NMO, as well as to develop new and improved therapies.

Interferon Does Not Affect Duration Of "Black Hole" Lesions In Multiple Sclerosis

Tue, 13 Sep 2005 13:56:38 PST

( from http://www.rxpgnews.com ) Although treatment with interferon appears to reduce the formation of new areas of damage in the brains of patients with multiple sclerosis (MS), including lesions that appear as highly contrasted images, called black holes, on magnetic resonance imaging (MRI), treatment does not appear to affect the duration of these damaged regions, according to a new study posted online today by the Archives of Neurology, one of the JAMA/Archives journals. The study will be published in the November print edition of the journal.

Previous studies have shown that treatment with interferon beta-1b, a chemical that has activity on the immune system, reduces the formation of lesions visible to MRI, according to background information in the article. Chronic, persisting black holes reflect areas of irreversible nerve fiber loss and permanent damage. Black holes of shorter duration are believed to reflect the presence of short-term swelling. Shortening the duration of black holes, the authors suggest, may prevent the formation of permanent detrimental lesions, ultimately exerting a neuro-protective effect.

Francesca Bagnato, M.D., of the National Institute of Neurological Disorders and Stroke, Bethesda, Md., and colleagues analyzed MRIs for both the formation and duration of black holes for six patients with relapsing-remitting type MS. Monthly MRIs were obtained for 36 months before the treatment was initiated (natural history phase) and for 36 months during treatment with interferon (therapy phase).

The researchers found that the number of new black holes increased during both the treatment and natural history phases for all patients, but the accumulation of new black holes was substantially lower for patients during the treatment phase. The duration of new black holes arising during the treatment phase was not shorter than the duration of black holes arising during the natural history phase, however.

"The sample size is small, but the length of the longitudinal followup (i.e., 72 months) represents a robust and valid data set for describing the course of MS during both the NHPs [natural history phase] and TPs [therapy phase]," the authors note. "We demonstrate that new BHs [black holes] may significantly accumulate over time even when IFNβ-1b [interferon beta-1b] is administered. However, repeated administration of the drug did significantly decrease the rate of BH formation, thus protecting the brain tissue from accumulating degenerative lesions."

"One can postulate that although IFNβ-1b may reduce the frequency of BHs, after the lesion occurs, the drug is not changing the pathological process," the authors write. They suggest larger studies over longer periods might reduce difficulties in interpretation encountered in this study, allowing a better assessment of whether the analysis used might be useful in establishing the proper role of neuroprotective drugs of the central nervous system in the treatment of patients with MS.

Oral Contraceptives Associated With Reduced Risk Of Multiple Sclerosis

Tue, 13 Sep 2005 13:47:38 PST

( from http://www.rxpgnews.com ) Over a three-year period, the risk of developing multiple sclerosis (MS) was reduced in women taking oral contraceptives, according to a study in the September issue of the Archives of Neurology, one of the JAMA/Archives journals.

In previous studies, estrogen delayed the onset and eased the course of a MS-like disease in animals, suggesting that oral contraceptives, which contain estrogen, and pregnancy and the postpartum period afterward, both states associated with profound hormonal changes, may alter the clinical course or affect the risk of developing the disease, according to background information in the article.

Álvaro Alonso, M.D., Ph.D., of the Harvard School of Public Health, Boston, and colleagues compared 106 women who had a new diagnosis of MS between January 1, 1993 and December 31, 2000 with 1,001 matched women without MS as controls. Individuals included in the analysis were drawn from a research database that includes medical and pharmacy records for three million Britons.

"The incidence of MS in OC [oral contraceptives] users was 40 percent lower than in nonusers," the authors report. "Women had a higher risk of developing first symptoms of MS in the six months following a pregnancy and a non-significant lower risk during pregnancy, compared with those with no pregnancy. ...This is consistent with studies on the effect of pregnancy in patients with MS and the immunological changes associated with pregnancy."

"Recent OC use and, possibly, current pregnancy are associated with a lower risk of developing MS," the authors conclude. "On the contrary, the postpartum period confers a higher risk of MS onset. Our findings suggest that high levels of exogenous [from outside the body] estrogens from OC use and of endogenous [from the body] estrogens during pregnancy may delay the first clinical attack of MS."

Fampridine-SR in Phase 3 Trial for Multiple Sclerosis Under FDA Guidance

Wed, 04 May 2005 21:55:38 PST

( from http://www.rxpgnews.com ) Acorda Therapeutics announced today that it has reached an agreement with the U.S. Food and Drug Administration (FDA) on a Special Protocol Assessment for a pivotal, Phase 3 clinical trial of Fampridine-SR in multiple sclerosis (MS). A Special Protocol Assessment (SPA) is a process in which the FDA provides evaluation and guidance on clinical trial protocols for Phase 3 studies.

"We are delighted to have reached this agreement with the FDA on the design of our pivotal study of Fampridine-SR in MS. We look forward to beginning the study as soon as possible," said Ron Cohen, M.D., President and CEO of Acorda Therapeutics.

The primary outcome measure for the study will be an improvement in walking as measured by the Timed 25-Foot Walk and the MS Walking Scale-12 (MSWS12). Currently, there are no treatments available that improve walking in MS sufferers, and physicians and patients regularly rate walking as one of the areas of greatest unmet medical need for this condition. Secondary outcome measures for the study include the Lower Extremity Manual Muscle Test (LEMMT), a standardized, 5-point manual assessment of leg strength, as well as the Ashworth score for spasticity and global impressions.

MS is characterized by frequent waxing and waning of the patient's walking ability, strength and other neurological functions. The objective of the study will be to show that individuals treated with Fampridine-SR are significantly more likely to have consistent improvements in their walking than those treated with placebo.

About Fampridine-SR

Fampridine-SR ("4-aminopyridine", "4-AP") is an investigational, sustained-release tablet formulation of 4-aminopyridine. It is being developed in human clinical trials for both MS and spinal cord injury (SCI). In laboratory studies fampridine has improved impulse conduction in nerve fibers in which the insulating layer, called myelin, has been damaged.

Results from the most recent Phase 2 MS clinical trial showed a positive trend for improvement in average walking speed (as measured by the Timed 25 Foot Walk) and a statistically significant improvement in LEMMT. A post-hoc analysis, using the methods to be applied in the Phase 3 study, showed a significant increase in the number of subjects with consistently improved walking speed in the Fampridine-SR treated group versus the placebo-treated subjects. These data are consistent with from the results of earlier Phase 2 trials.

Adverse events, including serious adverse events, seen in these studies were insomnia, paresthesias (numbness/tingling), dizziness and nausea, the majority of which were rated as mild to moderate. Seizure was reported in a small number of patients at higher doses than are currently being evaluated. As Fampridine-SR is an investigational drug, safety and efficacy have not been fully determined.

Cigarette Smoking linked with Progression of Multiple Sclerosis

Tue, 26 Apr 2005 02:19:38 PST

( from http://www.rxpgnews.com ) Researchers from the Harvard School of Public Health (HSPH) recently discovered that cigarette smoking may contribute to the progression of multiple sclerosis (MS), suggesting that quitting smoking could limit or delay central nervous system deterioration. This is the first time that a modifiable risk factor for MS progression has been identified, providing a new strategy for patients hoping to control neurological damage from the disease.

Miguel Hernán, lead author of the study and an assistant professor of epidemiology at HSPH, noted that the findings are interesting because no modifiable risk factors for the progression of MS are known. This was the first prospective study that identified a potential intervention (quitting smoking) for reducing the risk of progression of MS.

Analyzing over 2,000 medical records in the General Practice Research Database (GPRD), researchers identified 179 British patients who were originally diagnosed with relapsing-remitting MS, a form of the disease in which symptoms fade and recur in unpredictable patterns. Patients who were current or past smokers were 3.6 times as likely as patients who had never smoked to develop secondary progressive MS, a later stage of the disease marked by steady deterioration of the central nervous system. This disease progression also occurred more quickly in patients who were identified as current or past smokers. The study also supported earlier research showing that smoking may increase the risk of initial MS diagnosis. Current and past smokers were 30% more likely to be diagnosed with MS than those who had never smoked.

While more research is needed to understand the mechanisms behind these findings, Hernán and his colleagues speculate that nitrous oxide, a chemical present in cigarette smoke, may play a role in hastening the degeneration of nerve fibers. Alternatively, chemicals in cigarette smoke could damage the cells that create myelin, a protective coating for neurons, or may predispose smokers to autoimmune responses.

According to Hernán, Our findings raise a number of other questions that future research needs to address. Does a dose-response relation between cumulative exposure to tobacco and risk exist? How long does the tobacco effect last? Is second-hand smoking associated with an increased risk as well?

Naltrexone for HIV/AIDS, Cancer, and Autoimmune Diseases such as Multiple Sclerosis?

Tue, 19 Apr 2005 11:09:38 PST

( from http://www.rxpgnews.com ) The drug naltrexone, which in a 50 mg dose was approved by the FDA many years ago for drug abuse and for alcoholism, in less than one-tenth that dosage boosts the immune system and thus helps fight any disease that is characterized by inadequate immune function.

Investigators mounting successful clinical trials, along with physicians and patients utilizing low dose naltrexone (LDN), will make panel presentations on June 11th at a conference to be held at the New York Academy of Sciences. The keynote speaker will be Bernard Bihari, MD, a Manhattan physician and the discoverer of the clinical effects of LDN.

This discovery establishes a new paradigm in medical therapy: LDN not only tends to normalize the immune system by elevating the bodys endorphin levels but also accomplishes its results with virtually no side effects or toxicity.

Two pilot studies have recently been completed, one for Crohns disease and one for multiple sclerosis (MS), and the principal investigators, respectively from Hershey Medical Center at Penn State and from Dr. Evers Clinic, a hospital for neurological disease in Germany, will be present.

The promise of LDN is significant because:

(a) it can halt diseases (e.g., MS and other autoimmune diseases, HIV, and many cancers) where there are no effective treatment options;

(b) it provides successful treatment while being virtually free of side effects or toxicity; and

(c) were it produced in a developing country, this generic drug would offer an extremely inexpensive ($10 per year) HIV treatment, one that does not require close supervision by health professionalsthe patient need only take one small capsule each night at bedtime.

AVP-923 will Help Control the Inappropriate Emotions Associated with Multiple Sclerosis

Fri, 15 Apr 2005 11:04:38 PST

( from http://www.rxpgnews.com ) Now people with multiple sclerosis (MS) can have a better control over their emotions,thanks to the latest research scheduled to be presented at the American Academy of Neurology 57th Annual Meeting in Miami Beach, Fla., April 9 16, 2005.

Pseudobulbar affect, is a condition that results in episodes of uncontrollable laughing or crying that may be inappropriate or not related to the situation. The condition can also occur with other neurological disorders such as amyotrophic lateral sclerosis (ALS), Alzheimers disease, stroke, and brain injury.

For the study, 150 people with MS and pseudobulbar affect received either the drug AVP-923, which is a combination of the drugs dextromethorphan hydrobromide and quinidine sulfate, or a placebo for 12 weeks.

The study participants kept a diary tracking the number of laughing/crying episodes they experienced each day, as well as any side effects, and were assessed at four clinic visits.

Of those taking the drug, 84 percent reported improvement in the condition, compared to 49 percent of those on placebo. Those taking the drug had 46 percent fewer emotional episodes during the study than those who received the placebo. They also reported overall improvement in the condition and improvement in their quality of life, quality of relationships, and amount of pain they experienced. Those taking the drug reported the side effect of dizziness more often than those taking the placebo did.

This is the first drug designed specifically for this condition, said neurologist Hillel Panitch, MD, of the University of Vermont College of Medicine in Burlington, VT. The only treatment now is antidepressants, which can have unpleasant side effects.

Panitch said the treatment showed improvements as early as the first week of treatment.

Leptin's Role in Multiple Sclerosis

Wed, 30 Mar 2005 06:44:38 PST

( from http://www.rxpgnews.com ) According to Giuseppe Matarese et al., increased levels of the cytokine-like hormone leptin in individuals with multiple sclerosis (MS) inversely correlates with the frequency of CD4+CD25+ regulatory T cells (TRegs).

Previous research has shown that leptin plays a significant role in the pathogenesis of autoimmune diseases such as experimental autoimmune encephalomyelitis, an animal model for MS.

The role of leptin in the pathogenesis of human MS is not fully understood. The authors studied 126 naïve-to-therapy, relapsingremitting MS patients and detected an increase in leptin in both their cerebrospinal fluid and serum.

This increase correlated with elevated IFN-γ levels. Matarese et al. generated T cell lines from three of the individuals and, after activating the cells with human myelin basic protein, found an increase in leptin production and up-regulation of the leptin receptor.

Antileptin or an antileptin receptor blocking antibody inhibited the proliferative response of these T cells by up to 60%. Immunophenotypic analysis of peripheral blood from the MS patients showed a significant reduction in percentage and absolute number of TRegs, whereas no difference was observed in the frequency of other cell subpopulations. Treatment of experimental autoimmune encephalomyelitis mice with leptin antagonists increased the percentage of TRegs and slowed disease progression.

RPI-78M Decreases Progression of Multiple Sclerosis by Altering Gene Expression

Thu, 03 Mar 2005 16:23:38 PST

( from http://www.rxpgnews.com ) Nutra Pharma Corp.,a biotechnology holding company that owns rights to intellectual property related to the development of drugs for HIV and Multiple Sclerosis has announced that its contract researchers, Eno Research and Development, Inc. (ERDI) have completed their analysis of a series of microarray studies with RPI-78M in the gene expression of cells from Multiple Sclerosis (MS) patients.

RPI-78M is the lead drug candidate of Nutra Pharma's minority holding, ReceptoPharm, Inc. and is being studied in preclinical assays for its efficacy in treating MS. ERDI measured the effect of RPI-78M on gene expression using cDNA microarray technology to identify any potentially unique changes in gene expression that may be caused by the therapy.

ERDI was contracted by Nutra Pharma to analyze immune cells and brain lesions of Multiple Sclerosis patients with and without the addition of RPI-78M. They measured the changes in gene expression that occurred with treatment.

After statistical evaluation of the data, ERDI found more than sixty genes with significant changes in expression as compared to the control. In analyzing the affected genes, at least thirty of them may have a specific role in the progression of the disease and symptoms of MS.

"RPI-78M had a significant affect on the genes in the cytokine pathway as well as the myelination pathway," commented James Flowers, President and Chief Scientific Officer of Eno Research and Development, Inc. (ERDI).

"The cytokine pathway genes play a role in marshaling the attack on the nervous system by immune cells. Since this is one of the principle pathways that lead to the forward progression of MS, it is notable that if these results were replicated in the patient population it may greatly reduce the severity of the disease" he continued.

"Additionally, genes responsible for repair and maintenance of the myelin sheathes of neurons were upregulated. MS patients have a loss of myelin, the insulating material that surrounds the nerve fibers in the brain, spinal cord, and optic nerves. This damage or loss of myelin can prevent nerve signals from being conducted, or can cause those signals to be conducted too slowly. The data from this study suggests that RPI-78M may aid the patient in reversing some of the damage caused to the myelin by their disease." ERDI will continue to study RPI-78M and its effects on gene expression as well as the drug's effects in histoculture experiments that may further elucidate its mechanism of action.

There has been a great deal of interest surrounding research in Multiple Sclerosis therapies. There are currently four drugs on the market for the treatment of the disease. A fifth drug, Tysabri, was voluntarily pulled from the marketplace earlier this week by the drug's manufacturers, Biogen-Idec and Elan.

"We are working diligently with ERDI to bring this information to the scientific community," commented Rik J Deitsch, Chief Executive Officer of Nutra Pharma. "We expect to present the data at related conferences and to seek publication of the finished work. These studies, when coupled with the positive results in the recently-completed animal model, create substantial evidence of the drug's effects against MS. We are currently seeking potential partners that should allow us to move into sanctioned human trials," he added.

Multiple sclerosis (MS) is an autoimmune disease in which the immune system, the body's principal defense against foreign substances such as bacteria, mistakenly attacks normal tissues of the central nervous system. It afflicts approximately 400,000 people in the United States and more than 2.5 million worldwide. Specifically, the disease results in damage to a fatty tissue called myelin that surrounds and protects nerve fibers, creating scarring (sclerosis) that interferes with the normal transmission of nerve impulses. This damage, in turn, leads to a variety of chronic and highly individual and unpredictable neurological symptoms, ranging from movement and balance problems to vision impairment.

The disease is largely caused by activation of a specific subset of the patient's own white blood cells, T-cells that then attack the myelin and are largely responsible for disease progression.