Research in multiple sclerosis

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Juansempere (talk | contribs) at 22:12, 11 September 2011 (new publication). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Treatments under investigation may improve function, curtail attacks, or limit the progression of the underlying disease. Many treatments already in clinical trials involve drugs that are used in other diseases or medications that have not been designed specifically for MS. There are also trials involving the combination of drugs that are already in use for multiple sclerosis. Finally, there are also many basic investigations that try to understand better the disease and in the future may help to find new treatments.

The interventions below are sorted in alphabetical order.

Disease-modifying drugs and procedures in trial phase II and III

Disease-modifying drugs and procedures represent possible interventions able to modify the natural course of the disease instead of targeting the symptoms or the recovery from relapses. Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models.

Phase III

Phase III programs consist of studies on large patient groups (300 to 3,000 or more) and are aimed at being the definitive assessment of how effective and safe a test drug will be. It is the last stage of drug development and is followed by a submission to the appropriate regulatory agencies (e.g., European Medicines Agency (EMEA) for the European Union, the Food and Drug Administration (FDA) for the USA, Therapeutic Goods Administration (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually 2 years per patient.

  • Alemtuzumab (brand names: Campath and Lemtrada; under development by Genzyme and Bayer Schering) is a monoclonal antibody currently already used in the treatment of chronic lymphocytic leukemia and T-cell lymphoma. Results from the phase II study comparing it to Rebif (interferon beta-1a) were published in May 2007 showing efficacy. However, the trial was halted after 3 cases of immune thrombocytopenic purpura (ITP) were reported; later on, a further 3 more cases were found, and 1 patient died. This is a life-threatening side effect but is treatable if detected. Therefore, all patients receiving alemtuzumab should have their platelet count monitored.[1][2] Two phase 3 trials comparing with Rebif are due to end in 2011[3][4]. The results have been considered a success[5]
  • BG00012 (an oral fumarate ester under development by Biogen; anticipated brand name Panaclar). It has completed Phase II investigations[12] and Phase III started Jan 2007 and plans to follow approx 1000 patients until Dec 2010.[13]
  • Laquinimod (under development by Teva and Active Biotech) is an immunomodulatory substance developed as an orally available disease modifying treatment in multiple sclerosis. In a phase II study, oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing multiple sclerosis.[14] During 2009 was granted FDA fast-track status[15]

Phase II

Phase II studies are performed on mid-sized groups of patients (20 to 300) and are designed to assess whether a drug may work in the targeted disease area, as well as to continue earlier safety assessments obtained in healthy volunteers. Treatment in MS phase II studies is with 4–12 months usually shorter than in phase III studies.

  • Estradiol and estrogen receptors(ER): Both have been shown to be antiinflammatory and neuroprotective in a variety of neurological disease models and now is known that they work also in presence of inflammation[19][20]
  • Ibudilast: A phase II trial shows that Ibudilast does not reduce lesion rate, but prevents them to turn into black holes. They classify its action as class III evidence of delay on disease activity[21]
  • Inosine: Inosine is a compound that has shown interesting preliminary results in phases I and II clinical trials.[22][23] Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion,[24] which is a natural antioxidant;[25] second, it has been shown to induce axonal rewiring in laboratory animals with stroke,[26] and spinal cord injury.[27] However it can cause health problems in a long-term treatment,[28] mainly kidney stones.[29]. It seems that its mechanism of action is peroxynitrite inactivation[30]
  • Tovaxin. Also a vaccine against T-Cells, which in this case consist of attenuated autoreactive T cells. It is developed by Opexa Therapeutics, (previously known as PharmaFrontiers), and finished a phase IIb September 2008,[31] failing its primary target though in March 2008 was still performing good.[32]
  • Ocrelizumab, Anti-CD20 humanized monoclonal antibody, whose mechanism of action targets B-Cells, like Rituximab, currently in phase II.[33]
  • Ofatumumab, other anti-CD20 monoclonal antibody, also in phase II for MS, and phase III for others autoimmune diseases
  • Stem cell transplantation was found feasible in a phase I/II study in 21 patients with relapsing-remitting MS not responsive to interferon beta. It involves collecting some of the patient's own peripheral blood stem cells, giving low-intensity chemotherapy to eliminate auto-reactive lymphocytes, and then reinfusing the stem cells.[34] Earlier studies in the secondary-progressive stage of MS have failed to shown reversal of neurological symptoms.
  • BAF312, NOVARTIS' BAF312 is a sphingosine-1-phosphate receptor modulator for oral use that is currently (June 8, 2009) in Phase II trial. "A back-up compound for Fingolimod, BAF 312" is in Phase II studies.[35] It is being tested for the first time on people having multiple sclerosis. Worldwide 275 patients will participate in this phase II trial the outcome of which is to establish what the optimal dosage of BAF312 is for patients affected with Multiple Sclerosis for use in further trials. In order to identify "the optimal dosage", participants in group I will be randomly selected to take either placebo, or BAF312 in doses of 0.5 mg/day, 2 mg/day, or 10 mg./day and will be regularly controlled in order to measure and determine the effectiveness, the tolerability and the safety of the dosages. BAF312 acts on the lymphocytes to inhibit their migration to the location of the inflammation. BAF312, though information about it is extremely limited, may be very similar to Fingolimod: Fingolimod (rINN, codenamed FTY720) is a novel immunosuppressant drug that causes lymphopenia by preventing egress of lymphocytes from lymph nodes, which is well advanced in Phase III trials. BAF312 may be more selective in the particular sphingosine-1-phosphate receptors (8 in number) that it modulates.[36]

Phase I and animal models

Phase I and medicaments used in animal models would make a huge list. Here only some of them with special interest are listed.

  • GIFT15 is a treatment which suppresses the immune system, and has been successfully used in the treatment of mice. The immune system attacks the central nervous system in Multiple Sclerosis patients. Specifically a "granulocyte-macrophage colony–stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine]' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 Breg cells)."[37][38][39]

Other investigations on possible treatments

  • Antimicrobial agents against Chlamydophila pneumoniae: MS patients are more likely to have detectable levels of Chlamydophila pneumoniae DNA in their cerebrospinal fluid, compared to other patients with neurological diseases; however these findings are insufficient to establish an etiologic relation.[40] Anecdotal reports of the use of antimicrobial agents against Chlamydophila pneumoniae are favorable, but only one double-blind placebo-controlled trial has been published, in which the number of patients studied was too small (four in each arm of the trial) to reach statistical significance in the primary outcome measure (volume of gadolinium-enhancing lesions, as viewed on MRI).[41]
  • Antioxidants, available as supplements, are reported to reduce the blood-brain barrier permeability.[42] Related to this, MS patients have been reported to have low levels of uric acid, which is a natural antioxidant,[43] and has been observed that raising uric acid levels protects against blood-brain barrier destruction (through peroxynitrite scavenging ).[44] Peroxynitrite has been correlated with the axons degeneration and its removal can protect neurons from further damage after an attack. They can also remove other reactive oxygen species[45]
  • Bilirubin has been found to have immunomodulatory properties, apart of the already known antioxidant properties, and is a possible future treatment.[46]
  • Use of drugs to suppress myelin-reactive effector memory T cells by blocking voltage-gated Kv1.3 channels in these cells.[47][48][49][50][51]
  • Cyclophosphamide (trade name Revimmune): About RR-MS variant, in a 2006 study cyclophosphamide was given to patients with moderate to severe refractory (They had already tried approved medication) multiple sclerosis for four days. These patients were followed for two years. They showed a disease stabilization and improved functionality.[52] Later, a 2007 open label study found it equivalent to Mitoxantrone[53] and in 2008 evidence appeared that it can reverse disability.[54] About progressive variants, a review of the different studies that investigate its effects did not support its use in these cases.[55]
  • Helminthic therapy: A study showed a negative association between multiple sclerosis and infection with intestinal parasites, such as hookworm indicating that parasites may protect against multiple sclerosis.[57][58] Helminth therapy involves ingesting helminth eggs by the names of Trichuris suis, which are non parasitic worms. This is done in hopes that the body will redirect the immune response away from attacking the myelin, which produce lesions, and target the helminths. The study by Dr Fleming shows this is affective in reducing the amount of lesions seen through MRI’s taken before and after the study. [59]
  • BCG vaccine: The common, live, attenuated vaccine against tuberculosis, has substantially reduced recurrence of symptoms in multiple sclerosis patients.[60] The frequency of new enhancing lesions as detected by Gd-enhanced MRI was reduced by more than half in 12 patients, comparing the six-month run-in phase to the six-month post BCG phase of the experiment. Persistence at subsequent MR scan was reduced from 18 to 1 lesion, and evolution to black holes was reduced from 28 to 6 lesions.[61] The conventional explanation of such protection is that parasites (including bacteria) modulate the sensitivity of the immune system. BCG appears safe as a treatment for multiple sclerosis.[60][62]
  • Low dose naltrexone is also known as LDN. Naltrexone, a pure opiate antagonist, licensed by the FDA for the treatment of alcohol and opioid addictions, is currently being studied at a lower dosage for MS patients. A small, short-duration clinical trial[63] with MS patients was recently conducted at the University of California, San Francisco. In October 2007 data was presented at the European Congress of MS in Prague regarding safety findings of a pilot study of low dose naltrexone therapy in multiple sclerosis by neurological researchers in Milan, Italy.[64] However, no compelling efficacy results for LDN in MS therapy have been published. LDN is currently available to MS patients in the USA by off-label prescription.
  • Minocycline: the antibiotic minocycline has shown an effect on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in MS patients over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment relapse rate in patients in the study prior to treatment, no relapses occurred between months 6 and 24. The only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Clinical and MRI outcomes in this study were supported by systemic immunological changes and call for further investigation of minocycline in MS.[65][66][67]
  • Pixantrone: pixantrone (BBR2778) is an analogue of mitoxantrone devoid of toxic effects on cardiac tissue. It is as potent as mitoxantrone in animal models of MS; however results of human trials had not been published in 2007.[68]
  • Prolactin:In 2007 it was published that the hormone prolactin can ease the effects of demyelination in animal models of MS.[69] This effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women.[70]
  • Statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS.[71] However there is no evidence that statins are beneficial in the treatment of human MS patients, and concerns exist that, if ever shown to be effective, the high doses needed would prevent long-term use due to the potential for liver damage and muscle-wasting disease.
  • Testosterone has been studied for its potential benefits in men with Multiple Sclerosis, but the results are preliminary.[72]
  • Venous stents, based on the fact that an incorrect blood drainage system (CCSVI) can debilitate the blood-brain barrier[7][8], and the problems with angioplasties to treat CCSVI, mainly restenosis after angioplasties.
  • Vitamin D: a 2004 study found that women who took vitamin D supplements were 40% less likely to develop MS than women who did not take supplements. However, this study does not provide enough data to conclude that vitamin D has a beneficial influence on ongoing MS. Furthermore, it could not distinguish between a beneficial effect of vitamin D and that of multivitamin supplements including vitamin E and various B vitamins, which may also exert a protective effect.[73]
  • Omega-3 fatty acid: A study found that Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis[74]

Combined therapies

Several combinations of drugs have been tested. Some of them are couples of approved drugs. Other tests try one approved drug with one experimental substance. Finally, at some point there could appear some trials testing couples of non-approved drugs.

Combination of approved drugs

  • Mitoxantrone & Copaxone: A recent study in the United Kingdom revealed interesting results when using a combination of mitoxantrone and copaxone. In an open-label study of 27 patients with RRMS, the results suggested a rapid and sustained suppression of relapses. A three year controlled study of 60 patients is now being launched at 10 centres across the UK.[75] In another clinical trial, Glatimer Acetate (Copaxone) has been combined with Mitoxantrone in such a way that every course of Mitoxantrone is followed by GA treatment. It has yielded promising results twice, in a consistent way.[76][77]
  • Tysabri & Copaxone This combination has been found to be safe and well tolerated after six months.[78]
  • Mitoxantrone & beta-interferon: This combination has worked in some cases but not in others[79]
  • Avonex & Copaxone: Currently in phase III, with good results published [80]
  • Interferon beta 1a & Tysabri: Dangerous but effective.[81] Linked with PML, but is remarkable that Natalizumab alone is also linked with it.

Approved and experimental drugs combined

  • Copaxone & Minocycline. Good results[82]
  • Avonex & Atorvastatin: Avonex has also been combined with Atorvastatin in a clinical trial showing that is safe in its conditions,[83] even though high-dose statins are expected to produce liver problems and muscle-wasting disease over the long-term.[84] Other clinical trials have found problems combining IFN beta with Atorvastatin[85]
  • Cyclophosphamide & Beta-interferon has been tried on IFNbeta-unresponsive patients with success, but it is still under study.[86]
  • Avonex & Inosine: Avonex (interferon beta-1a) was combined with Inosine. Available data suggests that this combination is safe and well tolerated, though with no improvements respect interferon beta alone.[87][88]

Summary table

Summarizing in a table which combinations have been tried:

-------

Interferon beta-1a

Betaseron (beta-1b)

Copaxone

Mitoxantrone

Tysabri

Interferon beta-1a

------

------

------

------

------

Betaseron

NO

------

------

------

------

Copaxone

YES

NO

------

------

------

Mitoxantrone

NO

NO

YES

------

------

Tysabri

YES (linked to PML)

NO

YES

NO

------

Atorvastatin

YES

NO

NO

NO

------

Cyclophosphamide

NO

YES

NO

NO

NO

Inosine

YES

NO

NO

NO

NO

Investigation for agressive variants

Progressive variants have proved more difficult to treat than RRMS. This is the status of the research into progressive variants.

Highly Active Relapsing Remitting

Highly Active Relapsing Remitting, sometimes called Rapidly Worsening relapsing remitting, is a clinical form considered distinct from standard RR during clinical trials, being normally non responsive to standard medication.

As of 2011, fingolimod has been approved as the first disease modifying therapy for this clinical course.[89]

Primary progressive

This variant does not have any approved treatment currently. Some possible treatments have been published, such as methylprednisolone pulses[90] or riluzole,[91] and some reduction of spasticity was reported in a pilot Italian study on low dose naltrexone[64] but there is nothing conclusive still.

Secondary progressive and progressive-relapsing

Only Mitoxantrone has been approved, but most of the previous pipeline drugs have been or will be tried on it at some point. Since September 2008 Dirucotide is on fast-track for approval for SPMS.

References

  1. ^ Information from GenZyme on its clinical trial for Alemtuzumab
  2. ^ Coles AJ, Compston DA, Selmaj KW; et al. (2008). "Alemtuzumab vs. interferon beta-1a in early multiple sclerosis". N Engl J Med. 359 (17): 1786–801. doi:10.1056/NEJMoa0802670. PMID 18946064. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ clinicaltrial.gov Phase III Alemtuzumab Study 1;vs Rebif. Enrollment: 81, Start Sept 2007, Est' end date May 2011
  4. ^ clinicaltrial.gov Phase III Alemtuzumab Study 2;vs Rebif Enrollment: 840, Start Date: Oct 2007, Est End Date: Sept 2011.
  5. ^ Sanofi Reports Positive Top-Line Results From First Phase 3 Study Of Alemtuzumab (Lemtrada™) In Multiple Sclerosis, [1]
  6. ^ See clinicaltrials.gov [2]
  7. ^ a b Zamboni P, Galeotti R, Menegatti E; et al. (2009). "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". Journal of Neurology, Neurosurgery & Psychiatry. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ a b Zamboni P. et al.: Rationale and preliminary results of endovascular treatment of multiple sclerosis, the liberation procedure [3]
  9. ^ Montalban X, Wynn D, Kaufman M et al. Preliminary CHOICE results. ECTRIMS 2007
  10. ^ Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG (2007). "Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results". Neurology. 69 (8): 785–9. doi:10.1212/01.wnl.0000267662.41734.1f. PMID 17709711.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ ClinicalTrials.gov: Identifier NCT01064401. Updated on 7. April 2011.
  12. ^ Kappos L, Miller DH, MacManus DG; et al. (2006). "BG00012, a novel fumarate is effective in patients with relapsing-remitting multiple sclerosis". Mult Scler. 12 (Suppl 1): S85. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  13. ^ Efficacy and Safety of BG00012 in Relapsing-Remitting Multiple Sclerosis. ClinicalTrials.gov (2007-09-1). Retrieved on 2007-11-12.
  14. ^ Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T (2005). "Treatment with laquinimod reduces development of active MRI lesions in relapsing MS". Neurology. 64 (6): 987–91. doi:10.1212/01.WNL.0000154520.48391.69. PMID 15781813.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Laquinimod granted FDA fast track
  16. ^ ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
  17. ^ "Sanofi-Aventis' Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial". 15 Oct 2010.
  18. ^ clinicaltrial.gov CDP323 Phase II Study. Retrieved on 25 November 2007.
  19. ^ Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR (2007). "Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER){alpha} and ER{beta} ligand treatment". 104 (37): 14813–8. doi:10.1073/pnas.0703783104. PMID 17785421. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  20. ^ Palaszynski KM, Liu H, Loo KK, Voskuhl RR (2004). "Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis: implications for multiple sclerosis". J Neuroimmunol. 149 (1–2): 84–9. doi:10.1016/j.jneuroim.2003.12.015. PMID 15020068. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R (2010). "Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant?". Neurology. 74 (13): 1033–40. doi:10.1212/WNL.0b013e3181d7d651. PMID 20200338. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ "Treatment of Multiple Sclerosis Using Over the Counter Inosine". ClinicalTrials.gov. March 16, 2006. Retrieved 2006-05-10.
  23. ^ Toncev G (2006). "Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis". Vojnosanit Pregl. 63 (10): 879–82. doi:10.2298/VSP0610879T. PMID 17121380. {{cite journal}}: Unknown parameter |month= ignored (help)
  24. ^ Koch M, De Keyser J (2006). "Uric acid in multiple sclerosis". Neurol. Res. 28 (3): 316–9. doi:10.1179/016164106X98215. PMID 16687059.
  25. ^ Rentzos M, Nikolaou C, Anagnostouli M; et al. (2006). "Serum uric acid and multiple sclerosis". Clinical neurology and neurosurgery. 108 (6): 527–31. doi:10.1016/j.clineuro.2005.08.004. PMID 16202511. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  26. ^ Chen, Peng (2002). "Inosine induces axonal rewiring and improves behavioral outcome after stroke". PNAS. 99 (13): 9031–9036. doi:10.1073/pnas.132076299. PMC 124418. PMID 12084941. Retrieved 2006-05-10. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  27. ^ Liu F, You SW, Yao LP; et al. (2006). "Secondary degeneration reduced by inosine after spinal cord injury in rats". Spinal Cord. 44 (7): 421–6. doi:10.1038/sj.sc.3101878. PMID 16317421. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  28. ^ McNaughton L, Dalton B, Tarr J (1999). "Inosine supplementation has no effect on aerobic or anaerobic cycling performance". International journal of sport nutrition. 9 (4): 333–44. PMID 10660865.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Markowitz CE, Spitsin S, Zimmerman V; et al. (2009). "The Treatment of Multiple Sclerosis with Inosine". The Journal of Alternative and Complementary Medicine. 15 (6): 619–25. doi:10.1089/acm.2008.0513. PMID 19425822. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  30. ^ Markowitz CE, Spitsin S, Zimmerman V, Jacobs D, Udupa JK, Hooper DC, Koprowski H. The treatment of multiple sclerosis with inosine, PMID 19425822
  31. ^ Opexa shares lose most of value on study data
  32. ^ Opexa Therapeutics Announces Completion Of Mid Study Descriptive Analysis On Phase IIb Trial Of Tovaxin
  33. ^ Hutas G (2008). "Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies". Curr Opin Investig Drugs. 9 (11): 1206–15. PMID 18951300. {{cite journal}}: Unknown parameter |month= ignored (help)
  34. ^ Burt RK; et al. (2009). "Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study". Lancet Neurol. 8 (3): 244–53. doi:10.1016/S1474-4422(09)70017-1. PMID 19186105. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Explicit use of et al. in: |author= (help)
  35. ^ MULTIPLE SCLEROSIS AND THE PHARMACEUTICAL INDUSTRY/Medicines in development for MS: [4]
  36. ^ )WO/2008/000419) S1P RECEPTOR MODULATORS FOR TREATING MULTIPLE SCLEROSIS: [5]
  37. ^ "McGill/JGH researchers successfully reverse multiple sclerosis in animals New immune-suppressing treatment forces the disease into remission in mice". McGill University. August 11, 2009. Retrieved 2009-08-12.
  38. ^ "Multiple Sclerosis Successfully Reversed In Mice: New Immune-suppressing Treatment Forces The Disease Into Remission". Science Daily. August 12, 2009.
  39. ^ Moutih Rafei, Jeremy Hsieh, Simone Zehntner, MengYang Li, Kathy Forner, Elena Birman, Marie-Noëlle Boivin, Yoon Kow Young, Claude Perreault, Jacques Galipeau. (August 9, 2009). "A granulocyte-macrophage colony–stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties". Nature Medicine. 15 (9). Nature Medicine: 1038–45. doi:10.1038/nm.2003. PMID 19668193. Retrieved 2009-08-12.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  40. ^ Bagos PG, Nikolopoulos G, Ioannidis A (2006). "Chlamydia pneumoniae infection and the risk of multiple sclerosis: a meta-analysis". Mult Scler. 12 (4): 397–411. doi:10.1191/1352458506ms1291oa. PMID 16900753.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  41. ^ Sriram S, Yao SY, Stratton C, Moses H, Narayana PA, Wolinsky JS (2005). "Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS". J. Neurol. Sci. 234 (1–2): 87–91. doi:10.1016/j.jns.2005.03.042. PMID 15935383.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  42. ^ Oztaş B, Kiliç S, Dural E, Ispir T (2001). "Influence of antioxidants on the blood-brain barrier permeability during epileptic seizures". J Neurosci Res. 66 (4): 674–8. doi:10.1002/jnr.10023. PMID 11746387. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  43. ^ "Uric Acid In Multiple Sclerosis". 01/02/2006. Archived from the original on 2005-05-07. Retrieved 2006-05-10. {{cite web}}: Check date values in: |year= (help)
  44. ^ Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC (December 1, 2000). "The [[peroxynitrite]] scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity". J Immunol. 165 (11): 6511–8. PMID 11086092. {{cite journal}}: URL–wikilink conflict (help)CS1 maint: multiple names: authors list (link)
  45. ^ Schreibelt G, van Horssen J, van Rossum S, Dijkstra CD, Drukarch B, de Vries HE (2007). "Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology". Brain Research Reviews. 56 (2): 322–30. doi:10.1016/j.brainresrev.2007.07.005. PMID 17761296.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  46. ^ Liu Y, Li P, Lu J; et al. (2008). "Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis". J Immunol. 181 (3): 1887–97. PMID 18641326. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  47. ^ Beeton C, Wulff H, Barbaria J; et al. (2001). "Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis". Proceedings of the National Academy of Sciences. 98 (24): 13942–7. doi:10.1073/pnas.241497298. PMC 61146. PMID 11717451. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  48. ^ Wulff H, Calabresi PA, Allie R; et al. (2003). "The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS". Journal of Clinical Investigation. 111 (11): 1703–13. doi:10.1172/JCI16921. PMC 156104. PMID 12782673. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  49. ^ Vennekamp J, Wulff H, Beeton C; et al. (2004). "Kv1.3-Blocking 5-Phenylalkoxypsoralens: A New Class of Immunomodulators". Molecular Pharmacology. 65 (6): 1364–74. doi:10.1124/mol.65.6.1364. PMID 15155830. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  50. ^ Rus H, Pardo CA, Hu L; et al. (2005). "The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain". Proceedings of the National Academy of Sciences. 102 (31): 11094–9. doi:10.1073/pnas.0501770102. PMC 1182417. PMID 16043714. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  51. ^ Matheu MP, Beeton C, Garcia A; et al. (2008). "Imaging of Effector Memory T Cells during a Delayed-Type Hypersensitivity Reaction and Suppression by Kv1.3 Channel Block". Immunity. 29 (4): 602–14. doi:10.1016/j.immuni.2008.07.015. PMC 2732399. PMID 18835197. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  52. ^ Gladstone DE, Zamkoff KW, Krupp L; et al. (2006). "High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis". Arch. Neurol. 63 (10): 1388–93. doi:10.1001/archneur.63.10.noc60076. PMID 16908728. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  53. ^ Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, Pia Amato M (2007). "Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: An open-label comparative study of efficacy and safety". Journal of the Neurological Sciences. 266 (1–2): 25–30. doi:10.1016/j.jns.2007.08.023. PMID 17870094.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  54. ^ Krishnan C, Kaplin AI, Brodsky RA; et al. (2008). "Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis". Arch. Neurol. 65 (8): 1044–51. doi:10.1001/archneurol.65.8.noc80042. PMC 2574697. PMID 18541787. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  55. ^ La Mantia L, Milanese C, Mascoli N, D'Amico R, Weinstock-Guttman B (2007). La Mantia, Loredana (ed.). "Cyclophosphamide for multiple sclerosis". Cochrane database of systematic reviews (Online) (1): CD002819. doi:10.1002/14651858.CD002819.pub2. PMID 17253481.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  56. ^ Leung, G (2010). "Anti-acrolein treatment improves behavioral outcome and alleviates myelin damage in experimental autoimmune enchephalomyelitis mouse". Neuroscience. 173: 150–155. doi:10.1016/j.neuroscience.2010.11.018. PMC 3034379. PMID 21081153. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  57. ^ Correale J, Farez M (2007). "Association between parasite infection and immune responses in multiple sclerosis". Ann. Neurol. 61 (2): 97–108. doi:10.1002/ana.21067. PMID 17230481.
  58. ^ Correale J, Farez M, Razzitte G (2008). "Helminth infections associated with multiple sclerosis induce regulatory B cells". Ann. Neurol. 64 (2): 187–99. doi:10.1002/ana.21438. PMID 18655096. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  59. ^ Fleming, JO; Isaak, A.; Lee, J.; Luzzio, C.; Carrithers, M.; Cook, T.; Field, A.; Boland, J.; Fabry, Z. (3). "Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study". Multiple Sclerosis Journal. 0 (00): 1–12. doi:10.1177/1352458511398054. {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |month= ignored (help)
  60. ^ a b Ristori, G (1999). "Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis". Neurology. 53 (7): 1588–1589. PMID 10534275. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  61. ^ Paolillo, A (2003). "The effect of Bacille Calmette-Guérin on the evolution of new enhancing lesions to hypointense T1 lesions in relapsing remitting MS". J Neurol. 250 (2): 247–248. doi:10.1007/s00415-003-0967-6. PMID 12622098. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  62. ^ Rutschmann, OT; McCrory, DC; Matchar, DB; Immunization Panel of the Multiple Sclerosis Council for Clinical Practice Guidelines (2002). "Immunization and MS: a summary of published evidence and recommendations". Neurology. 59 (12): 1837–1843. PMID 12499473. {{cite journal}}: Unknown parameter |month= ignored (help)
  63. ^ 2007 clinical trial using LDN
  64. ^ a b Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G (2008). "A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis". Multiple Sclerosis. 14 (8): 1076–83. doi:10.1177/1352458508095828. PMID 18728058.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  65. ^ Zabad RK, Metz LM, Todoruk TR; et al. (2007). "The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study". Mult. Scler. 13 (4): 517–26. doi:10.1177/1352458506070319. PMID 17463074. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)"It has been available for over 30 years and, in the United Kingdom alone, more than 6.5 million people have been treated with minocycline for an average of 9 months, mostly for acne." Minocycline is probably the most cost effective, and effective treatment available for MS, but it's low cost, means that large pharmaceutical companies will fight to prevent its introduction as an MS treatment.
  66. ^ May 2003 Emerging Therapies for MS
  67. ^ Tilley BC, Alarcón GS, Heyse SP; et al. (1995). "Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group". Ann Intern Med. 122 (2): 81–9. doi:10.1001/archinte.122.1.81. PMID 7993000. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  68. ^ Gonsette RE, Dubois B (2004). "Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity". J. Neurol. Sci. 223 (1): 81–6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
  69. ^ Gregg C, Shikar V, Larsen P; et al. (2007). "White matter plasticity and enhanced remyelination in the maternal CNS". J. Neurosci. 27 (8): 1812–23. doi:10.1523/JNEUROSCI.4441-06.2007. PMID 17314279. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  70. ^ Vukusic S, Confavreux C (2006). "[Multiple sclerosis and pregnancy]". Rev Neurol. (Paris) (in French). 162 (3): 299–309. PMID 16585885.
  71. ^ Weber MS, Prod'homme T, Steinman L, Zamvil SS (2005). "Drug Insight: using statins to treat neuroinflammatory disease". Nature clinical practice. Neurology. 1 (2): 106–12. doi:10.1038/ncpneuro0047. PMID 16932506.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  72. ^ Sicotte NL, Giesser BS, Tandon V; et al. (2007). "Testosterone treatment in multiple sclerosis: a pilot study". Arch. Neurol. 64 (5): 683–8. doi:10.1001/archneur.64.5.683. PMID 17502467. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  73. ^ Munger KL, Zhang SM, O'Reilly E; et al. (2004). "Vitamin D intake and incidence of multiple sclerosis". Neurology. 62 (1): 60–5. PMID 14718698. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  74. ^ Shinto L, Marracci G, Baldauf-Wagner S; et al. (2009). "Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis,☆☆☆". Prostaglandins, Leukotrienes and Essential Fatty Acids. 80 (2–3): 131–6. doi:10.1016/j.plefa.2008.12.001. PMC 2692605. PMID 19171471. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  75. ^ United Kingdom early Mitoxantrone Copaxone trial
  76. ^ Vollmer T, Panitch H, Bar-Or A; et al. (2008). "Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis". Mult Scler. 14 (5): 663–70. doi:10.1177/1352458507085759. PMID 18424479. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  77. ^ Arnold DL, Campagnolo D, Panitch H; et al. (2008). "Glatiramer acetate after mitoxantrone induction improves MRI markers of lesion volume and permanent tissue injury in MS". J Neurol. 255 (10): 1473–8. doi:10.1007/s00415-008-0911-x. PMID 18854910. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  78. ^ Goodman AD, Rossman H, Bar-Or A; et al. (2009). "GLANCE: Results of a phase 2, randomized, double-blind, placebo-controlled study". Neurology. 72 (9): 806–12. doi:10.1212/01.wnl.0000343880.13764.69. PMC 2821836. PMID 19255407. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  79. ^ Zaffaroni M, Rizzo A, Baldini SM, Ghezzi A, Comi G (2008). "Induction and add-on therapy with mitoxantrone and interferon beta in multiple sclerosis". Neurol Sci. 29 (Suppl 2): S230–2. doi:10.1007/s10072-008-0946-x. PMID 18690501. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  80. ^ NIH Deepens Investment In Combination Study Of MS Drugs
  81. ^ Radue EW, Stuart WH, Calabresi PA; et al. (2010). "Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis". J. Neurol. Sci. 292 (1–2): 28–35. doi:10.1016/j.jns.2010.02.012. PMID 20236661. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  82. ^ Metz LM, Li D, Traboulsee A; et al. (2009). "Glatiramer acetate in combination with minocycline in patients with relapsing--remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial". Multiple Sclerosis. 15 (10): 1183–94. doi:10.1177/1352458509106779. PMID 19776092. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  83. ^ Paul F, Waiczies S, Wuerfel J; et al. (2008). Gwinn, Katrina (ed.). "Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis". PLoS ONE. 3 (4): e1928. doi:10.1371/journal.pone.0001928. PMC 2276246. PMID 18398457. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  84. ^ Patient Management in Multiple Sclerosis: A Canadian Expert Viewpoint, Mark S. Freedman [6]
  85. ^ Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT (2008). "Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis". Neurology. 71 (18): 1390–5. doi:10.1212/01.wnl.0000319698.40024.1c. PMID 18525027. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  86. ^ Perini P, Calabrese M, Rinaldi L, Gallo P (2008). "Cyclophosphamide-based combination therapies for autoimmunity". Neurol Sci. 29. Suppl 2 (S2): S233–4. doi:10.1007/s10072-008-0947-9. PMID 18690502. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  87. ^ Patient Management in Multiple Sclerosis: A Canadian Expert Viewpoint, Mark S. Freedman
  88. ^ Gonsette RE, Sindic C, D'hooghe MB, De Deyn PP, Medaer R, Michotte A, Seeldrayers P, Guillaume D; Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial. PMID 20200198
  89. ^ First Oral Treatment For Highly Active Relapsing Remitting Multiple Sclerosis Provides New Choice For UK Patients Failing On Injections, [7]
  90. ^ de Araújo EA, de Freitas MR (2008). "Benefit with methylprednisolone in continuous pulsetherapy in progressive primary form of multiple sclerosis: study of 11 cases in 11 years". Arq Neuropsiquiatr. 66 (2B): 350–3. doi:10.1590/S0004-282X2008000300013. PMID 18641870. {{cite journal}}: Unknown parameter |month= ignored (help)
  91. ^ Killestein J, Kalkers NF, Polman CH (2005). "Glutamate inhibition in MS: the neuroprotective properties of riluzole". J Neurol Sci. 233 (1–2): 113–5. doi:10.1016/j.jns.2005.03.011. PMID 15949499. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
Retrieved from "https://en.wikipedia.org/w/index.php?title=Research_in_multiple_sclerosis&oldid=449895820"