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Robert J Fox

Publications and source records attributed to Robert J Fox.

18 recordsLinked to original sources
PubMed2026

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years.

BACKGROUND: Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. METHODS: Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD) whereas placebo-treated participants were re-randomized (1:1:1) to respective ponesimod doses. In TP2 (TP2 and TP3 combined duration: ∼10.4 years), participants on 40 mg were re-randomized (1:1) to 10/20 mg, while others continued same dose; in TP3 all participants received 20 mg. Study outcomes included safety and efficacy (ARR, time-to 24-week confirmed-disability-accumulation [24-week CDA], total T1-weighted Gadolinium-enhanced (T1 Gd+) lesions, new/enlarging T2 lesions and Combined Unique Active Lesions [CUALs]). RESULTS: For 20 mg dose, total 92.4% participants experienced ≥1 TEAEs (73.1% mild/moderate severity) and 19 (13%) participants discontinued study. Mean (95% CI) ARR=0.14 (0.10-0.20); Kaplan-Meier estimate (95% CI) of confirmed relapse and 24-week CDA=52.5% (42.3-63.5) and 31.3% (22.6-42.3). Mean [SD] T1 Gd+ lesions decreased from ponesimod baseline (2.62 [7.06]) to 12.4 years (0.26 [1.48]), mean (95% CI) CUALs per participant/year=3.97 (2.75-5.73). CONCLUSION: Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes.

Humans↗
PubMed2006

Treatment of Susac syndrome with gamma globulin and corticosteroids.

Susac syndrome is a rare vasculopathy characterized by visual, hearing, and cognitive dysfunction. Optimal treatment is unknown, but many patients require chemotherapy to control disease activity. We describe two patients with Susac syndrome and their response to intravenous immune globulin (IVIg) and corticosteroids. Both patients improved following acute treatment with IVIg and intravenous methylprednisolone (IVMP), and no further relapses were observed. One patient showed significant improvement in hearing and MRI lesions shortly following acute treatment. Treatment with IVIg and corticosteroids provides a therapeutic option that avoids the toxicities of chemotherapy and suggests the possible importance of pathologic antibodies in the pathogenesis of Susac syndrome.

Adrenal Cortex Hormones↗
PubMed2006

Immunological studies of mitoxantrone in primary progressive MS.

Mitoxantrone (MX) has demonstrated efficacy in multiple sclerosis (MS), but its immunologic mechanisms of action are poorly understood. Furthermore, no study has examined the immunological effects of MX in primary progressive MS (PPMS). This study investigated the immunological effects of MX therapy in PPMS patients. Lymphocyte phenotypes and chemokine receptor (CCR) expression were evaluated by flow cytometry on fresh PBMC from 20 PPMS patients enrolled in a placebo (PLC)-controlled trial of MX. Longitudinal data were collected at weeks 0, 12, 24, 36 and short-term data (pre-/post-infusion) were collected at weeks 0 and 36. CXCR3, CCR1, CCR2 and CCR5 on CD4 and CD8 T cells and CD14 monocytes were evaluated. MX therapy induced a significant increase in the proportion of CD8 T cells (CD45RO(-)) over 9 months. Expression of several CCR increased following MX treatment. Two of the eight MX-treated patients demonstrated dramatic upregulation (70-76%) of CCR2 on monocytes. These two patients were the only MX-treated patients to demonstrate active inflammation by magnetic resonance imaging (MRI). PLC patients did not show significant changes in CCR expression. MX therapy was not associated with selective loss of CD4, CD8 or CD14 cells 1 month after treatment or over 9 months. These results suggest that MX therapy leads to a longitudinal increase in CD8 T cells and may increase CCR in patients with inflammation on MRI. Overall, MX did not show extensive immune changes in PPMS, although patients with active disease (gadolinium enhancing lesions) may identify a subset of PPMS subjects who respond immunologically to MX therapy. An improved understanding of MX may help identify markers of disease activity and response to therapy.

Adult↗
PubMed2006

Defending eponyms.

Explore the source record for details and available documents.

Acrocephalosyndactylia↗
PubMed2006

Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients.

OBJECTIVE: Degeneration of chronically demyelinated axons is a major cause of irreversible neurological disability in multiple sclerosis (MS) patients. Development of neuroprotective therapies will require elucidation of the molecular mechanisms by which neurons and axons degenerate. METHODS: We report ultrastructural changes that support Ca2+-mediated destruction of chronically demyelinated axons in MS patients. We compared expression levels of 33,000 characterized genes in postmortem motor cortex from six control and six MS brains matched for age, sex, and postmortem interval. As reduced energy production is a major contributor to Ca2+-mediated axonal degeneration, we focused on changes in oxidative phosphorylation and inhibitory neurotransmission. RESULTS: Compared with controls, 488 transcripts were decreased and 67 were increased (p < 0.05, 1.5-fold) in the MS cortex. Twenty-six nuclear-encoded mitochondrial genes and the functional activities of mitochondrial respiratory chain complexes I and III were decreased in the MS motor cortex. Reduced mitochondrial gene expression was specific for neurons. In addition, pre-synaptic and postsynaptic components of GABAergic neurotransmission and the density of inhibitory interneuron processes also were decreased in the MS cortex. INTERPRETATION: Our data supports a mechanism whereby reduced ATP production in demyelinated segments of upper motor neuron axons impacts ion homeostasis, induces Ca2+-mediated axonal degeneration, and contributes to progressive neurological disability in MS patients.

Aged↗
PubMed2006

Chemokine receptors as biomarkers in multiple sclerosis.

Leukocyte infiltrates characterize tissue inflammation and are thought to be integral in the pathogenesis of multiple sclerosis (MS). This attribute underlines the importance of understanding mechanisms of leukocyte migration. Chemokines are secreted proteins which govern leukocyte trafficking into targeted organs. Chemokine receptors (CKR) are differentially expressed on leukocytes and their modulation is a potential target for MS disease modifying therapies. Chemokines and their receptors are also potential biomarkers of both disease activity and response to treatment. We describe the fluctuations in CKR expression on peripheral leukocytes in a group of MS patients followed longitudinally for up to 36 months. We observed little fluctuation in CKR expression within each patient over time, despite considerable variability in CKR expression between patients. These observations suggest that individual patients have a CKR set point, and this set point varies from one patient to another. Evaluation of chemokines or chemokine receptors as biomarkers in MS will need to account for this individual variability in CKR expression.

Adult↗
PubMed2006

Multiple sclerosis: advances in understanding, diagnosing, and treating the underlying disease.

Recent advances in our understanding of the diagnosis, imaging, pathology, and clinical monitoring of multiple sclerosis (MS) have significantly increased our ability to successfully treat this often perplexing neurologic disorder. Magnetic resonance imaging (MRI) is now integral to the diagnostic process. Treatment of MS can be considered as three parallel pathways: treatment of relapses, symptom management, and long-term prevention of tissue injury.

Antibodies, Monoclonal↗
PubMed2006

Multiple sclerosis: treating symptoms, and other general medical issues.

Multiple sclerosis (MS) has protean manifestations, and the care of people with MS presents many unique challenges. Clinicians can have an important impact on health, quality of life, and daily functioning by participating in open dialogue, tailoring focused treatment plans, and anticipating general medical needs.

Activities of Daily Living↗
PubMed2005

Modulating CCR2 and CCL2 at the blood-brain barrier: relevance for multiple sclerosis pathogenesis.

Chemokines and chemokine receptors play a key role in the transmigration of leucocytes across the blood-brain barrier (BBB). CCR2 is the major receptor for CCL2, a potent monocyte and T cell chemoattractant. CCR2 and CCL2 have been consistently associated with a pathogenic role in experimental autoimmune encephalomyelitis, using knockout and transgenic mice, neutralizing antibodies, peptide antagonists and DNA vaccination. However, the significance of CCL2 and CCR2 in multiple sclerosis is enigmatic, because CCL2 levels are consistently decreased in the CSF of patients with this disease and other chronic neuroinflammatory conditions, despite abundant expression within lesional multiple sclerosis tissues. This study used an in vitro BBB model to test the hypothesis that CCL2 is removed from the extracellular fluid by CCR2-positive migrating cells as they cross the BBB, resulting in decreased CSF CCL2 levels. We showed that CCR2-positive T cells and monocytes migrated selectively across the in vitro BBB, and that CCL2 on the abluminal (tissue) side was consumed by migrating T cells and monocytes. Next, we used a new anti-CCR2 antibody to show that CCR2-positive mononuclear inflammatory cells could be readily detected in appropriate positive control tissues, but that CCR2+ cells were very infrequently found in multiple sclerosis lesions. We then showed that CCR2 receptor density on T cells and monocytes was specifically downregulated upon in vitro BBB transmigration in response to CCL2, but not irrelevant chemokines. These findings document a novel strategy for analysing chemokine receptor function in inflammatory CNS disease, and support the hypothesis that CCL2 is consumed by migrating inflammatory cells, which downregulate CCR2, as they cross the BBB.

Aged↗
PubMed2005

Brain atrophy and magnetization transfer ratio following methylprednisolone in multiple sclerosis: short-term changes and long-term implications.

BACKGROUND: The short-term effect of corticosteroids on MRI measures of multiple sclerosis (MS) is not well understood and may have a significant impact when using these quantitative measures to evaluate disease activity and changes following other therapeutic interventions. OBJECTIVE: To determine the impact of a course of intravenous methylprednisolone (IVMP) on quantitative measures of disease activity and tissue injury in MS patients. METHODS: We prospectively measured brain parenchymal fraction (BPF), magnetization transfer ratio (MTR, lesional and whole brain), and lesion volumes on nine weekly brain MRI studies in ten MS patients receiving a course of IVMP. A group of nine MS patients not receiving IVMP served as controls. RESULTS: In comparison to untreated controls, BPF declined over the eight weeks following IVMP treatment (P <0.02). BPF decline was most prominent in patients with secondary progressive MS (SPMS, P <0.03), and was not seen in relapsing-remitting (RR) MS patients. Short-term change in BPF correlated with baseline BPF (r =0.62, P =0.05) and short-term change in lesional MTR (r = -0.55, P =0.03), but not with change in enhancing lesion volume. Short-term change in lesional MTR inversely correlated with baseline lesional and whole brain MTR (r = -0.79, P =0.04 for both). There was no significant difference between treated and control patients in measures of MTR or T2, T1 or enhancing lesion volumes. CONCLUSIONS: Patients with SPMS showed a greater decline in BPF following IVMP than RRMS patients. A correlation between changes in BPF and MTR suggest that these changes are secondary to altered water content within MS lesions. Differential response to a standardized therapeutic intervention in RRMS and SPMS suggests that responses to therapy may differ due to a fundamental pathologic difference between early and late stage MS.

Adult↗
PubMed2004

New directions in MS therapeutics: vehicles of hope.

Basic immunological research has greatly expanded our understanding of the suspected immunopathology of multiple sclerosis (MS) and, more importantly, spawned a new generation of clinical trials evaluating dozens of immune-based therapies. Adhesion molecules are the furthest into development, although patient acceptance and neutralizing antibodies both support the development of small, orally available molecules. Progressive MS probably has a significant neurodegenerative component, so progress with neuroprotective strategies will require appropriate animal models, as well as more advanced clinical imaging techniques, such as brain atrophy and diffusion tensor. Dozens of therapies are in various stages of clinical development and results from these clinical studies will provide important tests of immune and inflammatory mechanisms of MS disease.

Animals↗
PubMed2004

Mitoxantrone as a potential therapy for primary progressive multiple sclerosis.

Mitoxantrone (Novantrone) was the first drug approved in western Europe and North America for treatment of secondary progressive multiple sclerosis (SPMS) and progressive relapsing MS (PRMS). Pharmacological properties of mitoxantrone, its role in SPMS, the study rational and design of an ongoing multi-centre, double blind, randomized, placebo-controlled phase 2 trial will be outlined in this article.

Humans↗