Symptomatic Treatment Of Multiple Sclerosis Research Articles

Radiosynthesis automation, non-human primate biodistribution and dosimetry of K+ channel tracer [11C]3MeO4AP

Background4-Aminopyridine (4AP) is a medication for the symptomatic treatment of multiple sclerosis. Several 4AP-based PET tracers have been developed for imaging demyelination. In preclinical studies, [11C]3MeO4AP has shown promise due to its high brain permeability, high metabolic stability, high plasma availability, and high in vivo binding affinity. To prepare for the translation to human studies, we developed a cGMP-compatible automated radiosynthesis protocol and evaluated the whole-body biodistribution and radiation dosimetry of [11C]3MeO4AP in non-human primates (NHPs).MethodsAutomated radiosynthesis was carried out using a GE TRACERlab FX-C Pro synthesis module. One male and one female adult rhesus macaques were used in the study. A high-resolution CT from cranial vertex to knee was acquired. PET data were collected using a dynamic acquisition protocol with four bed positions and 13 passes over a total scan time of ~ 150 min. Based on the CT and PET images, volumes of interest (VOIs) were manually drawn for selected organs. Non-decay corrected time-activity curves (TACs) were extracted for each VOI. Radiation dosimetry and effective dose were calculated from the integrated TACs using OLINDA software.ResultsFully automated radiosynthesis of [11C]3MeO4AP was achieved with 7.3 ± 1.2% (n = 4) of non-decay corrected radiochemical yield within 38 min of synthesis and purification time. [11C]3MeO4AP distributed quickly throughout the body and into the brain. The organs with highest dose were the kidneys. The average effective dose of [11C]3MeO4AP was 4.0 ± 0.6 μSv/MBq. No significant changes in vital signs were observed during the scan.ConclusionA cGMP-compatible automated radiosynthesis of [11C]3MeO4AP was developed. The whole-body biodistribution and radiation dosimetry of [11C]3MeO4AP was successfully evaluated in NHPs. [11C]3MeO4AP shows lower average effective dose than [18F]3F4AP and similar average effective dose as other carbon-11 tracers.

Effects of intrathecal Baclofen in reducing tremors in patients with multiple sclerosis

Symptomatic treatment of Multiple Sclerosis (MS) is crucial, since it helps to lessen the limitations that affect patients' daily lives. Tremors are a significant and frequent symptom in MS patients. However, there is still a lack of evidence supporting a specific therapeutic approach for MS patients' tremors. A 41-year-old man with a history of MS is presented in this study. He exhibited stiffness and tremors at the follow-up clinic, which affected his daily activities. For his spasticity, he received intrathecal baclofen (ITB). The patient's symptoms responded well to this treatment, as both stiffness and tremors decreased. In an MS patient, ITB therapy thus unexpectedly reduced and improved tremor symptoms.

Symptomatic treatment of multiple sclerosis

Symptomatic treatment of multiple sclerosis

Ontology for Symptomatic Treatment of Multiple Sclerosis.

Symptomatic treatment is an essential component in the overall treatment of multiple sclerosis (MS). However, knowledge in this regard is confusing and scattered. Physicians also have challenges in choosing symptomatic treatment based on the patient's condition. To share, update, and reuse this knowledge, the aim of this study was to provide an ontology for MS symptomatic treatment. The Symptomatic Treatment of Multiple Sclerosis Ontology (STMSO) was developed according to Ontology Development 101 and a guideline for developing good ontologies in the biomedical domain. We obtained knowledge and rules through a systematic review and entered this knowledge in the form of classes and subclasses in the ontology. We then mapped the ontology using the Basic Formal Ontology (BFO) and Ontology for General Medical Sciences (OGMS) as reference ontologies. The ontology was built using Protégé Editor in the Web Ontology Language format. Finally, an evaluation was done by experts using criterion-based approaches in terms of accuracy, clarity, consistency, and completeness. The knowledge extraction phase identified 110 articles related to the ontology in the form of 626 classes, 40 object properties, and 139 rules. Five general classes included "patient," "symptoms," "pharmacological treatment," "treatment plan," and "measurement index." The evaluation in terms of standards for biomedical ontology showed that STMSO was accurate, clear, consistent, and complete. STMSO is the first comprehensive semantic representation of the symptomatic treatment of MS and provides a major step toward the development of intelligent clinical decision support systems for symptomatic MS treatment.

Exercise Training for Multiple Sclerosis: A Narrative Review of History, Benefits, Safety, Guidelines, and Promotion.

Background: There have been significant advances in the medical treatment and management of multiple sclerosis pathogenesis, relapse and disease progression over the past 30 years. There have been advancements in the symptomatic treatment of multiple sclerosis, including management of secondary multiple sclerosis expressions such as walking, cognitive dysfunction, fatigue and depression. Scientific evidence and expert opinion suggest that exercise may be the single most effective non-pharmacological symptomatic treatment for multiple sclerosis. This article presents the historical context of exercise training within the multidisciplinary management of multiple sclerosis. We guide neurologists and healthcare providers on the recommended prescription of exercise and practical, theoretical methods to overcome barriers to exercise. Method: We undertook a critical search of the historical and current literature regarding exercise and multiple sclerosis from the viewpoint of exercise promotion by neurologists and the multidisciplinary care team. Results: We highlight the ever-strengthening body of research indicating that exercise is safe and effective for improving symptoms of multiple sclerosis. Further, exercise training may be necessary for reducing disease progression. Conclusion: We seek to encourage neurologists and specialists in multidisciplinary healthcare teams to prescribe and promote exercise at diagnosis and across all stages of the disease trajectory using prescriptive guidelines as part of comprehensive MS care. Available tools include clinical education to dispel any historical myths related to exercise in multiple sclerosis, clinical exercise guidelines and behaviour change theory to overcome patients barriers to exercise.

Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice.

NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced mobility and depressive behaviors. Dimethyl fumarate (DMF) is an immunomodulatory and anti-oxidative molecule commonly used for the symptomatic treatment of multiple sclerosis and psoriasis. In this study, we investigated the potential use of DMF against microglial NLRP3 inflammasome activation both in vitro and in vivo. For in vitro studies, LPS- and ATP-stimulated N9 microglial cells were used to induce NLRP3 inflammasome activation. DMF’s effects on inflammasome markers, pyroptotic cell death, ROS formation, and Nrf2/NF-κB pathways were assessed. For in vivo studies, 12–14 weeks-old male BALB/c mice were treated with LPS, DMF + LPS and ML385 + DMF + LPS. Behavioral tests including open field, forced swim test, and tail suspension test were carried out to see changes in lipopolysaccharide-induced sickness behavior. Furthermore, NLRP3 and Caspase-1 expression in isolated microglia were determined by immunostaining. Here we demonstrated that DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia via Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels via Nrf2 activation. Additionally, we showed that DMF pretreatment decreased miR-146a and miR-155 both in vivo and in vitro. Our results proved the effectiveness of DMF on the amelioration of microglial NLRP3 inflammasome activation. We anticipate that this study will provide the foundation consideration for further studies aiming to suppress NLRP3 inflammasome activation associated with in many diseases and a better understanding of its underlying mechanisms.

Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice.

4-Aminopyridine (4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP (10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research (UCAR) at the University of Rochester (UCAR-2009-019) on March 31, 2017.

A Potassium Channel Blocker, 4‐Aminopyridine, Attenuates Peripheral Nerve Injury‐induced Muscle Atrophy, Improves Intrinsic Muscle Force, and Suppresses the Expression of Muscle Atrophy‐related Transcription Factors in Mice

4‐Aminopyridine (4‐AP), a broad‐spectrum potassium channel blocker and FDA‐approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. The neurological benefits of 4‐AP are believed to result from increases in action potential duration, calcium influx, neurotransmitter release and synaptic transmission. Traumatic peripheral nerve injury (TPNI) represents a major health problem that often leads to significant functional impairment and permanent disability from the loss in axonal continuity, neuronal cell death, nerve demyelination, nerve conduction defects, muscle denervation, and muscle atrophy. We have recently repurposed the use of 4‐AP and demonstrated that systemic 4‐AP administration enhances global functional recovery of the affected limb, promotes remyelination of the nerve and improves the nerve conduction velocity in a mouse model of TPNI. While muscle atrophy occurs very rapidly following nerve injury, the effect 4‐AP on muscle atrophy and muscle contractile function is largely unknown. This study was designed to explore the possible beneficial effects of 4‐AP treatment in muscle atrophy, intrinsic muscle function, and muscle regeneration following acute sciatic nerve crush injury. Mice were assigned to moderate sciatic nerve crush injury and no‐injury groups and followed for 3, 7 and 14 days with/without 4‐AP (10 mg/daily, intraperitoneal injection) or saline treatment. Morphological, functional and transcriptional properties of skeletal muscle were assessed. In addition to improving in vivo global motor function as early as post‐operative day 3, 4‐AP treatment significantly attenuated muscle atrophy of the injured limb with increased muscle mass and muscle fiber area. 4‐AP also improved ex vivo intrinsic muscle contractile force 7 days post‐injury. Most importantly, the reduced muscle atrophy with 4‐AP treatment was concurrent with significantly reduced expression of atrophy‐related genes (myogenin, MuRF‐1, FoxO1, FoxO3) and increased expression of Pax7+ satellite cells and proliferating Ki67+ cells. These findings provide new insights into the beneficial effects of 4‐AP in nerve injury‐induced muscle atrophy and dysfunction and open a new window for further investigation.Support or Funding InformationThis work was supported by grants from the NIH (K08 AR060164‐01A) and DOD (W81XWH‐16‐1‐0725) in addition to institutional support from the University of Rochester and Pennsylvania State University Medical Centers.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Transdermal Delivery of 4‐Aminopyridine, a Potassium Channel Blocker, Accelerates Motor Functional Recovery with Improved Nerve Myelination and Conduction Velocity after Sciatic Nerve Crush Injury in Mice

4‐Aminopyridine (4‐AP), a broad‐spectrum potassium channel blocker and FDA‐approved drug for symptomatic treatment of multiple sclerosis, has been shown to improve neuromuscular function in patients with diverse demyelinating disorders. We recently repurposed 4‐AP and demonstrated that systemic 4‐AP administration enhances global functional recovery of the affected limb, promotes remyelination of the nerve and improves the nerve conduction velocity in a mouse model of traumatic peripheral nerve injury. However, despite its beneficial effects, the clinical ability of 4‐AP to restore function is limited because of its narrow therapeutic window, the need for frequent dosing throughout the day, and potential adverse effects. Although oral or injection routes are commonly used, the therapeutic benefits with transdermal delivery of drugs are well documented to provide a sustained circulating blood levels with enhanced patient compliance and importantly without the need for multiple daily oral dosing or injections of a drug with a short half‐life. There is no current data on the transdermal delivery of 4‐AP (plasma half‐life ~3.5 hours and the effect of therapeutic window 4–7 hours post dosing). We asked whether 4‐AP could be used as a transdermal agent with an eye towards its pharmacokinetics and effects on motor function and neuronal recovery after peripheral nerve injury. Mice were assigned to moderate sciatic nerve crush injury and the effects of acute and chronic treatments with transdermal 4‐AP and vehicle (DMSO) were investigated. Using Franz diffusion cells, the skin permeability of 4‐AP (40 mg/ml) in 0.5 mL water or DMSO was determined through mouse skin. Pharmacokinetic parameters of 4‐AP in serum were determined by HPLC method at specified time points after applying 7.5μL of 4‐AP in DMSO (10 mg/ml or 20mg/ml) to the lower back skin of anesthetized mice. 4‐AP showed similar skin permeability coefficients in water (0.014 mm/hr) and DMSO (0.011 mm/hr). The maximum concentrations of 4‐AP after 75 μg and 150 μg administrations were 6.93 μM and 9.8 μM, respectively, and the time to maximum blood concentration was 60 min for both dosages. The half‐life of 4‐AP was 171.4 min and 160.0 min for 75 μg and 150 μg administration, respectively. Importantly, while both acute and chronic 4‐AP (150 μg) treatments significantly improved sciatic function index, chronic 4‐AP‐treated mice had greater nerve conduction velocity, fewer degenerating axons and thicker myelin sheaths than vehicle‐treated controls. To the best of our knowledge, this is the first study to show that topical 4‐AP, absorbed through the skin, enhances in vivo global motor function recovery with decreased axonal degeneration and increased myelination of axons.Support or Funding InformationThis work was supported by grants from the NIH (K08 AR060164‐01A) and DOD (W81XWH‐16‐1‐0725) in addition to institutional support from the University of Rochester and Pennsylvania State University Medical Centers.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Symptomatology and symptomatic treatment in multiple sclerosis: Results from a nationwide MS registry

Background: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease. Over time, symptoms accumulate leading to increased disability of patients. Objective: The objective of this article is to analyze the prevalence of symptoms and symptomatic treatment patterns in a nationwide MS registry. Methods: Data sets from 35,755 patients were analyzed. Results: More than two-thirds of patients were women with a mean age of 46.1 (±12.8) years. Median Expanded Disability Status Score (EDSS) was 3.0. The most frequently reported symptoms were fatigue, spasticity, and voiding disorders. In patients with short disease duration, fatigue was reported most frequently. Symptomatic treatment was most common for spasticity and depression, whereas fatigue was treated only in a third of affected patients. Almost a fifth of patients with EDSS ⩽ 3.5 and neuropsychological symptoms had retired from work. Conclusion: Whereas treatment for spasticity and depression is common in our cohort, sexual dysfunction, dysphagia, cognitive dysfunction, and fatigue are treated to a far lesser extent. The need for psychological support, physical, and occupational therapy has to be recognized as neuropsychological symptoms have a great impact on retirement at an early stage. Overall symptomatic treatment rates for the most common symptoms have increased over the last years (p < 0.001).

Evidencias actuales sobre las potenciales aplicaciones terapéuticas de la estimulación magnética transcraneal en la esclerosis múltiple: Revisión sistemática de la literatura

IntroductionA growing number of studies have evaluated the effects of transcranial magnetic stimulation (TMS) for the symptomatic treatment of multiple sclerosis (MS). MethodsWe performed a PubMed search for articles, recent books, and recommendations from the most relevant clinical practice guidelines and scientific societies regarding the use of TMS as symptomatic treatment in MS. ConclusionsExcitatory electromagnetic pulses applied to the affected cerebral hemisphere allow us to optimise functional brain activity, including the transmission of nerve impulses through the demyelinated corticospinal pathway. Various studies into TMS have safely shown statistically significant improvements in spasticity, fatigue, lower urinary tract dysfunction, manual dexterity, gait, and cognitive deficits related to working memory in patients with MS; however, the exact level of evidence has not been defined as the results have not been replicated in a sufficient number of controlled studies. Further well-designed, randomised, controlled clinical trials involving a greater number of patients are warranted to attain a higher level of evidence in order to recommend the appropriate use of TMS in MS patients across the board. TMS acts as an adjuvant with other symptomatic and immunomodulatory treatments. Additional studies should specifically investigate the effect of conventional repetitive TMS on fatigue in these patients, something that has yet to see the light of day.

What is new in symptomatic MS treatment: Part3-bladder dysfunction

The symptomatic treatment of multiple sclerosis (MS) nowadays is of similar importance as immunotherapy within acomprehensive concept of therapy of this chronic disease, since it contributes considerably to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Klinisches Kompetenznetz Multiple Sklerose (KKNMS) in 2014 several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation took place. These new findings together with further aspects of disease measures and overall treatment strategies of the respective symptoms, as well as treatment goals are introduced in aseries of six individual contributions. Here, the symptoms of bladder dysfunction will be discussed.

New aspects of symptomatic MS treatment: Part6 - cognitive dysfunction and rehabilitation

The symptomatic treatment of multiple sclerosis (MS) is nowadays of similar importance as immunotherapy within acomprehensive treatment concept of this chronic disease. It makes a considerable contribution to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of the quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Clinical Competence Network Multiple Sclerosis ("Klinisches Kompetenznetz Multiple Sklerose", KKN-MS) in 2014 several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation have taken place. These new findings together with further aspects of disease measurement methods and overall treatment strategies of the respective symptoms, as well as treatment goals are introduced in several individual contributions. In this article the symptoms of cognitive disorders and the growing impact of rehabilitation are discussed.

New aspects of symptomatic MS treatment: Part5 - fatigue

The symptomatic treatment of multiple sclerosis (MS) is nowadays of similar importance as immunotherapy within acomprehensive treatment concept of this chronic disease. It makes a considerable contribution to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of the quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Clinical Competence Network Multiple Sclerosis (Klinisches Kompetenznetz Multiple Sklerose, KKN-MS) in 2014 several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation have taken place. These new findings together with further aspects of disease measurement methods and overall treatment strategies of the respective symptoms as well as treatment goals are introduced in aseries of 6individual contributions. In this article the symptom of fatigue is discussed.

Neues zur symptomatischen MS-Therapie: Teil 4 – Störungen der Sexualfunktion und der Augenbewegungen

The symptomatic treatment of multiple sclerosis (MS) is nowadays of similar importance as immunotherapy within acomprehensive treatment concept of this chronic disease. It makes a considerable contribution to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of the quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Clinical Competence Network Multiple Sclerosis (Klinisches Kompetenznetz Multiple Sklerose, KKNMS) in 2014, several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation have taken place. These new findings together with further aspects of disease measurement methods and overall treatment strategies of the respective symptoms as well as treatment goals are introduced in several individual contributions. In this article the symptoms of sexual dysfunction and eye movement disorders are discussed.

Use of Cannabinoids for Spasticity and Pain Management in MS.

Several randomized trials have demonstrated potential benefit of cannabis derivatives in the symptomatic treatment of multiple sclerosis (MS) patients. These provide class 1 and 2 evidence for cannabinoid product use for spasticity and pain in these patients. The precise best ratio or doses are not yet clear. The safety and potential long-term effects of these products on cognitive function in people with MS have not been evaluated. Since short-term memory and processing speed can be significantly impaired in many people with MS, the concern of potential cognitive impairment related to cannabis products needs consideration in clinical care and should be addressed in longer, prospective studies.

Symptomatic Treatment in Multiple Sclerosis

Symptomatic Treatment in Multiple Sclerosis

MULTIPLE SCLEROSIS AND NEUROMYELITIS OPTICA MANAGEMENT (ACCORDING THE MATERIALS OF 2014 JOINT ACTRIMS-ECTRIMS MEETING, SEPTEMBER 2014, BOSTON, USA (MSJ, 2014, V.20, № S1)

The article presents the results of researches concerning preventive therapy, relapse treatment and symptomatic treatment of multiple sclerosis, neuromyelitis optica and neuromyelitis optica spectrum disorders. The medicines of first and second line that modulate multiple sclerosis course (modifying medicines) are reviewed. The data about new testing drugs are presented.

Endocannabinoid signalling and the deteriorating brain.

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls--and is affected by--normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics.

Prostaglandin F2α FP receptor inhibitor reduces demyelination and motor dysfunction in a cuprizone-induced multiple sclerosis mouse model

Previously, we have demonstrated that prostamide/PGF synthase, which catalyzes the reduction of prostaglandin (PG) H2 to PGF2α, is constitutively expressed in myelin sheaths and cultured oligodendrocytes, suggesting that PGF2α has functional significance in myelin-forming oligodendrocytes. To investigate the effects of PGF2α/FP receptor signaling on demyelination, we administrated FP receptor agonist and antagonist to cuprizone-exposed mice, a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, glial activation, proinflammatory cytokine expression, and motor dysfunction. Administration of the FP receptor antagonist AL-8810 attenuated cuprizone-induced demyelination, glial activation, and TNFα expression in the corpus callosum, and also improved the motor function. These data suggest that during cuprizone-induced demyelination, PGF2α/FP receptor signaling contributes to glial activation, neuroinflammation, and demyelination, resulting in motor dysfunction. Thus, FP receptor inhibition may be a useful symptomatic treatment in multiple sclerosis.