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Multimodal exercise training in multiple sclerosis: A randomized controlled trial in persons with substantial mobility disability.
Sandroff, BM, Bollaert, RE, Pilutti, LA, Peterson, ML, Baynard, T, Fernhall, B, McAuley, E, Motl, RW
Contemporary clinical trials. 2017;:39-47
Abstract
BACKGROUND Mobility disability is a common, debilitating feature of multiple sclerosis (MS). Exercise training has been identified as an approach to improve MS-related mobility disability. However, exercise randomized controlled trials (RCTs) on mobility in MS have generally not selectively targeted those with the onset of irreversible mobility disability. OBJECTIVES The current multi-site RCT compared the efficacy of 6-months of supervised, multimodal exercise training with an active control condition for improving mobility, gait, physical fitness, and cognitive outcomes in persons with substantial MS-related mobility disability. METHODS 83 participants with substantial MS-related mobility disability underwent initial mobility, gait, fitness, and cognitive processing speed assessments and were randomly assigned to 6-months of supervised multimodal (progressive aerobic, resistance, and balance) exercise training (intervention condition) or stretching-and-toning activities (control condition). Participants completed the same outcome assessments halfway through and immediately following the 6-month study period. RESULTS There were statistically significant improvements in six-minute walk performance (F(2158)=3.12, p=0.05, ηp2=0.04), peak power output (F(2150)=8.16, p<0.01, ηp2=0.10), and Paced Auditory Serial Addition Test performance (F(2162)=4.67, p=0.01, ηp2=0.05), but not gait outcomes, for those who underwent the intervention compared with those who underwent the control condition. CONCLUSIONS This RCT provides novel, preliminary evidence that multimodal exercise training may improve endurance walking performance and cognitive processing speed, perhaps based on improvements in cardiorespiratory capacity, in persons with MS with substantial mobility disability. This is critical for informing the development of multi-site exercise rehabilitation programs in larger samples of persons with MS-related mobility disability.
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Standing up in multiple sclerosis (SUMS): protocol for a multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of a home-based self-management standing frame programme in people with progressive multiple sclerosis.
Freeman, JA, Hendrie, W, Creanor, S, Jarrett, L, Barton, A, Green, C, Marsden, J, Rogers, E, Zajicek, J
BMC neurology. 2016;:62
Abstract
BACKGROUND Multiple sclerosis (MS) is an incurable, unpredictable but typically progressive neurological condition. It is the most common cause of neurological disability in young adults. Within 15 years of diagnosis, approximately 50 % of affected people are unable to walk unaided, and over time an estimated 25 % depend on a wheelchair. Typically, people with such limited mobility are excluded from clinical trials. Severely impaired people with MS spend much of their day sitting, often with limited ability to change position. In response, secondary complications can occur including: muscle wasting, pain, reduced skin integrity, spasms, limb stiffness, constipation, and associated psychosocial problems such as depression and lowered self-esteem. Effective self-management strategies, which can be implemented relatively easily and cheaply within people's homes, are needed to improve or maintain mobility and reduce sedentary behaviour. However this is challenging, particularly in the latter stages of disease. Regular supported standing using standing frames is one potential option. METHODS/DESIGN SUMS is a pragmatic multi-centre randomised controlled trial evaluating use of Oswestry standing frames with blinded outcome assessment and full economic evaluation. Participants will be randomly allocated (1:1) to either a home-based, self-management standing programme (with advice and support) along with their usual care or to usual care alone. Those in the intervention group will be asked to stand for a minimum of 30 min three times weekly over 20 weeks. Each participant will be followed-up at 20 and 36 weeks post baseline. The primary clinical outcome is motor function, assessed using the Amended Motor Club Assessment. The primary economic endpoint is quality-adjusted life years. The secondary outcomes include measures of explanatory physical impairments, key clinical outcomes, and health-related quality of life. An embedded qualitative component will explore participant's and carer's experiences of the standing programme. DISCUSSION This is the first large scale multi-centre trial to assess the clinical and cost effectiveness of a home based standing frame programme for people who are severely impaired by MS. If demonstrated to be effective and cost-effective, we will use this evidence to develop recommendations for a health service delivery model which could be implemented across the United Kingdom. TRIAL REGISTRATION ISRCTN69614598 DATE OF REGISTRATION 3.2.16 (retrospectively registered).
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Therapeutic protein-drug interaction assessment for daclizumab high-yield process in patients with multiple sclerosis using a cocktail approach.
Tran, JQ, Othman, AA, Wolstencroft, P, Elkins, J
British journal of clinical pharmacology. 2016;(1):160-7
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Abstract
AIMS: To characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the high-affinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes. METHODS Twenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixed-effects model. RESULTS The 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0-12 h (0.93-1.15), S-warfarin AUC from 0 to infinity (AUC[0-inf]) (0.95-1.06), omeprazole AUC(0-inf) (0.88-1.13) and midazolam AUC(0-inf) (0.89-1.15) were within the no-effect boundary of 0.80-1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76-1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity. CONCLUSIONS DAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity.
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Body size and the risk of multiple sclerosis in Norway and Italy: the EnvIMS study.
Wesnes, K, Riise, T, Casetta, I, Drulovic, J, Granieri, E, Holmøy, T, Kampman, MT, Landtblom, AM, Lauer, K, Lossius, A, et al
Multiple sclerosis (Houndmills, Basingstoke, England). 2015;(4):388-95
Abstract
BACKGROUND Obesity may be a risk factor for developing multiple sclerosis (MS). OBJECTIVE We examined if body size influences the risk of MS in a population-based, case control study. METHODS A total of 953 cases and 1717 controls from Norway and 707 cases and 1333 controls from Italy reported their body size by choosing a silhouette 1 to 9 (largest) every fifth year from age 5 to 30 and at time of study. The body size-related MS risk was defined by odds ratios (ORs) in logistic regression analyses adjusting for age, smoking and outdoor activity. RESULTS In Norway a large body size (silhouettes 6-9) compared to silhouette 3 increased the risk of MS, especially at age 25 (OR 2.21; 95% CI 1.09-4.46 for men and OR 1.43; 95% CI 0.90-2.27 for women). When comparing silhouette 9 to 1, we found a significant dose-response from age 10 until age 30 peaking at age 25 (sex-adjusted OR 2.83; 95% CI 1.68-4.78). The association was present for at least 15 years prior to disease onset. No significant associations were found in Italy. CONCLUSIONS Obesity from childhood until young adulthood is a likely risk factor for MS with a seemingly stronger effect in Norway than in Italy.
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Association Between Glutamate Blockade and Fatigue in Patients With Multiple Sclerosis.
Nourbakhsh, B, Revirajan, N, Waubant, E
JAMA neurology. 2015;(11):1374-5
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Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study.
Mokry, LE, Ross, S, Ahmad, OS, Forgetta, V, Smith, GD, Goltzman, D, Leong, A, Greenwood, CM, Thanassoulis, G, Richards, JB
PLoS medicine. 2015;(8):e1001866
Abstract
BACKGROUND Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS. METHODS AND FINDINGS We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely. CONCLUSIONS A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.
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Positive association of vitamin D receptor gene variations with multiple sclerosis in South East Iranian population.
Narooie-Nejad, M, Moossavi, M, Torkamanzehi, A, Moghtaderi, A
BioMed research international. 2015;:427519
Abstract
Among the factors postulated to play a role in MS susceptibility, the role of vitamin D is outstanding. Since the function of vitamin D receptor (VDR) represents the effect of vitamin D on the body and genetic variations in VDR gene may affect its function, we aim to highlight the association of two VDR gene polymorphisms with MS susceptibility. In current study, we recruited 113 MS patients and 122 healthy controls. TaqI (rs731236) and ApaI (rs7975232) genetic variations in these two groups were evaluated using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. All genotype and allele frequencies in both variations showed association with the disease status. However, to find the definite connection between genetic variations in VDR gene and MS disease in a population of South East of Iran, more researches on gene structure and its function with regard to patients' conditions are required.
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Subcutaneous interferon Beta-1a in pediatric multiple sclerosis: a retrospective study.
Tenembaum, SN, Banwell, B, Pohl, D, Krupp, LB, Boyko, A, Meinel, M, Lehr, L, Rocak, S, Cantogno, EV, Moraga, MS, et al
Journal of child neurology. 2013;(7):849-56
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Abstract
To expand current knowledge, we examined the safety and tolerability of subcutaneous interferon β-1a in patients with pediatric-onset multiple sclerosis. Records from 307 patients who had received at least 1 injection of subcutaneous interferon β-1a for demyelinating events when aged younger than 18 years were reviewed. Overall, 168 (54.7%) patients had at least 1 prespecified medical event related to or under close monitoring with subcutaneous interferon β-1a or specific to pediatric patients, 184 (59.9%) had nonserious medical events related to treatment or of unknown causality, and 12 (3.9%) had serious medical events irrespective of causality. The most common laboratory abnormalities were increased alanine (74/195; 37.9%) and aspartate aminotransferase levels (59/194; 30.4%). Annualized relapse rates were 1.79 before treatment and 0.47 during treatment. In conclusion, adult doses of subcutaneous interferon β-1a (44 and 22 μg, 3 times weekly) were well tolerated in pediatric patients and were associated with reduced relapse rates.
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Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis.
Serpell, MG, Notcutt, W, Collin, C
Journal of neurology. 2013;(1):285-95
Abstract
Sativex is an endocannabinoid system modulator principally containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). During a 6-week randomised controlled trial, Sativex had a clinically relevant effect on spasticity associated with multiple sclerosis (MS). Patients self-titrated oromucosal Sativex to symptom relief or maximum tolerated dose (maximum of 130 mg THC and 120 mg CBD daily). The primary objective was to evaluate the safety and tolerability of long-term treatment by recording the incidence and severity of adverse events (AEs). Secondary outcomes were to determine evidence of developing tolerance and to assess the long-term dosing profile of Sativex. A validated 11-point Numerical Rating Scale of spasticity severity was used to assess efficacy. A total of 146 patients elected to enter this open-label follow-up safety trial. Mean treatment exposure was 334 days (standard deviation, SD = 209 days), and patients administered on average 7.3 (SD = 4.42) actuations per day. Fifty-two (36 %) patients withdrew from the study in the first year, 14 % due to AEs and 9 % due to lack of efficacy. Most AEs were mild/moderate in severity. Common (>10 %) treatment-related AEs were dizziness (24.7 %) and fatigue (12.3 %). Serious AEs occurred in five patients (3.4 %), with two psychiatric events reported by one patient. No psychoses, psychiatric AE trends, or withdrawal symptoms occurred following abrupt cessation of treatment. Baseline symptoms including spasticity did not deteriorate but were maintained to study completion in those patients who did not withdraw. No new safety concerns were identified with chronic Sativex treatment, and serious AEs were uncommon. There was no evidence of tolerance developing, and patients who remained in the study reported continued benefit.