minocycline and Multiple-Sclerosis--Relapsing-Remitting

Minocycline is proposed as an add-on therapy to improve the efficacy of glatiramer acetate in relapsing-remitting multiple sclerosis. The effect of minocycline plus glatiramer acetate was evaluated in this double-blind, placebo-controlled study by determining the total number of T1 gadolinium-enhanced lesions at months 8 and 9 in patients who were starting glatiramer acetate and had at least one T1 gadolinium-enhanced lesion on screening magnetic resonance imaging. Forty-four participants were randomized to either minocycline 100 mg twice daily or matching placebo for 9 months as add-on therapy. They were assessed at screening and months 1, 3, 6, 8 and 9. Forty participants completed the study. Compared with glatiramer acetate/placebo, glatiramer acetate/minocycline reduced the total number of T1 gadolinium-enhanced lesions by 63% (mean 1.47 versus 2.95; p = 0.08), the total number of new and enlarging T2 lesions by 65% (mean 1.84 versus 5.14; p = 0.06), and the total T2 disease burden (p = 0.10). A higher number of gadolinium-enhanced lesions were present in the glatiramer acetate/minocycline group at baseline; this was incorporated into the analysis of the primary endpoint but makes interpretation of the data more challenging. The risk of relapse tended to be lower in the combination group (0.19 versus 0.41; p = NS). Treatment was safe and well tolerated. We conclude that efficacy endpoints showed a consistent trend favoring combination treatment. As minocycline is a relatively safe oral therapy, further study of this combination is warranted in relapsing-remitting multiple sclerosis.

Topics: Adjuvants, Immunologic; Adult; Anti-Bacterial Agents; Brain; Double-Blind Method; Drug Therapy, Combination; Female; Gadolinium; Glatiramer Acetate; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Minocycline; Multiple Sclerosis, Relapsing-Remitting; Peptides; Treatment Outcome; Young Adult

Current multiple sclerosis (MS) treatment is only partially effective and not all patients respond well. The goal in this study was to evaluate minocycline for its safety, tolerability, and MRI impact as a potential therapy over 36 months after a three month run-in in ten relapsing-remitting (RR) MS patients.. Clinical assessments were at three month intervals until six months, then at six month intervals. Three Tesla MRI was performed monthly during the run-in and first six months of treatment, then at 12, 24, and 36 months.. Treatment was safe and well tolerated. Annualized relapse rate was 1.2 during the run-in and 0.25 during treatment. The proportion of active scans was lower during the first six months of treatment (5.6%, p < 0.001) and during the extension (8.7%, p = 0.002) than during the run-in (47.5%). Consistent with these outcomes, mean T2 lesion volume remained stable over three years and percent brain volume change was reduced during year three (-0.37%) of minocycline treatment.. This trial is limited by small sample and no control group but suggests that minocycline is safe and potentially beneficial in RRMS. This supports further investigation of its efficacy.

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Brain; Drug Administration Schedule; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Minocycline; Multiple Sclerosis, Relapsing-Remitting; Pilot Projects; Statistics, Nonparametric; Time Factors

The persistence of new enhancing T1 hypointense lesions (acute black holes, ABHs) in multiple sclerosis (MS) cannot be predicted visually at lesion onset. Texture analysis using the polar Stockwell transform (PST) applied to conventional MR images however shows promise in quantifying tissue injury early. The objective of this study was to explore whether ABHs that persist (pABHs) differ from those that are transient (tABHs) using PST texture analysis.. Fifteen ABHs (8 pABHs; 7 tABHs) from 9 patients were analyzed on 3T images obtained during a clinical trial. Persistence was defined as remaining T1 hypointense 5-8 months later. NAWM regions were examined to control for changes unrelated to ABHs.. At first appearance, there was higher coarse texture indicating greater tissue damage in the pABHs than in the tABHs (p<0.01). Both had greater coarse texture than the contralateral and general NAWM (p≤0.01). No difference was identified in normalized signal intensity between pABHs and tABHs and neither demonstrated location preference. While tABHs tended to be smaller than pABHs there was no correlation between lesion size and texture (r=0.44, p>0.05). Furthermore, coarse texture content appeared to predict persistence of individual lesions.. This preliminary study suggests that PST texture could predict persistence of tissue injury based on the severity of structural disorganization within acute lesions. While confirmation of this data is required texture analysis may prove to be a valuable tool to quantify tissue damage and predict recovery in proof-of-concept neuroprotection and repair trials.

Topics: Adult; Alberta; Analysis of Variance; Brain; Drug Therapy, Combination; Female; Fourier Analysis; Glatiramer Acetate; Humans; Image Interpretation, Computer-Assisted; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Minocycline; Multiple Sclerosis, Relapsing-Remitting; Odds Ratio; Peptides; Pilot Projects; Predictive Value of Tests; Severity of Illness Index; Time Factors

Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3T in 8 stable relapsing-remitting (RR) MS patients treated with minocycline over 3years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r=-0.94, P=0.02). This correlation was strongest in the head of caudate (r=-0.95, P=0.01) and putamen (r=-0.89, P=0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r=-0.72, P=0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients.

Topics: Adult; Analysis of Variance; Anti-Bacterial Agents; Atrophy; Brain; Disability Evaluation; Disabled Persons; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Minocycline; Multiple Sclerosis, Relapsing-Remitting; Nerve Fibers, Unmyelinated; Pilot Projects; Severity of Illness Index; Statistics as Topic; Time Factors

Topics: Adult; Female; Gadolinium; Humans; Magnetic Resonance Imaging; Male; Minocycline; Multiple Sclerosis, Relapsing-Remitting