38 results on '"Roy Freeman"'
Search Results
2. Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement
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David J. Hohenschurz-Schmidt, Dan Cherkin, Andrew S.C. Rice, Robert H. Dworkin, Dennis C. Turk, Michael P. McDermott, Matthew J. Bair, Lynn L. DeBar, Robert R. Edwards, John T. Farrar, Robert D. Kerns, John D. Markman, Michael C. Rowbotham, Karen J. Sherman, Ajay D. Wasan, Penney Cowan, Paul Desjardins, McKenzie Ferguson, Roy Freeman, Jennifer S. Gewandter, Ian Gilron, Hanna Grol-Prokopczyk, Sharon H. Hertz, Smriti Iyengar, Cornelia Kamp, Barbara I. Karp, Bethea A. Kleykamp, John D. Loeser, Sean Mackey, Richard Malamut, Ewan McNicol, Kushang V. Patel, Friedhelm Sandbrink, Kenneth Schmader, Lee Simon, Deborah J. Steiner, Christin Veasley, and Jan Vollert
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Anesthesiology and Pain Medicine ,Neurology ,Neurology (clinical) - Published
- 2023
3. Myeloid Mineralocorticoid Receptor Transcriptionally Regulates P-Selectin Glycoprotein Ligand-1 and Promotes Monocyte Trafficking and Atherosclerosis
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Gail K. Adler, Joshua J. Man, Marina Anastasiou, M. Elizabeth Moss, Brigett Carvajal, Pilar Alcaide, Roy Freeman, Qing Lu, Njabulo Ngwenyama, Wendy Baur, Iris Z. Jaffe, and Amanda E Garza
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Adult ,Male ,Myeloid ,Transcription, Genetic ,Mice, Knockout, ApoE ,Aortic Diseases ,Aorta, Thoracic ,Inflammation ,Spironolactone ,Article ,Monocytes ,Young Adult ,chemistry.chemical_compound ,Sex Factors ,Mineralocorticoid receptor ,Leukocyte Trafficking ,Cell Adhesion ,medicine ,Animals ,Humans ,Leukocyte Rolling ,Mineralocorticoid Receptor Antagonists ,Randomized Controlled Trials as Topic ,Membrane Glycoproteins ,Aldosterone ,business.industry ,Monocyte ,Transendothelial and Transepithelial Migration ,U937 Cells ,Middle Aged ,Atherosclerosis ,Hypoglycemia ,Mice, Inbred C57BL ,Disease Models, Animal ,HEK293 Cells ,Receptors, Mineralocorticoid ,Treatment Outcome ,medicine.anatomical_structure ,chemistry ,Macrophages, Peritoneal ,Cancer research ,Female ,P-selectin glycoprotein ligand-1 ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Selectin ,Signal Transduction - Abstract
Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex. Approach and Results: We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity. Conclusions: These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation. Graphic Abstract: A graphic abstract is available for this article.
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- 2021
4. Benefit–risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations
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Alejandro R. Jadad, Veeraindar Goli, Scott R. Evans, Jeffrey Tobias, Dmitri Lissin, Vibeke Strand, Hilary D. Wilson, Michael P. McDermott, Kushang V. Patel, Nathaniel P. Katz, Jasvinder A. Singh, Penney Cowan, Michael C. Rowbotham, Roy Freeman, Roderick Junor, Cristina Sampaio, John T. Farrar, Ilona Steigerwald, J Patrick Kesslak, Robert H. Dworkin, Bethea A. Kleykamp, John D. Markman, Louis P. Garrison, Zubin Bhagwagar, Alec B. O'Connor, Susan S. Ellenberg, Philip J. Mease, Ernest A. Kopecky, Christopher Eccleston, Leslie Tive, Mark P. Jensen, Jennifer S. Gewandter, Smriti Iyengar, Srinivasa N. Raja, Dennis C. Turk, and Ajay D. Wasan
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medicine.medical_specialty ,business.industry ,Chronic pain ,MEDLINE ,medicine.disease ,Risk Assessment ,Article ,law.invention ,Treatment and control groups ,Clinical trial ,Anesthesiology and Pain Medicine ,Neurology ,Randomized controlled trial ,Pain assessment ,law ,Outcome Assessment, Health Care ,medicine ,Humans ,Professional association ,Neurology (clinical) ,Metric (unit) ,Chronic Pain ,business ,Intensive care medicine ,Pain Measurement - Abstract
Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.
- Published
- 2021
5. Randomized, double-blind, placebo-controlled trial of ISC 17536, an oral inhibitor of transient receptor potential ankyrin 1, in patients with painful diabetic peripheral neuropathy: impact of preserved small nerve fiber function
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Robert Holland, Yacine Salhi, Neelufar Mozaffarian, Sunil M. Jain, Ralf Baron, Ramanathan Balamurugan, Monika Tandon, Roy Freeman, and Girish Gudi
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Ankyrins ,medicine.medical_specialty ,Placebo-controlled study ,Pain ,Nerve Fibers ,Diabetic Neuropathies ,Double-Blind Method ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,medicine ,Clinical endpoint ,Humans ,business.industry ,Chronic pain ,Peripheral Nervous System Diseases ,medicine.disease ,Treatment Outcome ,Anesthesiology and Pain Medicine ,Peripheral neuropathy ,Nociception ,Neurology ,Neuropathic pain ,Quality of Life ,Nociceptor ,Neuralgia ,Neurology (clinical) ,Chronic Pain ,business - Abstract
Patients with chronic pain syndromes, such as those with painful peripheral neuropathy due to diabetes mellitus, have limited treatment options and suffer ongoing attrition of their quality of life. Safer and more effective treatment options are needed. One therapeutic approach encompasses phenotypic characterization of the neuropathic pain subtype, combined with the selection of agents that act on relevant mechanisms. ISC 17536 is a novel, orally available inhibitor of the widely expressed pain receptor, transient receptor potential ankyrin 1, which mediates nociceptive signaling in peripheral small nerve fibers. In this randomized, placebo-controlled, proof-of-concept trial, we assessed the safety and efficacy of 28-day administration of ISC 17536 in 138 patients with chronic, painful diabetic peripheral neuropathy and used quantitative sensory testing to characterize the baseline phenotype of patients. The primary end point was the change from baseline to end of treatment in the mean 24-hour average pain intensity score based on an 11-point pain intensity numeric rating scale. The study did not meet the primary end point in the overall patient population. However, statistically significant and clinically meaningful improvement in pain were seen with ISC 17536 in an exploratory hypothesis-generating subpopulation of patients with preserved small nerve fiber function defined by quantitative sensory testing. These results may provide a mechanistic basis for targeted therapy in specific pain phenotypes in line with current approaches of "precision medicine" or personalized pain therapeutics. The hypothesis is planned to be tested in a larger phase 2 study.
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- 2021
6. Pure autonomic failure and the differential diagnosis of autonomic peripheral neuropathies
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Alejandra González-Duarte, Aditi Varma-Doyle, and Roy Freeman
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Diabetic Autonomic Neuropathy ,Pathology ,medicine.medical_specialty ,Synucleinopathies ,business.industry ,Peripheral Nervous System Diseases ,Neurodegenerative Diseases ,Disease ,medicine.disease ,Peripheral ,Diagnosis, Differential ,Cerebrospinal fluid ,Autonomic Nervous System Diseases ,Neurology ,Pure Autonomic Failure ,alpha-Synuclein ,Synuclein ,medicine ,Humans ,Protein Misfolding Cyclic Amplification ,Neurology (clinical) ,Differential diagnosis ,Pure autonomic failure ,business - Abstract
Purpose of the review Pure autonomic failure (PAF) is a peripheral autonomic neurodegenerative disease caused by alpha-synuclein deposition that is predominantly confined to peripheral autonomic neurons. Patients present with insidious features of autonomic failure that have a chronic course.In this review, we highlight the features of PAF, the differentiating features from other autonomic neuropathies, the diagnostic tests, and the predictors for conversion to a central synucleinopathy. Recent findings Natural history studies have defined the predictors for and rate of conversion to a central alpha-synucleinopathy. Skin immunohistochemistry techniques and demonstration of length-dependent neuronal loss of both somatic and autonomic small fiber nerves, and intraneural phosphorylated synuclein deposition provide diagnostic biomarkers. In the future, diagnosis maybe supported by measuring cerebrospinal fluid alpha-synuclein oligomers using techniques, such as protein misfolding cyclic amplification assay and real-time quaking-induced conversion. Summary PAF is a sporadic peripheral autonomic neurodegenerative disease that belongs to the group of disorders known as alpha-synucleinopathies. Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies. Novel diagnostic procedures like skin immunohistochemistry for alpha-synuclein, and protein amplification techniques are being investigated to provide an earlier and more specific diagnosis. A substantial number of PAF patients' phenoconvert to a central alpha-synucleinopathy.
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- 2021
7. Clinician-rated measures for distal symmetrical axonal polyneuropathy
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Robert H. Dworkin, Justin C. McArthur, Marta Campagnolo, A. Gordon Smith, Joonho Lee, Jennifer S. Gewandter, Jenna Chaudari, David N. Herrmann, Christopher H. Gibbons, Dennis C. Turk, Shannon M. Smith, Laurie B. Burke, Roy Freeman, Nam Ward, James W. Russell, Guido Cavaletti, Gewandter, J, Gibbons, C, Campagnolo, M, Lee, J, Chaudari, J, Ward, N, Burke, L, Cavaletti, G, Herrmann, D, Mcarthur, J, Russell, J, Smith, A, Smith, S, Turk, D, Dworkin, R, and Freeman, R
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medicine.medical_specialty ,Outcome Assessment ,media_common.quotation_subject ,Population ,Sensory system ,Polyneuropathies ,03 medical and health sciences ,Vibration perception ,0302 clinical medicine ,Physical medicine and rehabilitation ,Drug Development ,stomatognathic system ,Perception ,Outcome Assessment, Health Care ,medicine ,Humans ,education ,media_common ,Neurologic Examination ,Clinical Trials as Topic ,education.field_of_study ,business.industry ,Sensory loss ,Peripheral ,Health Care ,030220 oncology & carcinogenesis ,Reflex ,Neurology (clinical) ,Complication ,business ,030217 neurology & neurosurgery ,Human - Abstract
Distal symmetrical axonal polyneuropathy (DSP) is due to injury to peripheral sensory, motor, and autonomic nerve fibers, resulting in distal predominant sensory loss, pain, and gait instability. DSP occurs as a complication of multiple medical conditions including diabetes or HIV, or following exposure to various toxins such as chemotherapy. It affects at least 10% of the United States population. Few treatments for DSP are approved by regulatory agencies. Reliable and responsive outcome measures are integral to developing new DSP treatments. Multiple clinician-rated measures that incorporate neuropathy signs exist, however, it is not clear which of these measures performs best for various DSP phenotypes. This systematic review summarizes the content of 18 published measures of DSP identified using PubMed and from personal archives of the authors. The relative percentage of scoring dedicated to motor, reflex, large and small fiber sensory, and autonomic domains varied considerably among measures. The most common neurologic examination items included in the scales were (1) vibration perception (n = 18, 100%), (2) reflexes (n = 16, 89%), (3) pinprick perception (n = 14, 78%), (4) muscle strength (n = 11, 61%), (5) touch–pressure perception (n = 9, 50%), and (6) joint position perception (n = 8, 44%). This review can be used to inform decisions regarding which of the available clinician-rated sign outcome measures would be most appropriate for use in a particular DSP population, based on the domains most affected by that neuropathy or on the domains most likely to be affected by a particular experimental therapy.
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- 2019
8. Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: a systematic review
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Simon Haroutounian, Páll Karlsson, Alexander Hincker, Troels S. Jensen, and Roy Freeman
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medicine.medical_specialty ,Heat pain ,Nerve fiber ,Signs and symptoms ,Sensory system ,Polyneuropathies ,03 medical and health sciences ,Nerve Fibers ,0302 clinical medicine ,Physical medicine and rehabilitation ,030202 anesthesiology ,Psychophysics ,medicine ,Animals ,Humans ,In patient ,Screening instrument ,Skin ,Neurologic Examination ,business.industry ,Fiber morphology ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Neurology ,Neuropathic pain ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
The diagnosis of distal symmetric polyneuropathies (DSPs) relies on the presenting symptomatology and neurological sensory examination, supported by objectively quantified structural and functional changes in sensory nerves. Although these separate components have important diagnostic utility, the associations between the structural vs the symptomatic and functional findings in painful DSP are still unclear. It is assumed that delineation of the correlations, or lack of such, between structure, clinical presentation, and function will contribute to a better understanding and treatment of DSP. This systematic review assessed small fiber morphology in patients with different types of painful DSP, and compared it with symptoms, signs, and nerve fiber function. Overall, 111 papers met the inclusion criteria for the systematic review. The results indicate that epidermal nerve fiber loss, in isolation, is not a useful indicator of painful symptoms or their severity in DSP. Intraepidermal nerve fiber density correlated reasonably well with neuropathy scores on tools assessing signs and symptoms (such as the Michigan Neuropathy Screening Instrument and the Total Neuropathy Score), but less so with symptom measures only. Among various psychophysical sensory measures, warmth detection and heat pain thresholds correlated best with intraepidermal nerve fiber density, particularly when assessed at the same anatomical site. The observed sources of heterogeneity, and the lack of associations between structural and functional measures in several studies are discussed. A framework is proposed for uniform assessment of nerve fiber parameters for investigating clinically relevant mechanisms of neuropathic pain in DSP.
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- 2018
9. Trial designs for chemotherapy-induced peripheral neuropathy prevention
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Ann M. O'Mara, Paul G. Richardson, Lynn J. Howie, Joanna M. Brell, A. Gordon Smith, Simon Haroutounian, Robert H. Dworkin, Jennifer S. Gewandter, Charles L. Loprinzi, Michael P. McDermott, Daniela Dastros-Pitei, Dennis C. Turk, Patrick M. Dougherty, Ellen M. Lavoie-Smith, Lynn R. Gauthier, Matthew Jarpe, Guido Cavaletti, Roy Freeman, Scott R. Evans, Patrick Y. Wen, Nathaniel P. Katz, Gewandter, J, Brell, J, Cavaletti, G, Dougherty, P, Evans, S, Howie, L, Mcdermott, M, O'Mara, A, Smith, A, Dastros-Pitei, D, Gauthier, L, Haroutounian, S, Jarpe, M, Katz, N, Loprinzi, C, Richardson, P, Lavoie-Smith, E, Wen, P, Turk, D, Dworkin, R, and Freeman, R
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medicine.medical_specialty ,Organoplatinum Compounds ,MEDLINE ,Antineoplastic Agents ,chemotherapy, neuropathy, clinical trial, outcome measures ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,medicine ,Clinical endpoint ,Humans ,Medical Informatics Applications ,Dosing ,Intensive care medicine ,Randomized Controlled Trials as Topic ,business.industry ,Partnership Practice ,Peripheral Nervous System Diseases ,Assay sensitivity ,medicine.disease ,Clinical trial ,Peripheral neuropathy ,Chemotherapy-induced peripheral neuropathy ,030220 oncology & carcinogenesis ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapies. No therapies are available to prevent CIPN. The small number of positive randomized clinical trials (RCTs) evaluating preventive therapies for CIPN provide little guidance to inform the design of future trials. Moreover, the lack of consensus regarding major design features in this area poses challenges to development of new therapies. An Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION)–Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials (CONCEPPT) meeting attended by neurologists, oncologists, pharmacists, clinical trialists, statisticians, and regulatory experts was convened to discuss design considerations and provide recommendations for CIPN prevention trials. This article outlines considerations related to design of RCTs that evaluate preventive therapies for CIPN including (1) selection of eligibility criteria (e.g., cancer types, chemotherapy types, inclusion of preexisting neuropathy); (2) selection of outcome measures and endpoints, including those that incorporate alterations in chemotherapy dosing, which may affect the rate of CIPN development and its severity; (3) potential effects of the investigational therapy on the efficacy of chemotherapy; and (4) sample size estimation. Our hope is that attention to the design considerations and recommendations outlined in this article will improve the quality and assay sensitivity of CIPN prevention trials and thereby accelerate the identification of efficacious therapies.
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- 2018
10. Chemotherapy-induced peripheral neuropathy clinical trials
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Supriya G. Mohlie, Rachel A. Kitt, Robert H. Dworkin, Mohamedtaki Abdulaziz Tejani, Roy Freeman, Jennifer S. Gewandter, A. Gordon Smith, Dennis C. Turk, Guido Cavaletti, Lynn R. Gauthier, Nimish Mohile, Michael P. McDermott, Gewandter, J, Freeman, R, Kitt, R, Cavaletti, G, Gauthier, L, Mcdermott, M, Mohile, N, Mohlie, S, Smith, A, Tejani, M, Turk, D, and Dworkin, R
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medicine.medical_specialty ,medicine.medical_treatment ,MEDLINE ,Antineoplastic Agents ,Placebo ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Diabetes mellitus ,Humans ,Medicine ,Randomized Controlled Trials as Topic ,Chemotherapy ,business.industry ,Peripheral Nervous System Diseases ,medicine.disease ,Clinical trial ,Peripheral neuropathy ,Chemotherapy-induced peripheral neuropathy ,030220 oncology & carcinogenesis ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,chemotherapy-induced peripheral neuropathy - Abstract
Objective:To assess the design characteristics and reporting quality of published randomized controlled trials (RCTs) for treatments of chemotherapy-induced peripheral neuropathy (CIPN) initiated before or during chemotherapy.Methods:In this systematic review of RCTs of preventive or symptomatic pharmacologic treatments for CIPN initiated before or during chemotherapy treatment, articles were identified by updating the PubMed search utilized in the CIPN treatment guidelines published in the Journal of Clinical Oncology in 2014.Results:Thirty-eight articles were identified. The majority included only patients receiving platinum therapies (61%) and used a placebo control (79%). Common exclusion criteria were preexisting neuropathy (84%), diabetes (55%), and receiving treatments that could potentially improve neuropathy symptoms (45%). Ninety-five percent of studies initiated the experimental treatment before CIPN symptoms occurred. Although 58% of articles identified a primary outcome measure (POM), only 32% specified a primary analysis. Approximately half (54%) of the POMs were patient-reported outcome measures of symptoms and functional impairment. Other POMs included composite measures of symptoms and clinician-rated signs (23%) and vibration tests (14%). Only 32% of articles indicated how data from participants who prematurely discontinued chemotherapy were analyzed, and 21% and 29% reported the number of participants who discontinued chemotherapy due to neuropathy or other/unspecified reasons, respectively.Conclusions:These data identify reporting practices that could be improved in order to enhance readers' ability to critically evaluate RCTs of CIPN treatments and use the findings to inform the design of future studies and clinical practice. Reporting recommendations are provided.
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- 2017
11. Effects of orthostatic hypotension on cognition in Parkinson disease
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Christopher H. Gibbons, Alexander O. Canova, Justin Centi, Sandy Neargarder, Roy Freeman, and Alice Cronin-Golomb
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medicine.medical_specialty ,Supine position ,Working memory ,Neuropsychology ,Cognition ,030204 cardiovascular system & hematology ,medicine.disease ,Developmental psychology ,03 medical and health sciences ,Orthostatic vital signs ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Neurology (clinical) ,Verbal memory ,Psychology ,Pure autonomic failure ,030217 neurology & neurosurgery ,Executive dysfunction - Abstract
Objective:To investigate the relation between orthostatic hypotension (OH) and posture-mediated cognitive impairment in Parkinson disease (PD) using a cross-sectional and within-group design.Methods:Individuals without dementia with idiopathic PD included 18 with OH (PDOH) and 19 without OH; 18 control participants were also included. Neuropsychological tests were conducted in supine and upright-tilted positions. Blood pressure was assessed in each posture.Results:The PD groups performed similarly while supine, demonstrating executive dysfunction in sustained attention and response inhibition, and reduced semantic fluency and verbal memory (encoding and retention). Upright posture exacerbated and broadened these deficits in the PDOH group to include phonemic fluency, psychomotor speed, and auditory working memory. When group-specific supine scores were used as baseline anchors, both PD groups showed cognitive changes following tilt, with the PDOH group exhibiting a wider range of deficits in executive function and memory as well as significant changes in visuospatial function.Conclusions:Cognitive deficits in PD have been widely reported with assessments performed in the supine position, as seen in both our PD groups. Here we demonstrated that those with PDOH had transient, posture-mediated changes in excess of those found in PD without OH. These observed changes suggest an acute, reversible effect. Understanding the effects of OH due to autonomic failure on cognition is desirable, particularly as neuroimaging and clinical assessments collect data only in the supine or seated positions. Identification of a distinct neuropsychological profile in PD with OH has quality of life implications, and OH presents itself as a possible target for intervention in cognitive disturbance.
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- 2016
12. Pain in acquired inflammatory demyelinating polyneuropathies
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Roy Freeman, Kenneth C. Gorson, Robert H. Dworkin, Siddarth Thakur, and David N. Herrmann
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0301 basic medicine ,PubMed ,medicine.medical_specialty ,business.industry ,Pain ,Dermatology ,Polyneuropathies ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Anesthesiology and Pain Medicine ,Neurology ,Humans ,Medicine ,Neurology (clinical) ,Demyelinating polyneuropathies ,business ,030217 neurology & neurosurgery - Published
- 2016
13. Clinical implications of delayed orthostatic hypotension
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Roy Freeman and Christopher H. Gibbons
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Posture ,Blood Pressure ,Cohort Studies ,Hypotension, Orthostatic ,Tilt table test ,Orthostatic vital signs ,Tilt-Table Test ,Diabetes mellitus ,Humans ,Medicine ,Survival rate ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Mortality rate ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Surgery ,Survival Rate ,Blood pressure ,Female ,Neurology (clinical) ,business ,Follow-Up Studies ,Cohort study - Abstract
Objective: To define the long-term outcome of delayed orthostatic hypotension (OH). Hypothesis: Delayed OH is an early and milder form of OH that progresses over time. Methods: We reviewed the medical records of 230 previously reported patients who completed autonomic testing at our center from January 1, 2002, through December 31, 2003. All available information on clinical diagnosis, mortality, medication use, and autonomic testing were extracted and included in the reported outcomes. Standard criteria were used to define OH and delayed OH. Results: Forty-eight individuals with delayed OH, 42 individuals with OH, and 75 controls had complete follow-up data. Fifty-four percent of individuals with delayed OH progressed to OH. Thirty-one percent of individuals with delayed OH developed an α-synucleinopathy. The 10-year mortality rate in individuals with delayed OH was 29%, in individuals with baseline OH was 64%, and in controls was 9%. The 10-year mortality of individuals who progressed to OH was 50%. Progression to OH was associated with developing an α-synucleinopathy, baseline diabetes, and abnormal baseline autonomic test results. Conclusion: Delayed OH frequently progresses to OH with a high associated mortality.
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- 2015
14. Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa
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L. Arthur Hewitt, Christopher J. Mathias, Italo Biaggioni, Horacio Kaufmann, Phillip A. Low, and Roy Freeman
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Male ,Posture ,multiple system atrophy ,Blood Pressure ,norepinephrine ,Norepinephrine (medication) ,Hypotension, Orthostatic ,chemistry.chemical_compound ,Orthostatic vital signs ,Internal Medicine ,Humans ,Medicine ,Clinical Trials ,Young adult ,droxidopa ,business.industry ,autonomic nervous system ,Original Articles ,Prodrug ,Parkinson disease ,Autonomic nervous system ,Blood pressure ,chemistry ,Anesthesia ,Antiparkinson Agents ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Female ,Droxidopa ,business ,medicine.drug - Abstract
Supplemental Digital Content is available in the text., — We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100–600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa (P=0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient’s self-reported ability to perform activities requiring standing a short time (P=0.033) and standing a long time (P=0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa (P=0.013). There was no significant difference between groups for standing systolic blood pressure (P=0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00633880.
- Published
- 2015
15. Droxidopa for neurogenic orthostatic hypotension: A randomized, placebo-controlled, phase 3 trial
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Christopher J. Mathias, Simon Pedder, Italo Biaggioni, Phillip A. Low, Horacio Kaufmann, L. Arthur Hewitt, Joe Mauney, Michael Feirtag, and Roy Freeman
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Randomization ,business.industry ,Placebo ,medicine.disease ,3. Good health ,Orthostatic vital signs ,chemistry.chemical_compound ,Blood pressure ,chemistry ,Anesthesia ,medicine ,Neurology (clinical) ,Droxidopa ,Adverse effect ,Pure autonomic failure ,business ,Autonomic agent - Abstract
Objective: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). Methods: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100–600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. Results: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units ( p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units ( p = 0.010), with maximum change in “dizziness/lightheadedness.” Improvement in symptom-impact subscore favored droxidopa by 1.06 units ( p = 0.003), with maximum change for “standing a long time.” Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg ( p p 180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. Conclusions: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. Classification of evidence: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.
- Published
- 2014
16. Synuclein in cutaneous autonomic nerves
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Ningshan Wang, Christopher H. Gibbons, Roy Freeman, and Jacob Lafo
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Posture ,Statistics as Topic ,Adrenergic ,Sensory system ,Nerve fiber ,Biology ,Thigh ,Article ,Nerve Fibers ,Heart Rate ,medicine ,Humans ,Autonomic Pathways ,Aged ,Skin ,Neurologic Examination ,Cholinergic Fibers ,Respiration ,Parkinson Disease ,Middle Aged ,Sudomotor ,medicine.anatomical_structure ,Case-Control Studies ,alpha-Synuclein ,Biomarker (medicine) ,Female ,α synuclein ,Neurology (clinical) ,Nervous System Diseases - Abstract
To develop a cutaneous biomarker for Parkinson disease (PD).Twenty patients with PD and 14 age- and sex-matched control subjects underwent examinations, autonomic testing, and skin biopsies at the distal leg, distal thigh, and proximal thigh. α-Synuclein deposition and the density of intraepidermal, sudomotor, and pilomotor nerve fibers were measured. α-Synuclein deposition was normalized to nerve fiber density (the α-synuclein ratio). Results were compared with examination scores and autonomic function testing.Patients with PD had a distal sensory and autonomic neuropathy characterized by loss of intraepidermal and pilomotor fibers (p0.05 vs controls, all sites) and morphologic changes to sudomotor nerve fibers. Patients with PD had greater α-synuclein deposition and higher α-synuclein ratios compared with controls within pilomotor nerves and sudomotor nerves (p0.01, all sites) but not sensory nerves. Higher α-synuclein ratios correlated with Hoehn and Yahr scores (r = 0.58-0.71, p0.01), with sympathetic adrenergic function (r = -0.40 to -0.66, p0.01), and with parasympathetic function (r = -0.66 to -0.77, p0.01).We conclude that α-synuclein deposition is increased in cutaneous sympathetic adrenergic and sympathetic cholinergic fibers but not sensory fibers of patients with PD. Higher α-synuclein deposition is associated with greater autonomic dysfunction and more advanced PD. These data suggest that measures of α-synuclein deposition in cutaneous autonomic nerves may be a useful biomarker in patients with PD.
- Published
- 2013
17. NaV channel variants in patients with painful and nonpainful peripheral neuropathy
- Author
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Stefan Kirov, Samir Wadhawan, Linda J. Bristow, Saumya Pant, David M. Simpson, A. Gordon Smith, Irfan Qureshi, Ryan Golhar, John Thompson, Leslie Jacobsen, Ahmet Hoke, Roy Freeman, and Senda Ajroud-Driss
- Subjects
0301 basic medicine ,Nonsynonymous substitution ,medicine.medical_specialty ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Missense mutation ,Exome ,Allele frequency ,Genetics (clinical) ,business.industry ,Haplotype ,medicine.disease ,3. Good health ,Minor allele frequency ,030104 developmental biology ,Peripheral neuropathy ,Neurology (clinical) ,business ,Polyneuropathy ,030217 neurology & neurosurgery - Abstract
Objective:To examine the incidence of nonsynonymous missense variants in SCN9A (NaV1.7), SCN10A (NaV1.8), and SCN11A (NaV1.9) in patients with painful and nonpainful peripheral neuropathy.Methods:Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful).Results:We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations.Conclusions:These results suggest that identification of a genetically defined subpopulation for testing of NaV1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease “mutations,” are more important for the development of painful neuropathy than previously discussed.
- Published
- 2017
18. QDIRT: Quantitative direct and indirect test of sudomotor function
- Author
-
Christopher H. Gibbons, Ben Min-Woo Illigens, Justin Centi, and Roy Freeman
- Subjects
Adult ,Male ,Silicones ,Sweating ,Article ,SWEAT ,Sympathetic Fibers, Postganglionic ,Forearm ,Skin Physiological Phenomena ,Reflex ,medicine ,Humans ,integumentary system ,Both forearms ,Iontophoresis ,Clinical Laboratory Techniques ,business.industry ,Anatomy ,Axons ,Sudomotor ,medicine.anatomical_structure ,Data Interpretation, Statistical ,Indirect test ,Female ,Axon reflex ,Neurology (clinical) ,business ,Biomedical engineering - Abstract
To develop a novel assessment of sudomotor function.Postganglionic sudomotor function is currently evaluated using the quantitative sudomotor axon reflex test (QSART) or silicone impressions. We hypothesize that high-resolution digital photography has advanced sufficiently to allow quantitative direct and indirect reflex testing of sudomotor function (QDIRT) with spatial and temporal resolution comparable to these techniques.Sweating in 10 humans was stimulated on both forearms by iontophoresis of 10% acetylcholine. Silicone impressions were made and topical indicator dyes were digitally photographed every 15 seconds for 7 minutes after iontophoresis. Sweat droplets were quantified by size, location, and percent surface area. Each test was repeated eight times in each subject on alternating arms over 2 months. Another 10 subjects had silicone impressions, QDIRT, and QSART performed on the dorsum of the right foot.The percent area of sweat photographically imaged correlated with silicone impressions at 5 minutes on the forearm (r = 0.92, p0.01) and dorsal foot (r = 0.85, p0.01). The number of sweat droplets assessed with QDIRT correlated with the silicone impression, although the droplet number was lower (162 +/- 28 vs 341 +/- 56, p0.01, r = 0.83, p0.01). The sweat response and sweat onset latency assessed by QDIRT correlated with QSART measured at the dorsum of the foot (r = 0.63, p0.05; r = 0.52, p0.05).The quantitative direct and indirect reflex test of sudomotor function (QDIRT) measured both the direct and the indirect sudomotor response with spatial resolution similar to that of silicone impressions, and with temporal resolution similar to that of the quantitative sudomotor axon reflex test (QSART). QDIRT provides a novel tool for the evaluation of postganglionic sudomotor function.
- Published
- 2008
19. DISORDERS OF ORTHOSTATIC TOLERANCE-ORTHOSTATIC HYPOTENSION, POSTURAL TACHYCARDIA SYNDROME, AND SYNCOPE
- Author
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Roy Freeman and Horacio Kaufmann
- Subjects
Orthostatic vital signs ,medicine.medical_specialty ,Postural tachycardia ,biology ,business.industry ,Internal medicine ,Syncope (genus) ,medicine ,Cardiology ,Neurology (clinical) ,biology.organism_classification ,business ,Genetics (clinical) - Published
- 2007
20. PERIPHERAL AUTONOMIC NEUROPATHIES
- Author
-
Steven Vernino and Roy Freeman
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Medicine ,Neurology (clinical) ,business ,Genetics (clinical) ,Peripheral - Published
- 2007
21. Delayed orthostatic hypotension: A frequent cause of orthostatic intolerance
- Author
-
Christopher H. Gibbons and Roy Freeman
- Subjects
Adult ,Male ,Sympathetic Nervous System ,Time Factors ,Valsalva Maneuver ,Posture ,Population ,Diastole ,Adrenergic ,Orthostatic intolerance ,Blood Pressure ,Hypotension, Orthostatic ,Orthostatic vital signs ,Prevalence ,Humans ,Medicine ,Reflex syncope ,education ,Aged ,Analysis of Variance ,education.field_of_study ,business.industry ,Blood Pressure Determination ,Head up tilt ,Middle Aged ,medicine.disease ,Anesthesia ,Linear Models ,Female ,Neurology (clinical) ,business - Abstract
To investigate the prevalence, symptoms, and neurophysiologic features of delayed orthostatic hypotension (OH).Blood pressures (BP) were measured at 1-minute intervals on 230 patients during 60 degrees head-up tilt for 45 minutes and standing for 5 minutes. OH was defined as a sustained fall in BP (or=20 mm Hg systolic oror=10 mm Hg diastolic) and delayed OH as a sustained BP fall occurring beyond 3 minutes of standing or upright tilt table testing. Beat-to-beat BP, tests of cardiovagal function, and sympathetic-adrenergic function were performed.Of patients with OH, only 46% had OH within 3 minutes of head up tilt; 15% had OH between 3 and 10 minutes; and 39% had OH only after 10 minutes of tilt table testing. The magnitude and the temporal distribution of the BP fall did not differ between those with and without symptoms of orthostatic intolerance. Patients with OH beyond 10 minutes tended to be younger (p0.05), have smaller BP falls during phase II of the Valsalva maneuver (p0.01), and have greater phase IV overshoot (p0.01).Delayed orthostatic hypotension occurred in 54% of our tested population and was associated with milder abnormalities of sympathetic adrenergic function, suggesting this disorder may be a mild or early form of sympathetic adrenergic failure.
- Published
- 2006
22. Diagnosis and Treatment of Chronic Immune-mediated Neuropathies
- Author
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Norman Latov, John D. England, Morris A. Fisher, Slobodan Apostolski, Marinos C. Dalakas, P. James B. Dyck, Zarife Sahenk, Peter D. Donofrio, William J. Triggs, Walter G. Bradley, David N. Herrmann, Alan R. Berger, Neil A. Busis, Chiara Briani, Roy Freeman, Vera Bril, Jean Michel Vallat, Didier Cros, Thomas H. Brannagan, Howard W. Sander, Daniel L. Menkes, and Kenneth C. Gorson
- Subjects
business.industry ,Chronic inflammatory demyelinating polyneuropathy ,General Medicine ,medicine.disease ,Therapeutic trial ,Vasculitic neuropathy ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Peripheral neuropathy ,Neurology ,030225 pediatrics ,Immunology ,Medicine ,Neurology (clinical) ,business ,Inflammatory neuropathy ,030217 neurology & neurosurgery - Abstract
The chronic autoimmune neuropathies are a diverse group of disorders, whose diagnosis and classification is based on the clinical presentations and results of ancillary tests. In chronic inflammatory demyelinating polyneuropathy, controlled therapeutic trials demonstrated efficacy for intravenous gamma-globulins, corticosteroids, and plasmaphereis. In multifocal motor neuropathy, intravenous gamma-globulins have been shown to be effective. In the other immune-mediated neuropathies, there are no reported controlled therapeutic trials, but efficacy has been reported for some treatments in non-controlled trials on case studies. Choice of therapy in individual cases is based on reported efficacy, as well as severity, progression, coexisting illness, predisposition to developing complications, and potential drug interactions.
- Published
- 2006
23. Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension
- Author
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Melvin D. Yahr, David S. Goldstein, Daniela Saadia, Horacio Kaufmann, Andrei Voustianiouk, Courtney Holmes, Rachel Nardin, and Roy Freeman
- Subjects
Male ,Synaptic cleft ,Supine hypertension ,Posture ,Administration, Oral ,Blood Pressure ,Antiparkinson Agents ,Norepinephrine (medication) ,Hypotension, Orthostatic ,Norepinephrine ,chemistry.chemical_compound ,Orthostatic vital signs ,Double-Blind Method ,Physiology (medical) ,medicine ,Humans ,Single-Blind Method ,Pure autonomic failure ,Aged ,Cross-Over Studies ,business.industry ,Hemodynamics ,Carbidopa ,Neurodegenerative Diseases ,Middle Aged ,medicine.disease ,Treatment Outcome ,Blood pressure ,Droxidopa ,chemistry ,Aromatic-L-Amino-Acid Decarboxylases ,Anesthesia ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Vasoconstriction ,medicine.drug - Abstract
Background— In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture. Methods and Results— We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L–aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101±4 to 141±5 mm Hg) and standing (from 60±4 to 100±6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients Conclusions— Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system.
- Published
- 2003
24. Quantitative sensory testing cannot differentiate simulated sensory loss from sensory neuropathy
- Author
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Karen P. Chase, Roy Freeman, and Marcelo Risk
- Subjects
Adult ,Male ,medicine.medical_specialty ,Intraclass correlation ,media_common.quotation_subject ,Sensory system ,Neurological disorder ,Audiology ,Vibration ,Diagnosis, Differential ,Vibration perception ,Predictive Value of Tests ,Reference Values ,Physical Stimulation ,Perception ,Sensory threshold ,medicine ,Humans ,Thermosensing ,media_common ,Neurologic Examination ,Peripheral Nervous System Diseases ,Reproducibility of Results ,Sensory loss ,medicine.disease ,Surgery ,Cold Temperature ,Factitious Disorders ,Peripheral neuropathy ,Sensation Disorders ,Female ,Neurology (clinical) ,Psychology - Abstract
Objective: To differentiate the quantitative sensory testing (QST) results of subjects simulating small and large fiber sensory loss from those of normal subjects and subjects with sensory peripheral neuropathy.Background: QST is used to measure sensory thresholds in clinical, epidemiologic, and research studies. It is not known whether there are objective test results that characterize the subject seeking to deceive the examiner.Methods: The Computer Aided Sensory Examination IV 4, 2, and 1 stepping algorithm was used to determine vibration and cold perception in nine naïve subjects. Subjects were asked to simulate sensory loss (on two occasions) and to respond normally on one occasion. Test results were compared to those of subjects with diabetic sensory neuropathy. Each QST trial was performed three times.Results: Reproducibility, measured by the intraclass correlation coefficient, was similar in all groups for the vibration perception test (simulation 1: 0.68 [95% CI 0.31, 0.91], simulation 2: 0.82 [95% CI 0.54, 0.95], normal response: 0.77 [95% CI 0.47, 0.94], and subjects with peripheral neuropathy: 0.76 [95% CI 0.18, 0.95]) and the cold perception test (simulation 1: 0.53 [95% CI 0.12, 0.85], simulation 2: 0.82 [95% CI 0.55, 0.95], normal subjects: 0.67 [95% CI 0.30, 0.90] and subjects with peripheral neuropathy: 0.88 [95% CI 0.57, 0.97]), all just noticeable difference units. There were no differences between performance characteristics in the two simulation trials. Responses to null stimuli did not differentiate between groups.Conclusion: Test performance characteristics do not permit discrimination among subjects simulating sensory loss, subjects with normal responses, and subjects with peripheral neuropathy.
- Published
- 2003
25. The treatment of postprandial hypotension in autonomic failure with 3,4-DL-threo-dihydroxyphenylserine
- Author
-
Lewis A. Lipsitz, James B. Young, Lewis Landsberg, and Roy Freeman
- Subjects
Adult ,Male ,Sympathetic nervous system ,Supine hypertension ,Blood Pressure ,Norepinephrine (medication) ,Heart rate ,medicine ,Humans ,Pure autonomic failure ,Aged ,business.industry ,Middle Aged ,medicine.disease ,Postprandial ,Blood pressure ,medicine.anatomical_structure ,Autonomic Nervous System Diseases ,Droxidopa ,Anesthesia ,Vascular resistance ,Female ,Neurology (clinical) ,Hypotension ,business ,medicine.drug - Abstract
Postprandial hypotension occurs commonly in patients with autonomic failure and may be due to attenuation of the normal sympathetic nervous system activation in response to meal ingestion. In a randomized, double-blind, placebo-controlled study, we investigated the therapeutic effect of the norepinephrine precursor 3,4-DL-threo-dihydroxyphenylserine (DL-DOPS) on this condition. We measured blood pressure, heart rate, forearm vascular resistance, and plasma DL-DOPS and norepinephrine in 11 patients with autonomic failure. DL-DOPS attenuated the postprandial fall in blood pressure. This was associated with an increase in plasma norepinephrine and forearm vascular resistance. DL-DOPS therapy did not change the postprandial increase in heart rate. There was a trend toward increased supine hypertension associated with DL-DOPS treatment. This study shows that DL-DOPS is a promising treatment for postprandial hypotension and provides support for the hypothesis that postprandial hypotension is, at least in part, due to decreased activation of the sympathetic nervous system.
- Published
- 1996
26. Hemodynamic and autonomic nervous system responses to mixed meal ingestion in healthy young and old subjects and dysautonomic patients with postprandial hypotension
- Author
-
Roy Freeman, Ary L. Goldberger, Jeanne Y. Wei, Lewis A. Lipsitz, J.A.T.C. Parker, and Stanthia Ryan
- Subjects
Adult ,Male ,Aging ,medicine.medical_specialty ,Drinking ,Cardiac index ,Hemodynamics ,Blood volume ,Autonomic Nervous System ,Eating ,Electrocardiography ,Heart Rate ,Reference Values ,Physiology (medical) ,Internal medicine ,Heart rate ,medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,Dysautonomia ,Middle Aged ,Endocrinology ,Postprandial ,medicine.anatomical_structure ,Blood pressure ,Autonomic Nervous System Diseases ,Cardiology ,Vascular resistance ,Female ,Hypotension ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
BACKGROUND Although postprandial hypotension is a common cause of falls and syncope in elderly persons and in patients with autonomic insufficiency, the pathophysiology of this disorder remains unknown. METHODS AND RESULTS We examined the hemodynamic, splanchnic blood pool, plasma norepinephrine (NE), and heart rate (HR) power spectra responses to a standardized 400-kcal mixed meal in 11 healthy young (age, 26 +/- 5 years) and nine healthy elderly (age, 80 +/- 5 years) subjects and 10 dysautonomic patients with symptomatic postprandial hypotension (age, 65 +/- 16 years). Cardiac and splanchnic blood pools were determined noninvasively by radionuclide scans, and forearm vascular resistance was determined using venous occlusion plethysmography. In healthy young and old subjects, splanchnic blood volume increased, but supine blood pressure remained unchanged after the meal. In both groups, HR increased and systemic vascular resistance remained stable. Forearm vascular resistance and cardiac index increased after the meal in elderly subjects, whereas these responses were highly variable and of smaller magnitude in the young. Young subjects demonstrated postprandial increases in low-frequency HR spectral power, representing cardiac sympatho-excitation, but plasma NE remained unchanged. In elderly subjects, plasma NE increased after the meal but without changes in the HR power spectrum. Patients with dysautonomia had a large postprandial decline in blood pressure associated with no change in forearm vascular resistance, a fall in systemic vascular resistance, and reduction in left ventricular end diastolic volume index. HR increased in these patients but without changes in plasma NE or the HR power spectrum. CONCLUSIONS 1) In healthy elderly subjects, the maintenance of blood pressure homeostasis after food ingestion is associated with an increase in HR, forearm vascular resistance, cardiac index, and plasma NE. In both young and old, systemic vascular resistance is maintained. 2) Dysautonomic patients with postprandial hypotension fail to maintain systemic vascular resistance after a meal. This impairment in vascular response to meal ingestion may underlie the development of postprandial hypotension. 3) The measurement of mean HR or plasma NE does not adequately characterize autonomic cardiac control. Power spectral analysis suggests an impairment in the postprandial autonomic modulation of HR in healthy elderly and dysautonomic subjects, possibly predisposing to hypotension when vascular compensation is inadequate.
- Published
- 1993
27. The Treatment of Autonomic Dysfunction
- Author
-
Edison Miyawaki and Roy Freeman
- Subjects
medicine.medical_specialty ,Physiology ,Urinary incontinence ,Disease ,Hypotension, Orthostatic ,Orthostatic vital signs ,Physiology (medical) ,medicine ,Humans ,Fecal incontinence ,Gastroparesis ,Intensive care medicine ,business.industry ,Multiple sclerosis ,Urinary Bladder Diseases ,medicine.disease ,Intestinal Diseases ,Diarrhea ,Autonomic nervous system ,Autonomic Nervous System Diseases ,Neurology ,Neurology (clinical) ,medicine.symptom ,Gastrointestinal Motility ,business ,Muscle Contraction - Abstract
Autonomic dysfunction is responsible for much of the morbidity associated with frequently encountered neurological disorders, such as Parkinson's disease, multiple sclerosis, cerebrovascular disease, and peripheral neuropathies, as well as with the rarer primary autonomic nervous system degenerations. We review the treatment of those aspects of autonomic dysfunction that often present to the neurologist, including orthostatic hypotension, urinary incontinence and retention, and bowel dysmotility syndromes. Pathophysiology is discussed in each instance as it relates to a rational approach to therapy. For management of orthostatic hypotension, we review the use of mineralocorticoids, direct and indirect sympathomimetic agents, other pressors, dopamine-blocking agents, vasopressin receptor agonists, and others. Treatment of urinary incontinence and retention is addressed, with attention to drugs that modulate bladder contractility and bladder outlet resistance. Therapies for bowel dysmotility syndromes (such as gastroparesis, diarrhea, and fecal incontinence) are described, including bulk agents, laxatives, prokinetic agents, and antidiarrheal drugs.
- Published
- 1993
28. Corrigendum to 'Value of quantitative sensory testing in neurological and pain disorders: NEUPSIG consensus' [PAIN® 2013;154(9):1807–1819]
- Author
-
Valeria Tugnoli, Roman Rolke, Mark Drangsholt, Mark A. Ware, Roy Freeman, Dan Ziegler, Elena K. Krumova, Robert R. Edwards, Mark S. Wallace, Didier Bouhassira, Thomas R. Tölle, Miroslav Backonja, Christoph Maier, Maija Haanpää, David Yarnitsky, Gérard Mick, Jordi Serra, Nadine Attal, Richard H. Gracely, Ralf Baron, Samar Hatem, Per Hansson, Troels S. Jensen, Rolf-Detlef Treede, David Walk, Peter J. Dyck, and Andrew S.C. Rice
- Subjects
medicine.medical_specialty ,business.industry ,Quantitative sensory testing ,03 medical and health sciences ,0302 clinical medicine ,Anesthesiology and Pain Medicine ,Physical medicine and rehabilitation ,Neurology ,030202 anesthesiology ,Physical therapy ,Medicine ,Neurology (clinical) ,business ,Value (mathematics) ,030217 neurology & neurosurgery - Published
- 2014
29. Pure autonomic failure
- Author
-
Roy Freeman
- Subjects
medicine.medical_specialty ,Neurology ,business.industry ,Dementia with Lewy bodies ,Disease ,medicine.disease ,Preferred Name ,Sudomotor ,Orthostatic vital signs ,medicine.anatomical_structure ,Internal medicine ,Peripheral nervous system ,medicine ,Cardiology ,Neurology (clinical) ,Pure autonomic failure ,business - Abstract
In this issue of Neurology , Kaufmann et al.1 describe two patients who presented with isolated autonomic failure; years later, one developed features of Parkinson disease and the other features of dementia with Lewy bodies. Pure autonomic failure is now the preferred name for the disorder characterized by isolated peripheral autonomic failure.2 This disorder was previously called progressive autonomic failure, idiopathic orthostatic hypotension, and the Bradbury-Eggleston syndrome. Pure autonomic failure is characterized by gradually progressive autonomic dysfunction with prominent orthostatic hypotension in the absence of cognitive, motor, or sensory impairment.3 Bradbury and Eggleston comprehensively described three patients with an “extensive and peculiar disturbance in the functional activity of the vegetative nervous system.”4 These patients all had incapacitating postural hypotension with cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor dysfunction with “signs of slight and indefinite changes in the nervous system.” Their insightful description remains the paradigm for the disorder, characterized by isolated autonomic dysfunction without signs of central or peripheral nervous system disease, now known as pure autonomic failure. But cases such as …
- Published
- 2004
30. Treatment of Neurogenic Orthostatic Hypotension with Droxidopa: Results from a Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Induction Design Study (PL02.001)
- Author
-
Arthur Hewitt, Horacio Kaufmann, Simon Pedder, Roy Freeman, Phillip A. Low, Christopher J. Mathias, and Italo Biaggioni
- Subjects
medicine.medical_specialty ,business.industry ,Center (group theory) ,Placebo ,Surgery ,Double blind ,Orthostatic vital signs ,chemistry.chemical_compound ,chemistry ,Anesthesia ,Design study ,medicine ,Neurology (clinical) ,Droxidopa ,business - Published
- 2012
31. The Quantitative Pilomotor Axon-Reflex Test (QPART) - A Technique To Assess Autonomic Nerve Fiber Function (P05.197)
- Author
-
Christopher H. Gibbons, Timo Siepmann, Roy Freeman, and Ben Min-Woo Illigens
- Subjects
Vasomotor ,Iontophoresis ,Lidocaine ,business.industry ,Piloerection ,Sudomotor ,Anesthesia ,medicine ,Axon reflex ,Neurology (clinical) ,medicine.symptom ,business ,Phenylephrine ,Vasoconstriction ,medicine.drug - Abstract
Objective: To characterize phenylephrine evoked piloerection physiology. Background Sudomotor and vasomotor axon-reflex responses may be used to assess small fiber function. We have previously reported that piloerection is evoked by phenylephrine iontophoresis beneath the application (direct) site and in the surrounding (indirect) region most likely via an axon-reflex. The mechanism of the indirect response is not fully elucidated. Design/Methods: In this study, twenty subjects participated in 5 studies. Piloerection was stimulated by iontophoresis of 1% phenylephrine and quantified by silicon impressions. In studies 1 and 2, piloerection was measured after application of lidocaine gel and subcutaneous injection of 1% lidocaine-hydrochloride to block the axon reflex. In study 3, to isolate the contribution of ionophoretic current, piloerection was measured after saline iontophoresis. In study 4, the time-course of the piloerection was measured by digital photographing. In study 5, to examine the role played by blood flow, subjects were tested with and without iontophoretic nitroprusside pretreatment. Results: In lidocaine pretreated regions, there were reduced impressions in the indirect area (66.6±19.2 control vs. 7.2±4.3 lidocaine; P Conclusions: These data demonstrate that: The indirect pilomotor response is attenuated by lidocaine consistent with an axon-reflex response; 2)Iontophoresis alone does not induce piloerection; 3)Axon-reflex mediated piloerection is not secondary to vasoconstriction; and 4)Direct and indirect pilomotor responses to phenylephrine have different latencies suggesting different physiological mechanisms. These data are consistent with an axon-reflex mechanism for the pilomotor response and support QPART as a measure of small fiber function. Supported by: NIH; Langer Family Foundation; German Research Foundation. Disclosure: Dr. Siepmann has nothing to disclose. Dr. Illigens has nothing to disclose. Dr. Gibbons has nothing to disclose. Dr. Freeman has received personal compensation for activities with Pfizer Inc, Eli Lilly & Company, GlaxoSmithKline, Inc., Solvay S.A., and Chelsea Pharmaceuticals. Dr. Freeman has received personal compensation in an editorial capacity for Clinical Journal of Pain.
- Published
- 2012
32. Upregulation of Inflammatory Cytokines in Painful Diabetic Neuropathy (P05.154)
- Author
-
Ben Min-Woo Illigens, Christopher H. Gibbons, and Roy Freeman
- Subjects
medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,medicine.disease ,Gastroenterology ,Proinflammatory cytokine ,Pathogenesis ,Cytokine ,Downregulation and upregulation ,Painful diabetic neuropathy ,Interstitial fluid ,Internal medicine ,Diabetes mellitus ,Neuropathic pain ,medicine ,Neurology (clinical) ,business - Abstract
Objective: To quantify cutaneous cytokines in patients with painful diabetic neuropathy. We hypothesized that cutaneous interstitial fluid, obtained through vacuum blisters, would allow measurement of local cytokines within specific areas of interest. We also hypothesized that pro-inflammatory cytokines would be upregulated in patients with painful diabetic neuropathy compared to healthy control subjects. Background Inflammatory cytokines have been implicated in the pathogenesis of painful neuropathy. However, studies typically procure cytokines from circulating plasma, not from local tissues where neuropathic pain is generated. Design/Methods: Five patients with painful diabetic neuropathy (but only mild neuropathy impairment scores in the lower limb) and 5 healthy volunteers were recruited. Blisters (8mm diameter) were induced on the dorsum of the foot via 20 mmHg vacuum pressure, and blister fluid was collected after 90 minutes. Cytokine levels were measured using an Elisa bead-based multiplex assay. Results: Cytokine levels of IL-4, IL-13, IL-10, IL-8 and TNF-alpha were significantly higher in patients with painful diabetic neuropathy (p Conclusions: Analysis of blister fluid showed an increase of IL-8 and TNF-alpha in painful diabetic neuropathy compared to control subjects suggesting an involvement of macrophages and neutrophils, increase in IL-10 was evidence for a pro-inflammatory response and IL-4 and IL-13 recruitment of type 2 helper T cells. Results suggest an environment shifted towards pro-inflammatory cytokines in patients with painful diabetic neuropathy. Further study in larger numbers of patients with diabetes with and without painful neuropathy are necessary to further validate these findings and confirm the utility of this technique. Supported by: NIH NINDS K23NS050209 (CHG). Disclosure: Dr. Illigens has nothing to disclose. Dr. Freeman has received personal compensation for activities with Pfizer Inc, Eli Lilly & Company, GlaxoSmithKline, Inc., Solvay S.A., and Chelsea Pharmaceuticals. Dr. Freeman has received personal compensation in an editorial capacity for Clinical Journal of Pain. Dr. Gibbons has nothing to disclose.
- Published
- 2012
33. Effect of a Once-Daily Gastroretentive Formulation of Gabapentin on the Neuropathic Pain Scale Score in Patients with Postherpetic Neuralgia (P04.160)
- Author
-
Misha-Miroslav Backonja, Mark S. Wallace, Roy Freeman, and Michael O. Sweeney
- Subjects
Gabapentin ,Postherpetic neuralgia ,business.industry ,medicine.disease ,Placebo ,Tolerability ,Anesthesia ,Neuropathic pain ,medicine ,Neurology (clinical) ,Dosing ,medicine.symptom ,Adverse effect ,business ,Somnolence ,medicine.drug - Abstract
Objective: To investigate the effect of a once-daily formulation of gabapentin (G-QD) on pain characteristics using the Neuropathic Pain Scale (NPS). Background The NPS characterizes pain in 10 dimensions and has been validated in patients with postherpetic neuralgia (PHN). The G-QD formulation of gabapentin uses a patented, oral, gastroretentive delivery technology to overcome limitations of the immediate-release formulation of gabapentin, which include short elimination half-life, limited absorption in the small intestine, and poor tolerability, which in turn, may result in suboptimal dosing. Design/Methods: The effect of G-QD on pain characteristics was investigated using the NPS scale in two 11-week, double-blind, randomized, placebo-controlled studies. After 1 week of baseline observation, 669 PHN patients (mean age, 66.1 years; 42.6%, male; baseline NPS 10-item average, 5.6) were randomized and titrated over 2 weeks to G-QD 1800 mg or matched placebo (taken with the evening meal), followed by 8 weeks of stable dosing of once daily G-QD (1800 mg). The NPS was administered at Baseline and at Week 10. An Institutional Review Board approved both study protocols. Results: Last observation carried forward (LOCF) change in NPS 10-item average score from baseline to Week 10 was -2.5 for G-QD vs. -1.9 for placebo (p=0.001). Similar changes were seen in non-allodynia items (-2.4 vs. -1.8; p=0.002) and in the four peripheral pain items (-2.6 vs. -1.9; p=0.001). G-QD was generally well tolerated; the most common adverse events (AEs) with G-QD were dizziness (10.9% vs. 2.2% for placebo) and somnolence (4.5% vs. 2.7% for placebo). Thirty-five (9.7%) patients in the G-QD group and 25 (6.9%) patients in the placebo group withdrew from the study because of AEs. Conclusions: In patients with PHN, G-QD 1800 mg was well tolerated and improved all dimensions of pain as measured by the NPS. Disclosure: Dr. Backonja has received personal compensation for activities with Pfizer, NeurogesX, Lilly, J&J, Merck, UCB Pharma, GlaxoSmithKline as a consultant. Dr. Backonja has received research support from J&J and NeurogesX. Dr. Wallace has received personal compensation for activities with Depomed as a participant on an advisory board. Dr. Wallace has received research support from Elan Pharmaceuticals and Medtronic. Dr. Freeman has received personal compensation for activities with Pfizer Inc, Eli Lilly & Company, GlaxoSmithKline, Inc., Solvay S.A., and Chelsea Pharmaceuticals. Dr. Freeman has received personal compensation in an editorial capacity for Clinical Journal of Pain. Dr. Sweeney has received personal compensation for activities with Depomed, Inc., as an employee.
- Published
- 2012
34. The Pathophysiology of Neuropathic and Non-Neuropathic Postural Tachycardia Syndrome (P05.203)
- Author
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Roy Freeman, Istvan Bonyhay, Adam Benson, and Christopher H. Gibbons
- Subjects
medicine.medical_specialty ,business.industry ,Orthostatic intolerance ,medicine.disease ,Pathophysiology ,Postural tachycardia ,Quality of life ,Anesthesia ,Heart rate ,Sensory neuropathy ,medicine ,Physical therapy ,Anxiety ,Neurology (clinical) ,Analysis of variance ,medicine.symptom ,business - Abstract
OBJECTIVE: To define the clinical characteristics, fatigue severity, autonomic function and differentiating features in individuals with neuropathic and non-neuropathic POTS. BACKGROUND: The postural tachycardia syndrome (POTS) is defined as an exaggerated heart rate in the upright position with symptoms of orthostatic intolerance. Some patients with POTS have an underlying small fiber neuropathy. DESIGN/METHODS: Twenty-four subjects with POTS and 10 healthy controls had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were categorized as neuropathic and non-neuropathic POTS, based on abnormal IENFD and/or heat and heat-pain detection thresholds. Differences in autonomic function and symptom questionnaires were analyzed by ANOVA with corrections for multiple analyses. Significance was set at P RESULTS: POTS subjects had greater fatigue, anxiety, physical impairment, orthostatic intolerance and perceived disability than controls (P CONCLUSIONS: Small fiber sensory neuropathy measures may be used to differentiate POTS subtypes. Individuals with non-neuropathic POTS have greater anxiety, orthostatic intolerance and perceived disability despite better overall autonomic function than those with neuropathic POTS. These findings suggest that different pathophysiological mechanisms that underlie the postural tachycardia in neuropathic and non-neuropathic POTS. These findings may have implications for therapeutic interventions to treat this disorder. Supported by: NIH NINDS K23NS050209 (CHG) and NIH RO1 HL059459 (RF). Disclosure: Dr. Gibbons has nothing to disclose. Dr. Bonyhay has nothing to disclose. Dr. Benson has nothing to disclose. Dr. Freeman has received personal compensation for activities with Pfizer, Abbott, Depomed, Johnson & Johnson, Sanofi, and Chelsea Pharmaceuticals. Dr. Freeman has received personal compensation in an editorical capacity for Autonomic Neuroscience - Basic and Clinical and Clinical Journal of Pain.
- Published
- 2012
35. Experimental Hypoglycemia Is a Human Model of Stress-Induced Hyperalgesia (S38.002)
- Author
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Roy Freeman, Gail K. Adler, Adam Benson, Christopher H. Gibbons, and Istvan Bonyhay
- Subjects
medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Hyperalgesia ,Stress induced ,medicine ,Neurology (clinical) ,medicine.symptom ,Hypoglycemia ,medicine.disease ,business - Published
- 2012
36. November 22 Highlight and Commentary: Is time of the essence? The continuing search for a noninvasive measure of sympathetic adrenergic function
- Author
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Christopher H. Gibbons and Roy Freeman
- Subjects
Sympathetic nervous system ,medicine.medical_treatment ,Adrenergic ,medicine.disease ,medicine.anatomical_structure ,Blood pressure ,Sympathetic Fibers ,Anesthesia ,medicine ,Valsalva maneuver ,In patient ,Neurology (clinical) ,Pure autonomic failure ,Psychology ,Clinical evaluation - Abstract
Vogel et al. studied blood pressure (BP) changes in response to Valsalva maneuver to assess the integrity of baroreflexes. BP recovery time following termination of Valsalva maneuver provides an index that quantitates the full range of severity of systemic adrenergic failure in patients with autonomic failure. see page 1533 Commentary by Roy Freeman, MD, and Christopher Gibbons, MD Vogel et al. propose that the BP recovery time following phase III of the Valsalva maneuver is a useful index of sympathetic function, particularly in patients with severe sympathetic adrenergic dysfunction. Clinical evaluation of the sympathetic nervous system usually entails the use of tests that indirectly measure …
- Published
- 2005
37. The treatment of neurogenic orthostatic hypotension with 3,4-DL-threo-dihydroxyphenylserine: A randomized, placebo-controlled, crossover trial
- Author
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James B. Young, Roy Freeman, and Lewis Landsberg
- Subjects
Adult ,Male ,Supine position ,Blood Pressure ,Antiparkinson Agents ,Norepinephrine (medication) ,Hypotension, Orthostatic ,Norepinephrine ,chemistry.chemical_compound ,Orthostatic vital signs ,Double-Blind Method ,Tilt-Table Test ,medicine ,Humans ,Pure autonomic failure ,Aged ,Cross-Over Studies ,business.industry ,Middle Aged ,Multiple System Atrophy ,medicine.disease ,Crossover study ,Blood pressure ,medicine.anatomical_structure ,Autonomic Nervous System Diseases ,Droxidopa ,chemistry ,Anesthesia ,Vascular resistance ,Female ,Vascular Resistance ,Neurology (clinical) ,business ,medicine.drug - Abstract
To study the therapeutic effect and mechanism of action of 3,4-DL-threodihydroxyphenylserine (DL-DOPS) in neurogenic orthostatic hypotension.The blood pressure (BP) response to an orthostatic challenge on DL-DOPS was compared with that of placebo in a randomized, double-blind, placebo-controlled, crossover trial in 10 patients. The mechanism of action of DOPS was studied by measuring forearm vascular resistance and changes in supine and upright plasma DL-DOPS and norepinephrine levels. The effect of DL-DOPS on the quality of life was determined by questionnaire.DL-DOPS increased the supine (p0.001) and upright (p0.05) systolic blood pressure (SBP) and diastolic blood pressure (DBP) (both p0.01). The peak SBP on DL-DOPS in the supine position occurred 300 minutes after ingestion of the medication. The increase in BP was accompanied by an increase in plasma levels of norepinephrine and DL-DOPS in both the supine and upright positions after DL-DOPS ingestion (p0.0001). There was a trend toward improvement in symptoms of orthostatic intolerance.DL-DOPS improved features of neurogenic orthostatic hypotension in patients with central and peripheral autonomic nervous system disease. There was an increase in plasma norepinephrine. No major side effects occurred.
- Published
- 1999
38. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy
- Author
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Christopher J. Mathias, Irwin J. Schatz, D. Robertson, R. J. Polinsky, R. Bannister, Horacio Kaufmann, Niall Quinn, William C. Koller, D. H.P. Streeten, Joseph Jankovic, Roy Freeman, Phillip A. Low, and Christopher G. Goetz
- Subjects
medicine.medical_specialty ,business.industry ,Statement (logic) ,medicine.disease ,Orthostatic vital signs ,Atrophy ,Internal medicine ,medicine ,Cardiology ,Orthostatic blood pressure ,Neurology (clinical) ,Orthostatic hypertension ,medicine.symptom ,Pure autonomic failure ,business - Published
- 1996
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