Sleep Dysfunction in Fibromyalgia and Therapeutic Approach Options

Fibromyalgia, characterised by persistent pain, sleep disturbance, fatigue and cognitive dysfunction, is a central sensitivity syndrome that also involves abnormality in peripheral generators and in the hypothalamic pituitary adrenal axis. Heterogeneity of clinical expression of fibromyalgia with a multifactorial aetiology has made the development of effective therapeutic strategies challenging. Non-restorative sleep associated with poor sleep quality is a characteristic of fibromyalgia which is linked to symptom severity. A relationship between sleep disorder and central sensitization could be a possible factor involved in development, exacerbation and/or maintenance of fibromyalgia. Association between disordered sleep and the risk of fibromyalgia suggests that limiting sleep problems would reduce the incidence of the condition. Therapeutic approaches with treatments that consolidate or deepen sleep may be preferential to improve sleep in patients with fibromyalgia. Thus, disordered sleep appears fundamental to the pathophysiology of fibromyalgia and as such the risk of sleep disturbances needs to be proactively assessed and when identified in this patient group be actively managed to improve health outcomes for patients with fibromyalgia

Pharmacology and clinical applications of flupirtine: Current and future options

Flupirtine is the first representative in a class of triaminopyridines that exhibits pharmacological properties leading to the suppression of over-excitability of neuronal and non-neuronal cells. Consequently, this drug has been used as a centrally acting analgesic in patients with a range of acute and persistent pain conditions without the adverse effects characteristic of opioids and non-steroidal anti-inflammatory drug and is well tolerated. The pharmacological profile exhibited involves actions on several cellular targets, including Kv7 channels, G-protein-regulated inwardly rectifying K channels and γ-aminobutyric acid type A receptors, but also there is evidence of additional as yet unidentified mechanisms of action involved in the effects of flupirtine. Flupirtine has exhibited effects in a range of cells and tissues related to the locations of these targets. In additional to analgesia, flupirtine has demonstrated pharmacological properties consistent with use as an anticonvulsant, a neuroprotectant, skeletal and smooth muscle relaxant, in treatment of auditory and visual disorders, and treatment of memory and cognitive impairment. Flupirtine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of cells. Identification of molecules exhibiting specificity for the pharmacological targets (e.g., Kv7 isoforms) involved in the actions of flupirtine will provide further insight into clinical applications. Whether the broad-spectrum pharmacology of flupirtine or target-specific actions is preferential to gain benefit, especially in complex clinical conditions, requires further investigation. This review will consider recent advancement in understanding of the pharmacological profile and related clinical applications of flupirtine

Emerging pharmacological strategies for the treatment of fibromyalgia

Fibromyalgia (FM) has been described as a chronic clinical condition related to multisensory hypersensitivity presenting with a complex of symptoms dominated by chronic widespread pain associated with the existence of a range of co-morbidities, such as fatigue, sleep disturbance, cognitive impairment, anxiety and depression. Current treatments include drugs that target serotonin and noradrenaline levels within the central nervous system, e.g. , tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, and voltage-gated calcium channel subunit ligands, e.g. , gabapentin and pregabalin. Investigation of a range of novel targets, such as melatoninergic, cannabinoid, dopamine, NMDA, angiotensin, orexin and opioid receptors, and ion channels, in addition revisiting bioamine modulation and subunits has provided efficacy outcomes that improve the health status of patients with FM. Nevertheless, modest and limited efficacy is often observed reflecting the heterogeneity of FM with existence of subpopulations of patients, the contribution of peripheral and central components to the pathophysiology, and the extensive range of accompanying co-morbidities. The complexity and multidimensional nature of FM is emphasized by the diversity of pharmacological targets gaining interest. Clues to underlying mechanisms which offer themselves as novel and potential targets for new medications are being provided by advances in the understanding of the pathophysiology of FM

Kv7 channels a potential therapeutic target in fibromyalgia: A hypothesis

Fibromyalgia is characterized by the primary symptoms of persistent diffuse pain, fatigue, sleep disturbance and cognitive dysfunction. Persistent pain conditions, such as fibromyalgia, are often refractory to current available therapies. An involvement of K+ channels in the pathophysiology of fibromyalgia is emerging and supported by drug treatments for this condition exhibiting action at these molecular processes. K+ channels constitute potential novel target candidates for pain therapy offering peripheral and/or central actions. The Kv7 channel activators, flupirtine and retigabine, have exhibited pharmacological profiles compatible to the requirements needed for use as a therapeutic approach to fibromyalgia. Clinical trials to address the multidimensional challenges of fibromyalgia with flupirtine and retigabine will provide important insight to the role of K+ channels in this condition

Potential drug therapies for the treatment of fibromyalgia

INTRODUCTION: Fibromyalgia (FM) is a common, complex chronic widespread pain condition is characterized by fatigue, sleep disturbance and cognitive dysfunction. Treatment of FM is difficult, requiring both pharmacological and non-pharmacological approaches, with an empiric approach to drug therapy focused toward individual symptoms, particularly pain. The effectiveness of current medications is limited with many patients discontinuing use. AREAS COVERED: A systemic database search has identified 26 molecular entities as potential emerging drug therapies. Advances in the understanding of the pathophysiology of FM provides clues to targets for new medications. Investigation of bioamine modulation and α2δ ligands and novel targets such as dopamine receptors, NMDA receptors, cannabinoid receptors, melatonin receptors and potassium channels has identified potential drug therapies. EXPERT OPINION: Modest improvement of health status in patients with FM has been observed with drugs targeting a diverse range of molecular mechanisms. No single drug, however, offered substantial efficacy against all the symptoms characteristic of FM. Identification of new and improved therapies for FM needs to address the heterogeneity of the condition, which suggests existence of patient subgroups, the relationship of central and peripheral aspects of the pathophysiology and a requirement of combination therapy with drugs targeting multiple molecular mechanisms

Fibromyalgia pathogenesis provides drug target clues

Fibromyalgia (FM) has been described as a condition of heightened generalised sensitisation to sensory input presenting as a complex of symptoms dominated by chronic widespread pain characterised by hyperalgesia and allodynia. A range of co-morbidities of variable intensity, such as fatigue, sleep disturbance, cognitive impairment, anxiety and depression, are often present (Figure 1; page 46). The prevalence of this condition, which is more common in females than males, is reported to be 2-8% of the population and presents a major financial and social burden to patients and healthcare systems. Neuronal excitability associated with amplified responses of the central nervous system (CNS) to peripheral input leading to central sensitisation is believed to underlie the pathophysiology1,2. Peripheral nociceptive generators, such as nerve pathologies, neuro-inflammation, skeletal muscle abnormalities and ischaemia, play a role in the enhancement of the central components and the pain experienced by FM patients3,4

Local midpoints on smooth manifolds

In this paper we consider three methods for obtaining midpoints, primarily midpoints of geodesics of sprays, but also midpoints of symmetry (in symmetric spaces), and metric midpoints (in Riemannian manifolds). We derive general conditions under which these approaches yield the same result. We also derive a version of the Lie-Trotter formula based on the midpoint operation and use it to show that continuous maps preserving (local) midpoints are smooth

Smooth Bruck loops, symmetric spaces, and nonassociative vector spaces

Our purposes in this work include the following: (1) Extend and expand earlier work on symmetric spaces, particularly that done from a nonassociative algebra point of view, from the finite-dimensional setting to the Banach space setting. (2) Take a careful look at the equivalence of the categories of smooth pointed reflection quasigroups (a special class of symmetric spaces) and uniquely 2-divisible Bruck loops (= K-loops = gyrocommutative gyrogroups). (3) Propose a loop-theoretic analog of topological vector spaces. (4) Derive algebraic consequences and equivalences of smoothness notions, particularly the notion of parallel transport. (5) Illustrate the effective interaction of the algebraic operations of reflection, Bruck addition, and coaddition in the test case of parallelograms in symmetric spaces

Space-Time Covid-19 Bayesian SIR modeling in South Carolina

The Covid-19 pandemic has spread across the world since the beginning of 2020. Many regions have experienced its effects. The state of South Carolina in the USA has seen cases since early March 2020 and a primary peak in early April 2020. A lockdown was imposed on April 6th but lifting of restrictions started on April 24th. The daily case and death data as reported by NCHS (deaths) via the New York Times GitHUB repository have been analyzed and approaches to modeling of the data are presented. Prediction is also considered and the role of asymptomatic transmission is assessed as a latent unobserved effect. Two different time periods are examined and one step prediction is provided.Comment: 18 pages, 14 figure