WO2012116128A1 - Use of teriflunomide for treating cognitive impairment - Google Patents
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- WO2012116128A1 WO2012116128A1 PCT/US2012/026236 US2012026236W WO2012116128A1 WO 2012116128 A1 WO2012116128 A1 WO 2012116128A1 US 2012026236 W US2012026236 W US 2012026236W WO 2012116128 A1 WO2012116128 A1 WO 2012116128A1
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- the present invention relates to the use of teriflunomide for treating cognitive impairment in a patient in need thereof.
- Cognitive impairment is found in approximately 40% of patients with multiple sclerosis.
- the cognitive impairment in many patients does not correlate with the degree of neurological disability and disease duration.
- Deficits have been described in working, semantic, and episodic memory as well as in the person's ability to accurately assess his or her own memory function.
- patients may suffer from impaired attention, cognitive slowing, reduced verbal fluency, and difficulties with abstract reasoning and concept formation.
- MS Magnetic Resonance Image
- Teriflunomide is a novel oral disease-modifying therapy (DMT) in
- RMS relapsing-form multiple sclerosis
- the present invention relates to a method for treating cognitive impairment, in a patient in need thereof, comprising administering to the patient a
- teriflunomide or a pharmaceutically acceptable salt thereof.
- Figure I is a plot of change from baseline in cognitive function Z score over time -ITT population.
- “Clinically proven effective” mean that the results of clinical trial are statistically significant, i.e., the results of the clinical trial are not likely to be due to chance with an alpha level less than 0.05. "Cognitive impairment” means loss of operational judgment, failure of recent memory, need to keep written notes to circumvent the failure of recent memory, loss of insight, inappropriate behavior, uncritical statements or irritability.
- EDSS means the Kurtzke Expanded Disability Status Scale.
- IT population means intent to treat population
- MSFC Z score means Multiple Sclerosis Functional Composite score. It was developed by the National Multiple Sclerosis Society's Clinical Outcomes Assessment Task Force to address the poor reliability and insensitivity to change of the available MS clinical rating scales.
- the MSFC comprises three assessments: quantitative tests of arm and hand function (Nine-Hole Peg Test [9-HPT]), cognitive function (3" version of the Paced Auditory Serial Addition Test [PASAT]) and leg function and ambulation (25-foot Timed Walk Test [TWT]). The combination of these three domains produces a composite score by adding the number of standard deviations from a reference population. The composite score shows a high reliability and validity, a clear relationship with disease duration, and excellent intra- and interrater reliability.
- the MSFC can correlate with EDSS, relapse rates and is capable of demonstrating therapeutic effects in randomized, controlled clinical studies.
- Patient means mammals, particularly humans.
- “Pharmaceutically effective amount” means an amount of a
- Treating means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to slow the
- One specific embodiment of the invention is a method for treating cognitive impairment, in a patient having MS in need thereof, comprising administering to the patient a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.
- Another specific embodiment of the invention is a method for treating cognitive impairment, in a patient having RMS in need thereof, comprising administering to the patient a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.
- Another specific embodiment of the invention is a method for treating cognitive impairment, in a patient in need thereof, comprising administering to the patient about 7 mg or about 14 mg of teriflunomide daily.
- Another specific embodiment of the invention is a method for treating cognitive impairment, in a patient in need thereof, comprising administering to the patient about 7 mg or about 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
- Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for treating cognitive impairment.
- Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for treating cognitive impairment in a patient having MS.
- Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for treating cognitive impairment in a patient having RMS.
- Another specific embodiment of the invention is the use of about 7 mg or 14 mg of teriflunomide daily for treating cognitive impairment.
- Another specific embodiment of the invention is the use of about 7 mg or 14 mg of teriflunomide daily for treating cognitive impairment, wherein the use is clinically proven effective.
- teriflunomide is useful for treating cognitive impairment in a patient, particularly a patient having multiple sclerosis.
- TEMSO Teiflunomide Multiple Sclerosis Oral trial
- TEMSO Phase III randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of teriflunomide in reducing the frequency of relapses and accumulation of physical disability in patients with RMS over 2 years.
- McDonald's criteria for MS diagnosis and exhibited a relapsing clinical course, with or without progression. They were required to have a score of no more than 5.5 on the Kurtzke Expanded Disability Status Scale (EDSS), a minimum of two clinical relapses in the previous 2 years or one relapse during the preceding year, but no relapses in the 60 days before randomization. During the 4 weeks prior to randomization, patients were required to be clinically stable and have signed both the infornned consent form and infornned consent for HIV testing.
- EDSS Kurtzke Expanded Disability Status Scale
- cladribine Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporine, methotrexate or mycophenolate
- MRI Contraindication for MRI including presence of pacemaker, metallic implants in high-risk areas (e.g. artificial heart valves, aneurysm/vessel clips), presence of metallic material (e.g. shrapnel) in high-risk areas, known history of allergy to any contrast medium, or history of claustrophobia that would prevent completion of all protocol-scheduled MRI visits; hip implants were not contraindicated
- high-risk areas e.g. artificial heart valves, aneurysm/vessel clips
- metallic material e.g. shrapnel
- HlV Human immunodeficiency virus
- eligible patients were randomized ( 1 : 1 : 1 ) to receive a once-daily oral dose of placebo or
- teriflunomide 7 mg or 14 mg, for 108 weeks. Randomization was stratified by baseline EDSS score ( ⁇ 3.5 and >3.5) and by trial site.
- Results A total of 1 ,088 patients (PBO: 363; 7 mg: 365; 14 mg: 359) were randomized to study treatment; 73.2% of patients completed study treatment (71 .3% [PBO]; 74.9% [7 mg]; 73.3% [14 mg]). As shown in Table I and Figure I, it was found that there was a statistically significant treatment difference observed in cognitive function MSFC Z score at Week 96. The LS mean change from baseline in cognitive functional Z score were -0.022 for the placebo group, 0.075 for the teriflunomide 7 mg group, and 0.073 for the teriflunomide 14 mg group.
- the LS mean difference from placebo values were 0.097 (95% CI: 0.005 to 0.189) for the teriflunomide 7 mg group and 0.095 (95% CI: 0.003 to 0.187) for the teriflunomide 14 mg group with the
- MMRM analysis adjusted for EDSS strata at baseline, region and baseline value.
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Abstract
The present invention relates to the use of teriflunomide for treating cognitive impairment in a patient in need thereof, particularly in a patient having multiple sclerosis.
Description
USE OF TERIFLUNOMIDE FOR TREATING COGNITIVE IMPAIRMENT
Field of the Invention The present invention relates to the use of teriflunomide for treating cognitive impairment in a patient in need thereof.
Background of the Invention Cognitive impairment is found in approximately 40% of patients with multiple sclerosis. The cognitive impairment in many patients does not correlate with the degree of neurological disability and disease duration. Deficits have been described in working, semantic, and episodic memory as well as in the person's ability to accurately assess his or her own memory function. Also, patients may suffer from impaired attention, cognitive slowing, reduced verbal fluency, and difficulties with abstract reasoning and concept formation.
Correlations between cognitive impairment and Magnetic Resonance Image (MRI) location of lesions and indices of total lesion area have been described. A cognitive decline in multiple sclerosis (MS) patients may have a negative impact on the quality of life, affecting all active daily living domains. In MS studies cognitive function can be evaluated by MSFC and MRI. There is little data reported on the treatment of cognitive dysfunction in MS.
Teriflunomide is a novel oral disease-modifying therapy (DMT) in
development for the treatment of relapsing-form multiple sclerosis (RMS). Teriflunomide blocks de novo pyrimidine synthesis, which inhibits the replication and function of activated (but not resting) lymphocytes.
The compound of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'- trifluoromethylphenyl)-amide (also known as teriflunomide, Formula I) is described in U.S. Patent No. 5,679,709.
I
The use of teriflunomide for treating multiple sclerosis is described in U.S. Patent No. 6,794,410.
Summary of the Invention
The present invention relates to a method for treating cognitive impairment, in a patient in need thereof, comprising administering to the patient a
pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.
Brief Description of the Drawings
Figure I is a plot of change from baseline in cognitive function Z score over time -ITT population.
Detailed Description of the Invention As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Clinically proven effective" mean that the results of clinical trial are statistically significant, i.e., the results of the clinical trial are not likely to be due to chance with an alpha level less than 0.05.
"Cognitive impairment" means loss of operational judgment, failure of recent memory, need to keep written notes to circumvent the failure of recent memory, loss of insight, inappropriate behavior, uncritical statements or irritability.
"EDSS" means the Kurtzke Expanded Disability Status Scale. "ITT population" means intent to treat population "MSFC Z score" means Multiple Sclerosis Functional Composite score. It was developed by the National Multiple Sclerosis Society's Clinical Outcomes Assessment Task Force to address the poor reliability and insensitivity to change of the available MS clinical rating scales. The MSFC comprises three assessments: quantitative tests of arm and hand function (Nine-Hole Peg Test [9-HPT]), cognitive function (3" version of the Paced Auditory Serial Addition Test [PASAT]) and leg function and ambulation (25-foot Timed Walk Test [TWT]). The combination of these three domains produces a composite score by adding the number of standard deviations from a reference population. The composite score shows a high reliability and validity, a clear relationship with disease duration, and excellent intra- and interrater reliability. The MSFC can correlate with EDSS, relapse rates and is capable of demonstrating therapeutic effects in randomized, controlled clinical studies.
"Patient" means mammals, particularly humans.
"Pharmaceutically effective amount" means an amount of a
compound/composition according to the present invention effective in producing the desired therapeutic effect. "Treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to slow the
appearance of symptoms of the named disorder or condition.
One specific embodiment of the invention is a method for treating cognitive impairment, in a patient having MS in need thereof, comprising administering to the patient a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.
Another specific embodiment of the invention is a method for treating cognitive impairment, in a patient having RMS in need thereof, comprising administering to the patient a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.
Another specific embodiment of the invention is a method for treating cognitive impairment, in a patient in need thereof, comprising administering to the patient about 7 mg or about 14 mg of teriflunomide daily.
Another specific embodiment of the invention is a method for treating cognitive impairment, in a patient in need thereof, comprising administering to the patient about 7 mg or about 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for treating cognitive impairment.
Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for treating cognitive impairment in a patient having MS.
Another specific embodiment of the invention is the use of teriflunomide or a pharmaceutically acceptable salt thereof for treating cognitive impairment in a patient having RMS.
Another specific embodiment of the invention is the use of about 7 mg or 14 mg of teriflunomide daily for treating cognitive impairment.
Another specific embodiment of the invention is the use of about 7 mg or 14 mg of teriflunomide daily for treating cognitive impairment, wherein the use is clinically proven effective.
It is now found and clinically proved that teriflunomide is useful for treating cognitive impairment in a patient, particularly a patient having multiple sclerosis.
The present invention may be better understood by reference to the following non-limiting Example, which are exemplary of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.
Example
TEMSO (Teriflunomide Multiple Sclerosis Oral trial) is a Phase III randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of teriflunomide in reducing the frequency of relapses and accumulation of physical disability in patients with RMS over 2 years.
METHODS
Patients
Patients eligible for enrolment were aged 18-55 years, met
McDonald's criteria for MS diagnosis, and exhibited a relapsing clinical course, with or without progression. They were required to have a score of no more than 5.5 on the Kurtzke Expanded Disability Status Scale (EDSS), a minimum of two clinical relapses in the previous 2 years or one relapse during the preceding year, but no relapses in the 60 days before randomization. During the 4 weeks prior to randomization, patients were required to be
clinically stable and have signed both the infornned consent form and infornned consent for HIV testing.
Patients presenting with any of the following were excluded from the study.
- Patients with significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia:
o Hematocrit <24% and/or
o Absolute white blood cell count <4.0 x109/L and/or
o Platelet count <150 x109/L and/or
o Absolute neutrophil count <1 .5 x109/L
- Patients with a congenital or acquired severe immunodeficiency, a history of cancer (except for basal or squamous cell skin lesions which had been surgically excised with no evidence of metastasis), lymphoproliferative disease, or any patients who had received lymphoid irradiation
- Known history of active tuberculosis not adequately treated
- Persistent significant or severe infection
- Patients who were pregnant or breastfeeding or who planned to conceive during the course of the trial; women of childbearing potential and men were required to use an acceptable method of contraception
- Use of disallowed therapies including phenytoin, warfarin, tolbutamide, St John's Wort or cholestyramine in the 4 weeks prior to randomization
- Treatment with adrenocorticotrophic hormone (ACTH) or systemic corticosteroids 4 weeks prior to randomization
- Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporine, methotrexate or mycophenolate
- Previous treatment with teriflunomide or leflunomide
- Prior use of natalizumab
- Prior use of interferons or cytokine therapy in the preceding 4 months
- Prior use of glatiramer acetate therapy in the preceding 6 months
- Prior use of intravenous immunoglobulins in the preceding 6 months
- Prior use of any investigational drug in the preceding 6 months
- Patients likely to require treatment during the study period with drugs not permitted by the clinical study protocol
- Contraindication for MRI including presence of pacemaker, metallic implants in high-risk areas (e.g. artificial heart valves, aneurysm/vessel clips), presence of metallic material (e.g. shrapnel) in high-risk areas, known history of allergy to any contrast medium, or history of claustrophobia that would prevent completion of all protocol-scheduled MRI visits; hip implants were not contraindicated
- Patients with liver function impairment or persisting elevations of alanine aminotransferase, serum aspartate aminotransferase, or direct bilirubin greater than 1 .5-times the upper limit of normal (ULN)
- Persisting elevations of serum amylase or lipase greater than 2x ULN
- Known history of active hepatitis
- Hypoproteinemia (e.g. in case of severe liver disease or nephrotic syndrome) with serum albumin <3.0 g/dL
- Known history of chronic pancreatic disease or pancreatitis
- Moderate-to-severe impairment of renal function, as shown by serum creatinine >1 .5 mg/dL
- Clinically relevant cardiovascular, hepatic, neurologic, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult or that would put the subject at risk by participating in the study
- History of drug or alcohol abuse
- Psychiatric condition rendering the subject unable to understand the nature, scope, and possible consequences of the study
- Patients who were unlikely to comply with protocol (e.g. uncooperative attitude, inability to return for follow-up visits), and known unlikelihood of completing the study
- Patient was the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol
- Human immunodeficiency virus (HlV)-positive subject
- Patients were not allowed to be randomized into the study more than once Study design and randomization
Following a screening phase of up to 4 weeks, eligible patients were randomized ( 1 : 1 : 1 ) to receive a once-daily oral dose of placebo or
teriflunomide, 7 mg or 14 mg, for 108 weeks. Randomization was stratified by baseline EDSS score (<3.5 and >3.5) and by trial site.
Results: A total of 1 ,088 patients (PBO: 363; 7 mg: 365; 14 mg: 359) were randomized to study treatment; 73.2% of patients completed study treatment (71 .3% [PBO]; 74.9% [7 mg]; 73.3% [14 mg]). As shown in Table I and Figure I, it was found that there was a statistically significant treatment difference observed in cognitive function MSFC Z score at Week 96. The LS mean change from baseline in cognitive functional Z score were -0.022 for the placebo group, 0.075 for the teriflunomide 7 mg group, and 0.073 for the teriflunomide 14 mg group. The LS mean difference from placebo values were 0.097 (95% CI: 0.005 to 0.189) for the teriflunomide 7 mg group and 0.095 (95% CI: 0.003 to 0.187) for the teriflunomide 14 mg group with the
corresponding p values of 0.0379 and 0.0435, respectively.
Table I: Analysis of Change from Baseline in Cognitive Function Z score - ITT population
Teriflunomide
Placebo 7 mg 14 mg (N=363) (N=365) (N=358)
Baseline (Week 0)
Value
Number 362 363 356 Mean (SD) -0.062 (1 .007) 0.018 (1 .013) 0.044 (0.980) Median 0.242 0.326 0.326 Min : Max -3.94 : 1 .08 -3.94 : 1.08 -3.94 : 1 .08
Week 24
Value
Number 326 323 310 Mean (SD) -0.109 (1 .048) -0.006 (0.974) 0.063 (0.920) Median 0.158 0.242 0.326 Min : Max -3.94 : 1 .08 -3.94 : 1.08 -3.94 : 1 .08
Change from baseline
Number 326 323 309
Mean (SD) -0.084 (0.589) -0.031 (0.546) -0.006 (0.462)
Median 0.000 0.000 0.000
Min : Max -3.26 : 2.01 -4.02 : 1.84 -2.34 : 1 .51
Change from baseline
(MMRM)
Number 326 323 309
LS Mean (SE) -0.129 (0.030) -0.063 (0.030) -0.030 (0.031 )
LS Mean Difference from
placebo (SE) 0.066 (0.040) 0.099 (0.041 )
(-0.013 to ( 0.019 to
95% CI 0.145) 0.179)
P-value (vs. Placebo) 0.1010 0.0148
Week 48
Value
Number 298 299 291 Mean (SD) -0.01 1 (0.978) 0.057 (0.963) 0.122 (0.830) Median 0.242 0.326 0.326 Min : Max -3.94 : 1 .08 -3.94 : 1.08 -2.60 : 1 .08
Teriflunomide
Placebo 7 mg 14 mg (N=363) (N=365) (N=358)
Change from baseline
Number 298 298 291
Mean (SD) 0.021 (0.532) 0.024 (0.592) 0.045 (0.514)
Median 0.000 0.000 0.000
Min : Max -2.09 : 2.34 -4.77 : 2.18 -2.01 : 2.76
Change from baseline
(MMRM)
Number 298 298 291
LS Mean (SE) 0.083 (0.031 ) -0.002 (0.031 ) 0.017 (0.031 )
LS Mean Difference from
placebo (SE) 0.081 (0.041 ) 0.100 (0.041 )
(-0.000 to ( 0.018 to
95% CI 0.162) 0.181 )
P-value (vs. Placebo) 0.0500 0.0163
Week 72
Value
Number 273 278 272 Mean (SD) 0.048 (1 .079) 0.105 (0.940) 0.173 (0.831 ) Median 0.242 0.368 0.409 Min : Max -3.94 : 1 .08 -3.1 1 : 1.08 -2.94 : 1 .08
Change from baseline
Number 272 277 272
Mean (SD) 0.042 (0.630) 0.083 (0.567) 0.082 (0.533)
Median 0.000 0.000 0.000
Min : Max -4.94 : 1 .76 -1.59 : 2.51 -2.18 : 2.26
Change from baseline
(MMRM)
Number 272 277 272
LS Mean (SE) 0.099 (0.034) 0.048 (0.034) 0.053 (0.034)
LS Mean Difference from
placebo (SE) 0.147 (0.046) 0.152 (0.046)
( 0.057 to ( 0.062 to
95% CI 0.236) 0.242)
P-value (vs. Placebo) 0.0013 0.0010
Teriflunomide
Placebo 7 mg 14 mg
(N=363) (N=365) (N=358)
Week 96
Value
Number 258 266 264
Mean (SD) 0.026 (1 .080) 0.143 (0.922) 0.182 (0.862)
Median 0.326 0.409 0.409
Min : Max -3.94 : 1 .08 -3.86 : 1.08 -3.52 : 1 .08
Change from baseline
Number 257 265 262
Mean (SD) 0.044 (0.575) 0.095 (0.620) 0.103 (0.51 1 )
Median 0.000 0.084 0.000
Min : Max -2.18 : 1 .67 -4.35 : 2.68 -1.34 : 2.34
Change from baseline
(MMRM)
Number 257 265 262
LS Mean (SE) -0.022 (0.035) 0.075 (0.034) 0.073 (0.035)
LS Mean Difference from
placebo (SE) 0.097 (0.047) 0.095 (0.047)
( 0.005 to ( 0.003 to
95% CI 0.189) 0.187)
P-value (vs. Placebo) 0.0379 0.0435
Note: MMRM analysis adjusted for EDSS strata at baseline, region and baseline value.
Claims
1 . A method for treating cognitive impairment, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of teriflunomide or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1 , wherein the patient is having multiple sclerosis.
3. The method according to claim 1 , wherein the patient is having relapse-form multiple sclerosis.
4. The method according to claim 1 , wherein the patient is administered about 7 mg of teriflunomide daily.
5. The method according to claim 1 , wherein the patient is administered about 14 mg of teriflunomide daily.
6. The method according to claim 4, wherein the method is clinically proven effective.
7. The method according to claim 6, wherein the method is clinically proven effective.
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US201161446106P | 2011-02-24 | 2011-02-24 | |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5679709A (en) | 1985-09-27 | 1997-10-21 | Hoechst Aktiengesellschaft | Medicaments to combat autoimmune diseases |
US6794410B2 (en) | 2001-04-05 | 2004-09-21 | Aventis Pharmaceuticals Inc. | Use of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide for treating multiple sclerosis |
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- 2012-02-22 AR ARP120100576A patent/AR085305A1/en not_active Application Discontinuation
- 2012-02-23 TW TW101105928A patent/TW201249429A/en unknown
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5679709A (en) | 1985-09-27 | 1997-10-21 | Hoechst Aktiengesellschaft | Medicaments to combat autoimmune diseases |
US6794410B2 (en) | 2001-04-05 | 2004-09-21 | Aventis Pharmaceuticals Inc. | Use of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide for treating multiple sclerosis |
Non-Patent Citations (3)
Title |
---|
DE KEYSER JACQUES ET AL: "Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance", JOURNAL OF CEREBRAL BLOOD FLOW & METABOLISM, vol. 28, no. 10, October 2008 (2008-10-01), pages 1645 - 1651, XP002673923, ISSN: 0271-678X * |
MERRILL JEAN E ET AL: "Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis", JOURNAL OF NEUROLOGY, vol. 256, no. 1, January 2009 (2009-01-01), pages 89 - 103, XP002673924, ISSN: 0340-5354 * |
PATTI FRANCESCO ET AL: "Treatment options of cognitive impairment in multiple sclerosis", NEUROLOGICAL SCIENCES, vol. 31, no. Suppl. 2, November 2010 (2010-11-01), pages 265 - 269, XP002673922, ISSN: 1590-1874 * |
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