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21 results

Page 1 of 2

  • Chapter 10 - Multiple sclerosis

  • Edited by James E. Barrett, Joseph T. Coyle, Michael Williams
  • Book:
    Translational Neuroscience
    Published online:
    05 July 2012
    Print publication:
    28 June 2012, pp 178-196

  • Summary

    Clinically, the principles of extinction learning form much of the foundation for the most effective behavioral therapies for fear-related anxiety disorders. Within the general class of anxiety disorders, posttraumatic stress disorder (PTSD) is unique in the sense that the precipitating traumatic event may provide the opportunity for acute intervention before the onset of symptoms and before memories have been consolidated. The use of propranolol to treat individuals with posttraumatic stress symptoms was initially described in a case series of physically and sexually abused children with severe symptoms of agitation. An alternative consolidation-blockade approach to the use of propranolol involves the administration of glucocorticoids to trauma-exposed patients. Finally, clinically directed interference with initial memory consolidation through the use of beta-blockers or glucocorticoids following acute trauma exposure could prevent or attenuate the formation of traumatic emotional memory and reduce risk of PTSD.

  • 23 - Multiple Sclerosis

  • from Section 6
  • Edited by Bernard Ravina, Jeffrey Cummings, Michael McDermott, R. Michael Poole
  • Book:
    Clinical Trials in Neurology
    Published online:
    05 May 2012
    Print publication:
    12 April 2012, pp 257-272

  • Summary

    Special trial designs have been developed to distinguish the symptomatic and disease modifying effects of treatment using clinical outcome measures. These designs, termed 'two-period' designs, include the so-called withdrawal and delayed-start (or 'staggered-start') designs and their variations. This chapter describes these study designs in terms of their rationale, assumptions, design features, implementation, statistical analysis, and sample size considerations. It also discusses the important limitations of the designs. Simulation studies using disease progression modeling suggest that the withdrawal design may provide more power than the delayed start design to detect disease-modifying effects of a treatment. A statistical model for data from a complete two-period design assumes that a normally-distributed outcome termed µ 2. There are alternative approaches to evaluating the disease-modifying effects of an intervention that require only a single treatment period.

Multiple Sclerosis Therapeutics
  • 4th edition
  • Edited by Jeffrey A. Cohen, Richard A. Rudick
  • Published online:
    05 December 2011
    Print publication:
    20 October 2011
  • This book comprehensively reviews the current state of clinical trial methods in multiple sclerosis treatment, providing investigators, sponsors and specialists with current knowledge of outcome measures and study designs for disease and symptom management. The status of the rapidly evolving field of disease-modifying drugs is presented, with emphasis on the most promising therapies currently being tested. Experts discuss disease and symptom management for MS subtypes, including neuromyelitis optica and pediatric MS. In addition, key scientific advances in MS pathology, genetics, immunology and epidemiology are presented. The fourth edition has been extensively revised, featuring more than 50% new material. All chapters have been substantially updated to provide current information on rapidly evolving topics and this volume contains 15 new chapters, reflecting the growth of the field in recent years. This book is an essential reference for practitioners caring for MS patients, investigators planning or conducting clinical trials, and clinical trial sponsors.

  • 1 - Aspects of multiple sclerosis that relate to experimental therapeutics

  • from Section I - Introduction
  • Edited by Jeffrey A. Cohen, Richard A. Rudick
  • Book:
    Multiple Sclerosis Therapeutics
    Published online:
    05 December 2011
    Print publication:
    20 October 2011, pp 1-11

  • Summary

    Relapsing remitting multiple sclerosis (RRMS) patients have periodic relapses occurring at variable rates, but generally less than one per year. The factor complicating MS clinical trials is disease heterogeneity, which is one of the hallmarks of MS. The annualized relapse rate or the number of relapses is the most common primary outcome measure for RRMS clinical trials. Relapses are subjective. As symptoms fluctuate, and are influenced by many factors- fever, high ambient temperature, anxiety, intercurrent illness, and sleep deprivation, among others - it is often not clear whether an individual MS patient has experienced a relapse or not. Also, the required duration beyond which symptoms must persist has not been standardized. There are no demonstrably effective therapies for primary neuroprotection, though it appears possible to slow the neurodegerative process in early-stage MS with immunomodulatory or immunosuppressive drugs. Presumably, this form of neuroprotection is secondary to the anti-inflammatory effect.

  • Section II - Clinical trial methodology

  • Edited by Jeffrey A. Cohen, Richard A. Rudick
  • Book:
    Multiple Sclerosis Therapeutics
    Published online:
    05 December 2011
    Print publication:
    20 October 2011, pp 56-299

  • Summary

    This chapter deals with the measurement of impairment or disability for use in multiple sclerosis (MS) clinical trials from a medical model perspective, focusing on global clinical trial outcome measures. It addresses the methodological issues in measuring impairment and disability. The measures of neurological impairment and disability in MS can be grouped into four classes: biological assays, performance measures, rating scales and self-report measures. The Incapacity Status Scale and the multiple sclerosis (MS) Quality of Life Inventory are examples of such self-report measures, also called patient reported outcomes or PROs. Surrogate outcome measures have been studied in a variety of diseases and have been hoped for within the MS community. The development of the Multiple Sclerosis Functional Composite (MSFC) resulted from the analysis of a pooled data set of placebo control groups and natural history study databases.

  • Section IV - Therapy in clinical practice

  • Edited by Jeffrey A. Cohen, Richard A. Rudick
  • Book:
    Multiple Sclerosis Therapeutics
    Published online:
    05 December 2011
    Print publication:
    20 October 2011, pp 583-730

  • Summary

    Disease modifying therapy (DMT) with one of the approved agents should be considered in all patients with active relapsing-remitting multiple sclerosis (RRMS) once the diagnosis of MS is confirmed and in selected patients with a clinically isolated demyelinating syndrome (CIS). Interferon beta modulates T-cell and B-cell function, decreases expression of matrix metalloproteinases reversing blood-brain barrier disruption, and alters expression of cytokines. A series of double-blind, placebo-controlled Phase 3 trials in RRMS supported the benefit of interferon in reducing relapses, disability progression, and MRI lesion activity and accrual. All of the available agents have been reported to reduce relapse rate, magnetic resonance imaging (MRI) lesion activity, and accumulation of disability in RRMS. Patients need to be seen on a regular basis after starting treatment to address potential side effects. This chapter discusses treatment of acute relapses, progressive multiple sclerosis and treatment in special populations including children.

  • Section I - Introduction

  • Edited by Jeffrey A. Cohen, Richard A. Rudick
  • Book:
    Multiple Sclerosis Therapeutics
    Published online:
    05 December 2011
    Print publication:
    20 October 2011, pp 1-55

  • Summary

    Relapsing remitting multiple sclerosis (RRMS) patients have periodic relapses occurring at variable rates, but generally less than one per year. The factor complicating MS clinical trials is disease heterogeneity, which is one of the hallmarks of MS. The annualized relapse rate or the number of relapses is the most common primary outcome measure for RRMS clinical trials. Relapses are subjective. As symptoms fluctuate, and are influenced by many factors- fever, high ambient temperature, anxiety, intercurrent illness, and sleep deprivation, among others - it is often not clear whether an individual MS patient has experienced a relapse or not. Also, the required duration beyond which symptoms must persist has not been standardized. There are no demonstrably effective therapies for primary neuroprotection, though it appears possible to slow the neurodegerative process in early-stage MS with immunomodulatory or immunosuppressive drugs. Presumably, this form of neuroprotection is secondary to the anti-inflammatory effect.

  • 27 - Natalizumab to treat multiple sclerosis

  • from Section III - Clinical trials of multiple sclerosis therapies
  • Edited by Jeffrey A. Cohen, Richard A. Rudick
  • Book:
    Multiple Sclerosis Therapeutics
    Published online:
    05 December 2011
    Print publication:
    20 October 2011, pp 330-343

  • Summary

    Multiple sclerosis (MS) research in recent years has identified an increasing number of potential therapeutic products that can be evaluated. The ultimate goal of a drug development program is to establish that the drug has a favorable effect upon the patient and has risks that are acceptable in light of the benefit. The Kurtzke Expanded Disability Status Scale (EDSS) is employed as the chief physical disability measure in development programs for many of the currently available therapies. An important aspect of drug development is determining what drug benefits should be claimed in the approved drug labeling. Biomarkers have the potential to be informative on a number of different aspects of biological responses in much shorter time and fewer patients, and contribute to feasible and successful drug development. An important aspect of efficient and informative drug development programs is selection of appropriate end-points for each study in the clinical development program.

  • Section III - Clinical trials of multiple sclerosis therapies

  • Edited by Jeffrey A. Cohen, Richard A. Rudick
  • Book:
    Multiple Sclerosis Therapeutics
    Published online:
    05 December 2011
    Print publication:
    20 October 2011, pp 300-582

  • Summary

    This chapter summarizes interferon (IFN) biological effects, its possible mechanisms of action, and the key studies in clinically isolated syndromes (CIS), relapsing remitting multiple sclerosis (RRMS), and progressive MS. Measures of specific IFNβ-induced products, such as oligoadenylate synthetase (OAS), β-2 microglobulin, or neopterin, have been useful in pharmacodynamic studies to determine the magnitude and duration of the IFNβ-response, since serum levels of IFNβ are undetectable following injections. A consistent finding of follow-up studies from the three pivotal IFNβ RRMS trials and two CIS trials is that early treatment is beneficial compared with delayed treatment. IFNβ is partially effective in clinical trial groups. Since approval 18 years ago of the first IFNβ product for RRMS, treatment effects of β at all stages of MS have become fairly clear. The development of β for MS has illustrated many of the challenges in developing treatments for MS.

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