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Asian Journal of Biochemical and Pharmaceutical Research Issue 3 (Vol. 1) 2011 ISSN: 2231-2560

Review Article

Asian Journal of Biochemical and Pharmaceutical Research

An updated review on multiple sclerosis

Gaurav Sharma*, Sunil Kumar, Neha Sharma & Sidharth Mehan

Department of pharmacology, Shoolini University , Solan, (H.P), India

Received: 12 June 2011; Revised: 1July 2011; Accepted: 10 August. 2011

Abstract: Multiple sclerosis is a diseases bewilder us all. It is lifelong diseases of the brain and spinal cord begins in early adulthood and afflicts women two times as often as men.MS is a chronic inflammatory demyelination disorder of the CNS and the spinal cord in which the myelin sheaths around axons of the brain and spinal cord are damaged leading to demyelination and scarring. The primary cause of multiple sclerosis is unknown. Environmental risk factors and multiple genetic loci contribute to susceptibility to the disease. The onset of the symptoms of multiple sclerosis is often associated with breakdown of the blood–brain barrier, as visualized by MRI, evoked potential, lumbar puncture. purpose of this review article to update the knowledge of the multiple sclerosis and future prospect under treatments which are under clinical trials. Keywords: Multiple Sclerosis, Mylination , Blood Brain Barrier, Demylination

INTRODUCTION:

Multiple sclerosis (MS) though rare in Asia, is the commonest progressive neurological disease in the temperate climates. There are approximately 2,50,000 to 3,50,000 people in United States of America with MS with the prevalence being approximately 100 cases per 1,00,000 population and approximately 80,000 people in United Kingdom with the prevalence being approximately 130 cases per 1,00,000 population. The onset of MS usually occurs between 20 and 50 years of age, with a peak at 30 years[1]. MS disease of the central nervous system affecting approximately 1 million young adults,mostly women, worldwide. It is characterized by episodic neurologic symptoms that are often followed by fixed neurologic deficits, increasing disability, and medical, socioeconomic, and physical decline over a period of 30 to 40 years[2].

What is Multiple sclerosis?

Multiple sclerosis is a disease of the central nervous system. It most commonly occurs in individuals between the ages of twenty and forty and in higher numbers of women than men[3]. In Multiple Sclerosis (or "MS") a loss of the nerves' axon coating myelin prohibits the nerve axons from efficiently conducting action and synaptic potentials. Scar tissue (called plaques or lesions) forms at the points where demyelination occurs in the brain and spinal cord, hence the name "Multiple Sclerosis and many scars"[4] .

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FIG:--Nerve axon with myelin sheath

Pathophysiology :- The pathogenesis of MS are not fully understood, but most research supports immunological involvement in which the myelin sheath surrounding the neurons is attacked by sensitized T-cells which trigger a non-specific inflammatory response, mediated by cytokines and other immune modulating substances. Demyelination may have either negative or positive effects on axonal conduction. Negative conduction abnormalities consist of slowed axonal conduction, variable conduction block that occurs in the presence of high - but not low - frequency trains of impulses or complete conduction block. Positive conduction abnormalities include ectopic impulse generation, spontaneously or following mechanical stress, and abnormal “crosstalk” between demyelinated axons. Conduction block may account for the fluctuations in function that vary from hour to hour and from day to day in MS. Conduction of nerve impulse is impaired due to edema at the perivascular cuff, causing compression of the axons MS appears to be an autoimmune disease mediated at least in part by T lymphocytes. In the laboratory model experimental allergic encephalomyelitis (EAE),an autoimmune disease resembling MS is induced by immunization with CNS antigens. Antigens that can elicit EAE are myelin basic protein (MBP), proteolipid protein, myelin oligodendrocyte glycoprotein and other myelin proteins or neural antigens. The sequence of immunopathogenic events is as follows: (1) Neural antigens are processed by antigen - presenting cells in regional lymphnodes and presented to T cells capable of recognizing them. (2) Small number of sensitized memory T cells migrate to the CNS, where they are reactivated by antigen presented by macrophages or microglial cells. (3) Proinflammatory cytokines, including interleukins (IL-1, IL-2, IL-6), tumor necrosis factor (TNF)�, RANTES, interferon (IFN)�are secreted that enhance expression of adhesion molecules by vascular endothelium, alter the permeability of the blood brain barrier (BBB) and induce a second wave of inflammatory cell recruitment to the site. Multiple effector mechanisms may contribute to the formation of lesions, including auto-antibodies, cytotoxicity mediated by T cells or natural killer cells and cytokine mediated injury to oligodendrocytes or myelin .The mutations resulting from chronic stimulation of MBP reactive T cells in vivo, appears to be specific for MS. Continuation of non-specific secondary inflammatory reaction with enlargement of existing lesions and further plaque formation produces the chronic phase of MS. The extent of axonal damage is controversial, but evidence that some axons may remain intact provides encouragement to research targeted at


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stimulating remyelination[5]. Remyelination does occur to some extent, but obviously cannot keep pace with the rate of demyelination[6].

SIGN and SYMPTOMS : MS is unpredictable. It varies from person to person and can result in a wide variety of symptoms, none of which are unique to MS. Many people experience only a few symptoms and it is unlikely that anyone will develop them all. People can have different symptoms at different times and, although some are very common, there is no typical pattern that applies to everyone. Some of the common symptoms are: • fatigue – an overwhelming sense of tiredness making physical or mental activity difficult and, for some, impossible • balance problems and vertigo – walking difficulties, problems with coordination • visual problems – blurred or double vision, temporary loss of sight in one eye or both • numbness or tingling – commonly in the hands or feet • pain – sometimes mild, sometimes severe • loss of muscle strength and dexterity • stiffness and spasms – tightening or rigidity in particular muscle groups • anxiety, depression or mood swings


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• cognitive problems – difficulty with memory and concentration • speech problems – slurring, slowing of speech, or changes in pitch or tone • incontinence – a lack of control over bladder or bowel functions • sexual problems – lack of libido, erectile difficulties.7

What causes Multiple sclerosis? The causes of MS are unknown. Research suggests that a combination of genetic and environmental factors may play a role in its development.

Genes and family history :MS is not directly inherited and, unlike some conditions, there is no single gene that causes it. It seems likely that a combination of genes make some people more susceptible to developing MS. Indeed there is only around.a two per cent chance of a child developing .MS when a parent is affected[8].

Environmental factors :MS is more common in areas further away from the equator. It is virtually unheard of in places like Malaysia or Ecuador, but relatively common in Britain, North America, Canada, Scandinavia, southern Australia and New Zealand. It is not clear why, but it is possible that something in the environment, perhaps bacteria or a virus, plays a role. No single virus has been identified as definitely contributing to MS, but there is growing evidence that a common childhood virus, such as Epstein Barr virus, may act as a trigger. like genes. There is also a growing amount of research that suggests vitamin D could be a factor. We get most of our vitamin D from exposure to sunlight. Low levels of vitamin D have been linked to higher numbers of people developing many different conditions, including MS. Vitamin D may be one of many factors and research into this area continues[8].

DIAGNOSTIC METHODS : By now you are probably aware that MS is not easily diagnosed. This is because there is currently no single test to determine whether a person has the disease. Rather, a clinical diagnosis is made on the basis of a person's medical history, an assessment of symptoms reported by the person, and the presence of abnormalities detected by the physician. During the comprehensive neurologic examination. At the present time, a physician can make a definite MS diagnosis only if the following criteria are met: 1) There must be evidence of plaques (lesions) in at least two separate areas of the CNS. 2) It must be clear that the plaques have formed at different points in time or progressively over six

months' time. 3) And, most importantly, there must be no other reasonable explanation for the plaque formation or the person's symptoms.

Laboratory Tests :-There are no laboratory tests that are completely specific for multiple sclerosis. However, several laboratory tests generate abnormal results in patients with MS and are helpful in diagnosing or excluding this disease. The most useful tests look for evidence of immunolgloblin G (IgG) production within the central nervous system. They include:


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CSF Analysis : Evalutes physicial and chemical aspects of the CSF that may be altered by MS.\ Cerebrospinal Fluid (CSF) Electrophoresis and Isoelectric Focusing:-Electrophoresis and isoelectric focusing are two methods for separating the proteins in a biological fluid. A patient’s CSF and serum evaluated side-by-side on a test surface using either of these two techniques. Following the separation step, a protein stain is applied to both specimens, and the banding patterns of the proteins in CSF and serum that appear are compared to one another. The presence of two or more IgG bands in CSF that are not present in serum is a positive test for oligoclonol banding. About 90% of MS patients show oligoclonal banding in their CSF. CSF Immunoglobulin G (IgG) Index:- Increased levels of CSF IgG can be due to excess production of IgG within the central nervous system, which is seen with multiple sclerosis and several other diseases, or they can be due to leakage of plasma proteins into the CSF, such as might occur with inflammation or trauma. To discriminate between these two possibilities, the IgG index is calculated from IgG and albumin measurements performed in CSF and serum. The calculation usually takes the following form :

IgG index = [IgG (CSF) / IgG (serum)] / [Albumin (CSF) /Albumin (serum)]

An elevated IgG index indicates increased production of IgG within the central nervous system. It is found in about 90% of MS cases. Myelin basic protein :-is a major component of myelin. Increased concentrations of myelin in CSF indicate that demyelination is taking place. This process is not specific for MS, as other inflammatory diseases of the central nervous system can also elevate the amount of myelin basic protein in CSF. This test is not widely used; however, it may be used to assess disease activity in cases of established MS. Non-Laboratory Tests:-MRI (magnetic resonance imaging) scans allow doctors to literally see into the brain. They can show both permanent scarring as well as new lesions. These scans are used to help diagnose MS and to track its progression over time. In addition to the standard MRI, there are a variety of specialized techniques that may be performed, such as functional MRI, magnetic resonance spectroscopy, and diffusion-tensor MRI.

Visual evoked potentials (VEP) :-are electrical diagnostic studies that measure the speed of nerve transmissions (messages) in various parts of the brain. They are sensitive to MS damage and can detect evidence of scarring along nerve pathways[9].

Types of MS:The course of MS is difficult to predict, as the disease may lie dormant one moment and progress steadily the other. Nevertheless, several subtypes, or patterns of progression, have been described. Subtypes use the course of the disease so far in order to extrapolate the future development of it. The probable prognosis gives a better groundwork for therapeutic decisions. As a standard, the subtypes are relapsing-remitting, secondary progressive, primary progressive and progressive relapsing.


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Relapsing-remitting : Relapsing-remitting describes the initial course of 85% to 90% of individuals with MS. This subtype is characterized by unpredictable attacks (relapses) followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during the attacks may either resolve or may be permanent. When deficits always resolve between attacks, this is referred to as "benign" MS. Primary progressive : Primary progressive describes the approximately 10% of individuals who never have remission after their initial MS symptoms. Decline occurs continuously without clear attacks. The primary progressive subtype tends to affect people who are older at disease onset. Secondary progressive : Secondary progressive describes around 80% of those with initial relapsing-remitting MS, who then begin to have neurologic decline between their acute attacks without any definite periods of remission. This decline may include new neurologic symptoms, worsening cognitive function, or other deficits. Progressive relapsing: Progressive relapsing describes those individuals who, from the onset of their MS, have a steady neurologic decline but also suffer superimposed attacks; and is the least common of all subtypes . Others :-Special cases of the disease with non-standard behavior have also been described although many researchers believe they are different diseases. These cases are sometimes referred to as borderline forms of multiple sclerosis and are Neuromyelitis optica (NMO),Balo concentric sclerosis,Schilder’s diffuse sclerosis and Marburg MS[10].

THERAPEUTIC MANAGEMENT : There are many treatment options available for MS, both conventional and unconventional. Keep in mind that if you decide to use any “untested” compounds or follow untested procedures, you need to consider the following factors: safety, effectiveness, cost, and quality-of-life trade-offs. Anecdotal information rarely provides you with all the data you need to assess these areas. Even “all natural” products and supplements can be dangerous, expensive, ineffective, or painful. Diseases modifying therapies:-The most plausible theory concerning the cause of MS is that it is an abnormal, autoimmune response. Therefore, most drugs in this category set out to modify the immune system, either by stimulation or suppression[11].

INTERFERONS: The interferons are naturally occurring amino acids and are cytokines. They are synthesised in response to viruses and act on other cells to prevent them becoming infected. Gamma interferon produced by T cells is thought to activate macrophages which then destroy myelin directly and has been shown to exacerbate MS. Interferons alpha and beta are produced by many different cells, including macrophages, fibroblasts and endothelial cells. Interferon beta is known to have immunomodulatory effects.12 These include inhibition of leukocyte proliferation and antigen presentation, inhibition of T-cells migration across the blood brain barrier and modulation of cytokine production to produce antiinflammatory environment.13 Of the beta interferons, 1a and 1b (IFNB-1a


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and IFNB-1b) have been shown to be most beneficial in multiple sclerosis. IFNB-1a and IFNB -1b are similar in their biological activity and in vivo pharmacokinetics.14 There are three preparations inuse, Avonex, Rebif (interferon beta-1a) and Betaferon (interferon beta-1b). Avonex is given by intramuscular injection at a dose of 30 �g (6 million IU) once a week. Rebif is given subcutaneously at a dose of 22 �g (6 million IU) three times a week. Betaferon is given subcutaneously at a dose of 0.25 mg (8 million IU) on alternate days. The most common adverse effect is a flu-like syndrome, which is prominent at the start of therapy and then wear off with continued treatment. NSAIDs are recommended prophylactically before each interferon dose to alleviate the symptoms. Glatiramer acetate (copolymer-1):- Glatiramer acetate is a synthetic compound made of four amino acids (the building blocks of proteins) that are found in myelin.15 It has been shown in clinical trials that glatiramer acetate reduces the number and severity of relapses and appears to slow the onset of disability in somepeople with MS. While the mode of action of glatiramer acetate is not completely understood, it is different from that of the interferons. Over the past 15 years, there have been many clinical trials to investigate the efficacy and safety of glatiramer acetate in people with MS. The best results were seen in people with MS who had the lowest levels of neurological disability. Studies have shown that at the end of 2 years there were about 25% fewer relapses in people taking glatiramer acetate compared with those not taking the drug, and more people on the drug tended to improve.It is a synthetic polypetide analogue of myelin basic protein. It was accidentally discovered during attempts to induce experimental allergic encephalomyelitis in animals (the animal model of MS). Its mode of action has not been defined, although it is thought to involve inhibition of lymphocyte migration16 and suppression of T-cell activation.17 It may exert its effect by competing with myelin basic protein and perhaps other myelin autoantigens for binding to MHC Class II molecules expressed on antigen presenting cells. It is given daily at a dose of 20 mg subcutaneously and is well tolerated with the most common adverse experience being injection site reaction. A two year study demonstrated a 29% reduction in relapse rate in patients with RRMS[18-19]. Intravenous immunoglobulin (IgG):- In a two-year randomised controlled trial, approximately 150 patients with RRMS showed a favourable effect on relapse rate in the treatment group, who received intravenous immunoglobulin 0.15-2g/kg/month. The beneficial mechanism of action of immunoglobulins in MS may involve binding of the Fc receptor portion of the Ig molecule to the B cell, creating negative signals and thus causing B cell down regulation. The beneficial effects on disability and annual relapse rates were modest, although comparable to the copolymer 1, interferon beta - 1 band interferon beta - 1a trial results. A beneficial effect has also been demonstrated on MRI activity The main side effects are malaise, headache, fever,rash and rarely aseptic meningitis, thromboembolism and transmission of infection[20].

Steroids:- Used for acute flares/attacks of MS, steroids Solumedrol, Decadron, Prednisone for example) can be given intravenously (IV) or by mouth (PO). They are used to shorten the duration and reduce the severity of the attack. Although well tolerated by most, these drugs can also result insignificant side effects in some people. Types:The use of steroid-based drugs for ‘attacks’ or ‘relapses’ of MS has been the standard treatment for MS for some years, and many people may still find that this is the first line of treatment offered to them.There are several types of steroid drugs:


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Adrenocorticosteroids: (such as ACTH – AdrenoCorticoTrophic Hormone), used to be one of the most commonly used steroids in MS. Glucocorticosteroids: (such as prednisolone, given by mouth; or methylprednisolone, usually given through a drip, intravenously) are used more commonly now. Effects of steroids:There is substantial evidence that both types reduce the inflammation at active disease sites in the CNS and, in particular, reverse disruptions of the blood–brain barrier that may occur when the disease is active. These effects, in turn, should reduce the duration and degree of symptoms. However, most studies suggest that the effects of steroids are relatively short term, perhaps lasting a few weeks, although there have been one or two studies which suggest tantalizingly that there may be far longer positive effects of the combined short-term use of methylprednisolone and prednisolone.

How are steroids given?

ACTH has now been replaced by the use of methylprednisolone and prednisolone, but there is widespread debate amongst neurologists about the most appropriate steroid and mode of administration in MS. People with MS are likely to come across different ways in which steroids are currently given – intravenously administered methylprednisolone (called IVMP for short) normally requires a hospital stay for one to several days, depending on precisely how the drug is administered. There may need to be other hospital stays for assessment purposes.21

Unconventional:- CAM (Complementary and Alternative Medicine): Complementary and alternative therapies can be used in conjunction with or instead of conventional medicine. This is a category of medical therapies that includes some very old and some very new methods of treating people with disease. An increasing number of physicians are seeking out additional training in alternative therapies. Why? Because patients are seeking it out in large numbers. A recent study appearing in the journal Multiple Sclerosis found that more than half of all people with MS have sought out alternative therapies at one time or another[21].

A few of the major CAM therapies are discussed below:-

Homeopathy: Homeopathy is a form of “alternative”medicine that has been around for hundreds of years. Two centuries ago, a physician in Germany experimented with a vast number of natural remedies and authored the “Materia Medica.” Curiously, he found that infinitesimal doses of many substances were more effective than large doses. Indeed, large doses of some homeopathic remedies are extremely toxic (arsenic, for example!). Lately, homeopathic medicine has undergone a resurgence. Can homeopathic remedies help you and your MS? Maybe yes and maybe no – since appropriate drug trials have not yet been done, there is no data to tell how likely it is that a specific homeopathic remedy will help you[22].

Traditional Chinese medicine:- The body is understood quite differently by traditional Chinese medicine, which has been handed down from practitioner to practitioner for many centuries. Far more importance is given to the individual patient as opposed to the body system that is ailing. Thus, a practitioner may treat two people with the same condition completely differently. A problem


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frequently cited by doctors regarding traditional Chinese medicine is that the remedies (mostly of natural origin) are not standardized the way “approved” medications are in the United States. Each preparation may contain many components and the ratios of each component may vary from dose to dose. One infamous case concerned a preparation later found to contain ephedrine, a compound that can cause heart palpitations. Chinese practitioners are, on the whole, very well trained, many of them in both traditional and modern medicine[22].

Acupuncture:- This form of ancient medicine has recently found its way into the mainstream. Acupuncture involves the insertion of very fine needles over various places in the body. These places are along the lines of “chi” which represent energy flow in the body. There have been a number of well-conducted clinical trials that have found acupuncture to be effective for a variety of complaints related to MS.

Chiropractic treatment:- The idea behind chiropractic treatment is that pain or dysfunction caused by misaligned vertebrae in the spinal column can be relieved by adjustments that realign the vertebrae. Chiropractic care is often sought out by people with MS for symptomatic relief, although as with many of the treatments in this section, the evidence for its benefits in MS is largely anecdotal.2

Energy medicine:- There are various forms of energy medicine, including reiki, craniosacral therapy, reflexology, and many more. Many people believe them to be effective, but there are no studies to prove this.

Vedic medicine:- Vedic medicine is a comprehensive traditional system of natural medicine designned to balance overall health and to relieve symptoms of chronic diseases, such as MS. Vedic medicine is reportedly the oldest continuously practiced medical system with its heritage in ancient civilizations of India. Using pulse diagnosis and other well established diagnostic and clinical assessment techniques, Vedic practitioners prescribe a variety of techniques that results in an individualized treatment plan. These treatment plans, which vary from disease to disease, often include dietary modifications and Vedic exercise according to body type, transcendental meditation, dietary herbs, and herbal oil and massage treatments. Some people with MS have reportedly found Vedic medicine a helpful adjunct to their Western therapy.2

Apitherapy: This therapy involves being stung by a bee or injected with extracted bee venom, and is thought by some to be helpful in MS as well as other conditions such as arthritis.22

FUTURE therapies under clinical trial :

ORAL THERAPIES :- Teriflunomide:-This is a dihydro-orotate dehydrogenase inhibitor which has been shown to affect favourably the experimental allergic encephalomyelitis model\ of inflammatory demyelination. In a short phase II trial it was shown to impact significantly and beneficially on MRI scan unique active lesions and there was a trend in the higher treatment group towards a lower annualised relapse rate with fewer patients demonstrating an increase in disability even though the trial lasted only 36 weeks


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[23]. This, rather surprising effect upon clinical parameters, led to phase III studies, two of which are looking at the effect of teriflunomide in RRMS examining its effect in CIS. Cladribine :- This adenosine deaminase-resistant purine nucleoside analogue preferentially depletes sub-populations of lymphocytes. It is already used in treatment of people with haematological malignancy and it was originally used parenterally in people with MS almost 20 years ago. There are two phase III studies currently underway, using doses between 0.7-2.0 mg/kg, the first is a two year randomised, placebo controlled trial of cladribine mono-therapy in people with relapsing remitting multiple sclerosis (RRMS) and the second is a combination study involving induction with oral cladribine and maintenance therapy with interferon ß-1a 44µg given thrice weekly [24]. In the first study the primary outcome measure is relapse rate during the two years of the trial, and in the latter is the number of new gadolinium enhancing lesions on MRI scan. Cladribine has been awarded “fast-track” status by the FDA and it is probable that the results of these studies will be available early in 2009. Fingolimod:-Fingolimod (FTY720) is an analogue of sphingosine-1-phosphate which modulates S1P receptors and entraps lymphocytes in secondary lymphoid organs inhibiting their ability to enter the CNS. The drug is already used in transplant management and in an initial phase II trial showed a significant and rapid reduction in MRI measures of inflammation and in clinical relapses. There was an extension phase of the initial 6 month trial and the difference in MRI and clinical relapses has continued to three years. There are two phase III trials underway, one against placebo and one in comparison with an approved DMT[25]. The diffuse effects of the S1P analogue result in changes in pulse rate, blood pressure and symptoms of breathlessness, headache and nausea. There is a significant lymphopaenia in the peripheral blood and in the phase II study there was a single case of posterior reversible leukoencephalopathy syndrome (PRES) with a persistent neurological abnormality. In the phase III trials there have been two fatalities due to Herpes infection. In future it is possible that more specific S1P molecules will become available and lessen side-effects. There is some suggestion in vitro that fingolimod (FTY720) can increase mature and immature oligodentrocyte populations and therefore might have a potential effect on remyelination.

Fumaric acid:- Fumaric acid (BG12) was developed for the treatment of psoriasis in the belief that the dermatological problem was caused by an abnormality on the Krebbs cycle. It appears to inhibit the expression of pro-inflammatory adhesion molecules on endothelium and reduce cytokine production, and it may have novel neuroprotective effects by an action on oxidative metabolism. A phase II trial showed a significant reduction of gadolinium enhancing lesions on MRI and a reduction in T1 weighted black holes.It is now in phase III studies where minor problems include headache, nasopharyngitis and flushing which, in some patients, is so severe as to preclude continued use of the agent[26].

Monoclonal Antibody:- Monoclonal antibodies are selective immunoglobulins which bind to specific molecules of the surface of targeted cells. In MS agents acting against both T and B cells have been considered and are being studied in phase III trials. They are very effective immune modulating therapies and therefore have potential toxicity, including infusion related reactions, the development of neutralising antibodies and the occurrence of opportunistic infections or neoplasia[27].


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Natalizumab:-The first monoclonal to be licensed for use in MS is natalizumab (Tysabri) which targets alpha-4 integren, an adhesion molecule on the surface on T-lymphocytes. By blocking this molecule it prevents the lymphocyte interaction with surface adhesion molecules on the endothelium of the cerebral vessels and the ingress of such activated T-cells to the central nervous system. Two major phase III trials were performed and the agent was licensed in 2004. It was withdrawn from the market in 2005 after 2 patients, who had completed one of the phase III trials in which they took natalizumab together with interferon ß-1a, developed PML.17 In another trial in patients with Crohn’s disease a further case was identified retrospectively. Once a risk management plan had been devised and two monitoring studies (TOUCH in the USA and TYGRIS in the rest of the world) had been implemented, the drug was allowed to be used again from 2007[28]. Rituximab:-The anti-CD20 monoclonal rituximab has been used in MS because of the belief that B cells are involved in the immunopathogenesis. It has been shown, in a large phase II trial, to provide a significant reduction in mean total gadolinium enhancing lesions on MRI scan and there was a trend towards lower annualised relapse rates in the study which was performed for a year. It was well tolerated, but it seems likely that more humanised versions of the anti-CD20 monoclonal will be studied in future[29].

Alemtuzumab:-This is a humanised monoclonal antibody binding to CD-52 on the surface of T and B cells. It is already used in haematological malignancy and the profound depression in T cells lasts for more than 12 months. The drug has been tried in the past in people with progressing MS but shown to be ineffective ,though to reduce greatly the number of T2 weighted MRI lesA recent phase II study in RRMS compared two doses of alemtuzumab with interferon ß-1a and showed significant benefit in reduction in relapses and in EDSS of the monoclonal over the interferon ß. The trial was interrupted during its planned 3 year course due to 6 patients who developed idiopathic thrombocytopaenic purpura, one of whom died.22 There has also been recognition of autoimmune thyroiditis occurring in patients treated with alemtuzumab. There are now two phase III trials of the agent underway, one as comparison against placebo and one in comparison to interferon ß-1a in patients who have failed earlier DMT ions [30]. FUTURE DIRECTIONS:-

1. Charcot Research Fund 2010 -- Most clinical trials running right now are working towards replacing injections with a pill form of the drugs for comfort. They are reporting that most are in Phase 2 studies where the most promising molecules are selected ( fumaric acid, cladribine, and laquinmod ) to use in Phase 3 studies. Fingolimod Phase 2 results were published previously and were given the green-light for Phase 3 which is already underway. These are included in the list for continued study, even though most of these have been used [31].

2. Interactive robots are available to help with intensive arm movements and though it is promising, nothing is as yet known about the relationship between performance and the arm function or the effect of robotics training compared to a more conventional power training. The measurements the doctors will be mapping are the possibilities for movement and the quality of the movement.


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3. Dr. G. LAUREYS - Prof. J. DE KEYSER - Dr. R. CLINCKERS VUB -- They are focusing on the dysfunction of the astrocytes (the 'support cells' in the brain). In MS patients these astrocytes lack certain receptors that are crucial to the proper working of the brain. The aim of the study is to gain a better insight into the role of this receptor deficiency so as to further unravel the pathology of MS and develop new treatments [31].

4. Mesenchymal stem cells -- They are found in the bone marrow of adult humans. They have the potential to develop into mature cells that produce fat, cartilage, bone, tendons, and muscle. Work done at various centers has demonstrated that these mesenchymal cells can be isolated from human bone marrow and transferred into cell cultures. It is still too early as of yet to know whether it will prove to be safe and beneficial, but studies are to continue into [31] .

5. Italian doctor have surprisingly simple cure for Multiple sclerosis:-Italian Dr. Paolo Zamboni has put forward the idea that many types of MS are actually caused by a blockage of the pathways that remove excess iron from the brain - and by simply clearing out a couple of major veins to reopen the blood flow, the root cause of the disease can be eliminated.[32]

6. Crimni mushrooms may help to beat multiple sclerosis[33]. Magnetic resonance research in MS (MAGNIMS) -- published new information on imaging and clinical findings that might help explain why some people experience a mild course or benign MS. MRI abnormalities in someone with seemingly benign MS serve as potential red flags pointing to another course of MS. They recommend that studies of large cohorts of people classified as having benign MS are warranted to validate their findings.

1. REFERENCES:-

2. Multiple sclerosis society of Great Britain and Northern Ireland: notes for students and

professionals (GR\506 -WEL). London: The Society; 1995

3. http://www.nejm.org/doi/full/10.1056/NEJM199711273372207

4. http://www.medicinenet.com/multiple_sclerosis/article.htm#1whatis

5. http://dictionary.reference.com/browse/multiple+sclerosis

6. Matthews WB. Mc Alpine’s multiple sclerosis. 2nd ed. London: Churchill Livingstone; 1991.

7. Thompson AJ, Mc Donald WI. Multiple sclerosis. In : Hart Y, Kennedy A. Medicine. Oxford:

Medicine Group Ltd.;1996, 69.

8. http://en.wikipedia.org/wiki/Multiple_sclerosis_signs_and_symptoms

9. http://www.mssociety.org.uk/about_ms/first_questions/causes_of_ms.html

10. http://www.teamms.org/media/documents/pdf/NMSS_KnowledgeIsPower_v1.pdf


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11. http://www.themcfox.com/multiple-sclerosis/types-of-ms/types-of-multiple-sclerosis.htm

12. http://medind.nic.in/ibi/t02/i1/ibit02i1p3.pdf

13. Weinstock-Guttman B, Ransohoff RM, Kinkel RP, Rudick RA., Ann Neurol, 1995,37,7.

14. Yong VW, Chabot S, Stuve O, Williams G. Interferon beta in the treatment of multiple

sclerosis-mechanisms of action. Neurology 1998,51,682.

15. The IFNB multiple sclerosis study group. Interferon beta- 1b is effective in relapsing-remitting

multiple sclerosis: Clinical results at a multicentre, randomised, double-blind, placebo-

controlled trial. Neurology 1993;43:655

16. http://www.flowers4ms.com/flowers_4_ms_-_with_changes_103.htm

17. Prat A, Al-Asmi A, Duquette P, Antel JP., Ann Neurol., 1999,46,253.

18. Miller A, Shapiro S, Gershtein R, Kinarty A, Rawashdeh H, Honigman S., J. Neuroimmunol.,

1998,92,113.

19. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP. Neurology., 1995,45,

1268.

20. Johnson KP, Brooks BR, Cohen JA. Ford CC, Goldstein J, Lisak RP., Neurology ., 1998,50,

701.

21. http://medind.nic.in/ibi/t02/i1/ibit02i1p3.pdf

22. http://www.msassociation.org/publications/process_treatments/p_07_drugs.html

23. http://www.acceleratedcure.org/downloads/bcp-ms-whatsnext.pdf

24. O’Connor PW, Li D, Freedman MS, et al., Neurology., 2006, 66(6), 894.

25. Leist TP, Vermerch P., Curr Med Res Opin., 2007, 23(11), 2667.

26. Kappos L, Antel J, Comi G, et al., N Engl J Med., 2006a, 355(11), 1124.

27. Gold R, Fox R, Dawson K, et al. Two phase 3 studies to determine the efficacy and safety of

BG00012, a novel, oral fumaric acid derivative, in patients with relapsing multiple sclerosis.

Mult Scler 2007; 13(suppl 2):S173.


428

28. http://www.unitedspinal.org/msscene/2008/05/28/monoclonal-antibodies-a-new-way-to-treat-

ms/

29. Kleinschmidt- DeMasters BK, Tyler KL., N Engl J Med., 2005, 353, 369.

30. http://www.nejm.org/doi/full/10.1056/NEJMoa0706383

31. http://www.davidscampathstory.org/

32. http://www.examiner.com/multiple-sclerosis-in-lima/amazing-multiple-sclerosis-research-for-

2010

33. http://www.gizmag.com/ccsvi-multiple-sclerosis-ms-cure-zamboni/13447/picture/105635/

34. http://intelligentguidetoms.wordpress.com/2010/10/26/crimini-mushrooms-may-help-beat-

multiple-sclerosis-and-ccsvi/

*Correspondence Author: Gaurav Sharma, Department of pharmacology , Shoolini University , Solan, (H.P), INDIA

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