Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

BACKGROUND: BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate). METHODS: In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate. RESULTS: At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12. CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).clinical trial, phase iiicomparative studyjournal articlemulticenter studyrandomized controlled trialresearch support, non-u.s. gov't2012 Sep 20importedErratum in : N Engl J Med. 2012 Oct 25;367(17):1673

Les myoclonies vélo-pharyngées et leurs conséquences sur les troubles de la déglutition (à propos de douze cas)

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Approche physiopathologique et thérapeutique de l'hyperactivité neurogène du détrusor après lésion médullaire (mécanisme et cibles d'action des substances vanilloïdes sur l'appareil vésico-sphinctérien)

La thématique générale de notre recherche est l'exploration du circuit afférent du réflexe mictionnel dans l'espèce humaine et de sa neuroplasticité après lésion médullaire. Les objectifs étaient de favoriser la compréhension des mécanismes neurogènes intervenant dans la réorganisation du réflexe mictionnel après lésion médullaire et de préciser les mécanismes et les cibles d'action des vanilloïdes sur la néo physiologie du réflexe mictionnel afin de favoriser le développement de thérapeutiques innovantes de l'incontinence urinaire. Nos travaux confortent l'importance de la neuroplasticité des fibres C et des réflexes courts vésico-urétraux dans l'exagération du réflexe mictionnel après lésion médullaire et corroborent la participation d'interactions neurono-musculo-urothéliales. Ils ont permis de valider l'intérêt de solution alcoolique et glucidique de capsaïcine dans l'hyperactivité neurogène du détrusor. Ils apportent des données originales sur l'efficacité et la tolérance des vanilloïdes intravésicaux dans l'hyperactivité neurogène du détrusor et démontrent le rôle clef joué par leurs vecteurs.The purpose of our research is the exploration of afferent branch of micturitional reflex in human and its neuroplasticity occuring after spinal cord lesion. Our study intend to complete the knowledge of neurogenic factor involved in voiding reflex after spinal cord injury and to precise the mechanism and target of vanilloid agents in neurogenic detrusor overactivity in order to prone the development of new therapeutic option for refractory urinary incontinence. Our work contributes to better understanding of fundamental and therapeutic aspects of neurogenic bladder. They strongly argue for the importance of unmyelinated C fiber and bladder-sphincter reflexes in neuroplasticity occuring after spinal lesion. They suggest an interaction between neuronal, urothelial and muscular factor in detrusor overactivity pathogenicity. Our study allow to valid the interest of alcoholic and glucidic capsaicin vesical instillation in patients suffering from neurogenic detrusor hyperreflexie, reporting original data about the efficacy and safety of capsaicin and resiniferatoxin, and demonstrates the key role of the vanilloid vector.BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Intradetrusor Injections of Botulinum Toxin A in Adults with Spinal Dysraphism.

The aim of the current study was to determine the outcomes of botulinum toxin A intradetrusor injections in adult patients with spina bifida. All patients with spinal dysraphism who underwent intradetrusor injections of botulinum toxin A from 2002 to 2016 at a total of 14 centers were retrospectively included in analysis. The primary end point was the global success of injections, defined subjectively as the combination of urgency, urinary incontinence and detrusor overactivity/low bladder compliance resolution. Univariate and multivariate analysis was performed to seek predictors of global success. A total of 125 patients were included in study. The global success rate of the first injection was 62.3% with resolution of urinary incontinence in 73.5% of patients. All urodynamic parameters had improved significantly by 6 to 8 weeks compared to baseline, including maximum detrusor pressure (-12 cm H &lt;sub&gt;2&lt;/sub&gt; O, p &lt;0.001), maximum cystometric capacity (86.6 ml, p &lt;0.001) and compliance (8.9 ml/cm H &lt;sub&gt;2&lt;/sub&gt; O, p = 0.002). A total of 20 complications (3.6%) were recorded for the 561 intradetrusor botulinum toxin A injections, including 3 muscular weakness complications. The global success rate of the first injection was significantly lower in patients with poor compliance (34.4% vs 86.9%, OR 0.08, p &lt;0.001). On multivariate analysis poor compliance was associated with a lower global success rate (OR 0.13, p &lt;0.001). Female gender (OR 3.53, p = 0.01) and patient age (OR 39.9, p &lt;0.001) were predictors of global success. Intradetrusor botulinum toxin A injections were effective in adult patients with spina bifida who had detrusor overactivity. In contrast, effectiveness was much lower in adult patients with spina bifida who had poor bladder compliance. The other predictors of global success were female gender and older age

Recommandations sur la gestion du risque et la prise en charge urologique du patient adulte atteint de dysraphisme spinal (spina bifida)

International audienceIntroduction: Improved life expectancy and prenatal screening have changed the demographics of spina bifida (spinal dysraphism) which has presently become a disease of adulthood. Urinary disorders affect almost all patients with spinal dysraphism and are still the leading cause of mortality in these patients. The aim of this work was to establish recommendations for urological management that take into account the specificities of the spina bifida population. Materials and methods: National Diagnosis and Management Guidelines (PNDS) were drafted within the framework of the French Rare Diseases Plan at the initiative of the Centre de Référence Maladies Rares Spina Bifida - Dysraphismes of Rennes University Hospital. It is a collaborative work involving experts from different specialties, mainly urologists and rehabilitation physicians. We conducted a systematic search of the literature in French and English in the various fields covered by these recommendations in the MEDLINE database. In accordance with the methodology recommended by the authorities (Guide_methodologique_pnds.pdf, 2006), proposed recommendations were drafted on the basis of this literature review and then submitted to a review group until a consensus was reached. Results: Bladder dysfunctions induced by spinal dysraphism are multiple and varied and evolve over time. Management must be individually adapted and take into account all the patient's problems, and is therefore necessarily multi-disciplinary. Self-catheterisation is the appropriate micturition method for more than half of the patients and must sometimes be combined with treatments aimed at suppressing any neurogenic detrusor overactivity (NDO) or compliance alteration (anticholinergics, intra-detrusor botulinum toxin). Resort to surgery is sometimes necessary either after failure of non-invasive treatments (e.g. bladder augmentation in case of NDO resistant to pharmacological treatment), or as a first line treatment in the absence of other non-invasive alternatives (e.g. aponeurotic suburethral tape or artificial urinary sphincter for sphincter insufficiency; urinary diversion by ileal conduit if self-catheterisation is impossible). Conclusion: Spinal dysraphism is a complex pathology with multiple neurological, orthopedic, gastrointestinal and urological involvement. The management of bladder and bowel dysfunctions must continue throughout the life of these patients and must be integrated into a multidisciplinary context