Jeffrey Dunn, MD

Journal Articles

• Randomized study combining interferon and glatiramer acetate in Multiple Sclerosis Annals of Neurology Lublin, F., CombiRx Investigators 2013; 73 (3): 327-340
• Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein MULTIPLE SCLEROSIS JOURNAL Herges, K., de Jong, B. A., Kolkowitz, I., Dunn, C., Mandelbaum, G., Ko, R. M., Maini, A., Han, M. H., Killestein, J., Polman, C., Goodyear, A. L., Dunn, J., Steinman, L., Axtell, R. C. 2012; 18 (4): 398-408

  Abstract

  The pathology of neuromyelitis optica (NMO), in contrast to multiple sclerosis, comprises granulocyte infiltrates along extensive lengths of spinal cord, as well as optic nerve. Furthermore, IFN-? treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis (EAE) induced with Th17 cells is exacerbated by IFN-?, in contrast to disease induced with Th1 where treatment attenuated symptoms.This study demonstrates the similarities between NMO and Th17 EAE and how neutrophils mediate pathology in Th17 disease.Levels of blood biomarkers in NMO were assessed by Luminex and ELISA. Effects of IFN-? on neutrophils were assessed by culture assays and immunofluorescence. EAE was induced by transfer of myelin-specific Th1 or Th17 cells and treated with Sivelestat sodium hydrate, a neutrophil elastase inhibitor.We show Th17 cytokines, granulocyte chemokines, type 1 interferon and neutrophil elastase are elevated in patients with definitive NMO. In culture, we find that IFN-? stimulates neutrophils to release neutrophil elastase. In Th17 EAE, we demonstrate neutrophilic infiltration in the optic nerve and spinal cord which was not present in Th1 EAE. Blockade of neutrophil elastase with Sivelestat had efficacy in Th17 EAE but not Th1 EAE.The similarities between Th17 EAE and NMO indicate that this model represents several aspects of NMO. Neutrophils are critical in the pathologies of both Th17-EAE and NMO, and therefore blockade of neutrophil elastase is a promising target in treating NMO.

  View details for DOI 10.1177/1352458512440060

  View details for Web of Science ID 000302289900006

  View details for PubMedID 22343184

• Protective Effect of elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin olidodendrocyte glycoprotein Multiple Sclerosis Herges K, DeJong BA, Kolkowitz I, Dunn C, Mandelbaum G, Maini A, Han M, Killestein J, Polman C, Goodyear A, Dunn J, Steinman L, Axtell RC 2012; 18 (4): 398-408
• Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis CURRENT MEDICAL RESEARCH AND OPINION Dunn, J., Blight, A. 2011; 27 (7): 1415-1423

  Abstract

  Multiple sclerosis (MS) can cause progressive walking impairment that contributes to disability, loss of independence, and reduced quality of life. Dalfampridine (4-aminopyridine), a voltage-dependent potassium channel blocker, has been shown to improve walking in patients with MS, as demonstrated by an increase in walking speed.To summarize knowledge about the mechanism of action of dalfampridine in the context of clinical evidence of walking improvement in MS patients.Although this was not a systematic review, which is the primary limitation of this study, searches of PubMed were performed using relevant search terms to identify studies that examined the mechanism of action related to MS and its effects in patients with MS in clinical trials.Voltage-gated potassium channels represent a family of related proteins that span cell membranes, open and close in response to changes in the transmembrane potential, and help regulate ionic potassium currents. Action potential conduction deficits in demyelinated axons result in part from the exposure after demyelination of the paranodal and internodal potassium channels that are distributed in the axonal membrane. This exposure leads to abnormal currents across the axonal membrane that can slow action potential conduction, result in conduction failure, or affect the axon's capacity for repetitive discharge. While dalfampridine is a broad-spectrum blocker of voltage-dependent potassium channels at millimolar concentrations, studies have shown improvement in action potential conduction in demyelinated axons at concentrations as low as 1 ?M, and therapeutic plasma concentrations (associated with improved walking) are in the range of 0.25 µM. However, no specific potassium channel subtype has yet been characterized with significant sensitivity to dalfampridine in this range, and the effects of the drug at this low concentration appear to be quite selective. Improved conduction translates into clinical benefit as measured by objectively and subjectively assessed walking relative to placebo. Such improvements were observed in approximately one third of patients treated with an extended-release formulation of dalfampridine in clinical trials. These patients who responded to dalfampridine had an average increase in walking speed of approximately 25%, and greater improvements than nonresponders on a self-reported subjective measure of walking.The extended-release formulation of dalfampridine has been shown in clinical trials to improve walking speed in approximately one third of MS patients with ambulatory impairment. The putative mechanism of action of dalfampridine is restoration of action potential conduction via blockade of an as yet uncharacterized subset of potassium channels in demyelinated axons.

  View details for DOI 10.1185/03007995.2011.583229

  View details for Web of Science ID 000291662300014

  View details for PubMedID 21595605

• Dalfampridine: A brief review of its Mechanism of Action and Efficacy as a treatment to improve walking in patients with Multiple Sclerosis Current Research Medical Opinion Dunn J, Blight A 2011; 27 (7): 1415-1423
• Impact of mobility impairment on the burden of caregiving in individuals with multiple sclerosis EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH Dunn, J. 2010; 10 (4): 433-440

  Abstract

  Multiple sclerosis (MS) is a chronic, immune-mediated neurologic disease that typically strikes young adults during their most productive years, and is associated with a wide range of functional deficits and progressive disability. Loss of mobility is among the most disabling effects of MS, adversely affecting multiple outcomes, including independence, employment and quality of life. Relative to other common diseases, MS is associated with a disproportionately high socioeconomic burden. Informal and unpaid caregivers, such as family and friends, play a vital, sustained and often difficult role in supporting the ability of MS patients to live and function at home. However, there are few data characterizing caregiver burden in MS. This review was conducted to examine the need and impact of caregiving for patients with MS, focusing on the contribution of mobility impairment to loss of patient independence.

  View details for DOI 10.1586/ERP.10.34

  View details for Web of Science ID 000297009800017

  View details for PubMedID 20482233

• Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta LANCET NEUROLOGY Wynn, D., Kaufman, M., Montalban, X., Vollmer, T., Simon, J., Elkins, J., O'Neill, G., Neyer, L., Sheridan, J., Wang, C., Fong, A., Rose, J. W. 2010; 9 (4): 381-390

  Abstract

  Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment.We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161.From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4.75 in the interferon beta and placebo group compared with 1.32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0.004) and 3.58 in the interferon beta and low-dose daclizumab group (25%, -76% to 68%; p=0.51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56(bright) natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0.002; interferon beta and high-dose daclizumab group p<0.0001). Common adverse events were equally distributed across groups.Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone.Facet Biotech and Biogen Idec.

  View details for DOI 10.1016/S1474-4422(10)70033-8

  View details for Web of Science ID 000276142000016

  View details for PubMedID 20163990

• The impact of mobility impairment on the burden of caregiving in individuals with multiple sclerosis Expert Rev. Pharmacoeconomics Outcomes Res. Dunn, J. 2010; 10 (4): 433-440
• Cytomegalovirus Infection with MRI Signal Abnormalities Affecting the Optic Nerves, Optic Chiasm, and Optic Tracts JOURNAL OF NEURO-OPHTHALMOLOGY Pershing, S., Dunn, J., Khan, A., Liao, Y. J. 2009; 29 (3): 223-226

  Abstract

  A 49-year-old woman who had been immunosuppressed after a renal transplant developed bilateral severe visual loss. Visual acuities were finger counting and hand movements in the two eyes. Both optic nerves were pale. There were no other ophthalmic abnormalities. Brain MRI disclosed marked signal abnormalities involving the optic nerves, optic chiasm, and optic tracts. Cerebrospinal fluid polymerase chain reaction (PCR) was positive for cytomegalovirus. Treatment did not restore vision. Such extensive clinical and imaging involvement of the anterior visual pathway, which has been previously reported with other herpes viruses, illustrates the propensity for this family of viruses to track along axons.

  View details for Web of Science ID 000270048700011

  View details for PubMedID 19726946

• CMV Optic Neuritis with Extensive Tracking along the Visual Pathway J Neuro-Ophthalmology Pershing S, D. K. 2009; 29 (3): 223-226
• Glatiramer Acetate after Induction Therapy with Mitoxantrone in Relapsing Multiple Sclerosis Multiple Sclerosis Vollmer T, P. B. 2008; Apr 18
• Tovaxin for Early Relapsing Multiple Sclerosis Phase 2b Placebo Controlled Trial of Autologous T cell vaccination in patients with CIS or RRMS Multiple Sclerosis Fox, E., The TERMS Study Investigators 2008; 14: S5-S27
• Glatiramer Acetate after Mitoxantrone Induction improves MRI markers of lesion volume and permanent tissue injury in MS J Neurol Arnold D., Campagnolo D., Panitch H., Bar-Or A., Dunn J, Freedman M., Gazda S.K., Vollmer T. 2008; 255: 1473-1478
• Daclizumab in Patients with Active Relapsing Multiple Sclerosis on Concurrent Interferon beta Therapy; Week 24 data Phase II ECTRIMS Montalban X, K. W. 2007; 10/11/07: S18
• Randomized, Double Blind, Dose Comparison Study of Glatiramer Acetate in Relapsing Remitting MS Neurology Cohen JA, R. G. 2007; 68 (12): 939-944
• Safety and Tolerability of Glatiramer Acetate in Pediatric Patients with Relapsing Remitting Multiple Sclerosis ECTRIMS/ACTRIMS Krupp L, Banwell B, Picone M, Dunn J, Weinstock-Guttman B, Pardo L. 2005: abstract
• Comprehensive Outpatient Management of Patients with Multiple Sclerosis RIMS MS Symposium Odderson I, D. 2001: abstract
• Novantrone in the Treatment of Multiple Sclerosis Alliance News Dunn Jeffrey, Kita M., Lucas S., Bowen J., 2001: 1-3
• Clinical Advisory Committee Statement Health Care Connection Bowen J., Dunn Jeffrey E., Kraft G.H., Ratley G., Shilling J., Smith C., Thompson L. 1999; I (1): 1-2
• Gingko Biloba in the Treatment of Alzheimer's Disease Alternative Medicine Dunn Jeffrey E., Maidan R., Pallis J. 1998; 1 (15): 1-2
• Atherosclerotic Aortic Disease as a Source of Embolic Infarct Journal of Neurovascular Disease Bursell John P.,Odderson I., Dunn Jeffrey E. 1996; 1 (2): 35-38
• INTRACEREBRAL BACILLARY ANGIOMATOSIS IN A PATIENT INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS ANNALS OF INTERNAL MEDICINE Spach, D. H., Panther, L. A., Thorning, D. R., Dunn, J. E., Plorde, J. J., MILLER, R. A. 1992; 116 (9): 740-742

  View details for Web of Science ID A1992HQ62300008

  View details for PubMedID 1558347

• Intracerebral Bacillary Angiomatosis in a Patient Infected with HIV Annals of Internal Medicine Spach, D., Panther L., Thorning D., Dunn Jeffrey E., Plorde J.L., Miller, R. 1992; 116: 740-743