scholarly journals An argument for broad use of high efficacy treatments in early multiple sclerosis

2019 ◽  
Vol 7 (1) ◽  
pp. e636 ◽  
Author(s):  
James M. Stankiewicz ◽  
Howard L. Weiner
Keyword(s):  
Multiple Sclerosis ◽  
Treatment Approach ◽  
Disease Course ◽  
Long Term Outcomes ◽  
The Past ◽  
Recent Developments ◽  
The Brain

Two different treatment paradigms are most often used in multiple sclerosis (MS). An escalation or induction approach is considered when treating a patient early in the disease course. An escalator prioritizes safety, whereas an inducer would favor efficacy. Our understanding of MS pathophysiology has evolved with novel in vivo and in vitro observations. The treatment landscape has also shifted significantly with the approval of over 10 new medications over the past decade alone. Here, we re-examine the treatment approach in light of these recent developments. We believe that recent work suggests that early prediction of the disease course is fraught, the amount of damage to the brain that MS causes is underappreciated, and its impact on patient function oftentimes is underestimated. These concerns, coupled with the recent availability of agents that allow a better therapeutic effect without compromising safety, lead us to believe that initiating higher efficacy treatments early is the best way to achieve the best possible long-term outcomes for people with MS.

Cannabinoid effects on adenylate cyclase and phosphodiesterase activities of mouse brain

1977 ◽  
Vol 55 (4) ◽  
pp. 934-942 ◽  
Author(s):  
Thomas W. Dolby ◽  
Lewis J. Kleinsmith
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Mouse Brain ◽  
Biogenic Amine ◽  
Specific Activity ◽  
Intraperitoneal Administration ◽  
The Brain

The experiments presented in this paper examine the mechanisms underlying the ability of cannabinoids to alter the in vivo levels of cyclic adenosine 3′,5′-monophosphate (cyclic AMP) in mouse brain. It was found that changes in cyclic AMP levels are a composite result of direct actions of cannabinoids on adenylate cyclase (EC 4.6.1.1) activity and indirect actions involving the potentiation or inhibition of biogenic amine induced activity of adenylate cyclase. Furthermore, the long-term intraperitoneal administration of 1-(−)-Δ-tetrahydrocannabinol to mice produced a form of phosphodiesterase (EC 3.1.4.17) in the brain whose activity is not stimulated by Ca2+, although its basal specific activity is similar to that of control animals. In vitro, the presence of the cannabinoids caused no significant changes in activity of brain PDE at the concentrations tested. Some correlations are presented which imply that many of the observed behavioral and physiological actions of the cannabinoids in mammalian organisms may be mediated via cyclic AMP mechanisms.

Idiopathic Pulmonary Arterial Hypertension: Evolving Therapeutic Strategies

2017 ◽  
Vol 38 (05) ◽  
pp. 606-618 ◽  
Author(s):  
Manreet Kanwar ◽  
Amresh Raina ◽  
Michael Passineau ◽  
Raymond Benza
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Treatment Approach ◽  
Long Term Outcomes ◽  
Treatment Algorithms ◽  
The Past ◽  
Early Use ◽  
Short And Long Term ◽  
Pulmonary Arterial

AbstractThe field of pulmonary arterial hypertension (PAH) has seen substantial changes in the epidemiology, associated comorbidities, treatment algorithms, and prognosis in the past decade. Specifically for idiopathic PAH (IPAH), there has been a noted increase in the age of initial diagnosis. Increasing focus is being placed on appropriate categorization of patients with PAH, both in terms of diagnosis and individualized risk stratification. This is especially relevant given that patients being diagnosed with incident IPAH are now older and with multiple comorbidities, putting them at a higher risk of being mislabeled as PAH. The biggest impact has been seen in the number of pharmaceutical options available for these patients, resulting in improvement in both short- and long-term outcomes. In addition, there has been a shift in the treatment approach to the early use of combination therapies in PAH, since it has been demonstrated to improve clinical outcomes. Novel therapies are in the pipeline for patients with IPAH to impact both the morbidity and mortality of this deadly disease.

scholarly journals Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 15
Author(s):  
Paweł Piatek ◽  
Magdalena Namiecinska ◽  
Małgorzata Domowicz ◽  
Marek Wieczorek ◽  
Sylwia Michlewska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cumulative Effect ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Cns Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d+CD154+ lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d+CD154+ lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d+CD154+ lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d+CD154+ lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d+CD154+ cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG35-55) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d+/CD154+ cells were found to be co-localized with O4+ cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d+CD154+ lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.

scholarly journals The Anti-inflammatory Effect of the Tricyclic Antidepressant Clomipramine and Its High Penetration in the Brain Might Be Useful to Prevent the Psychiatric Consequences of SARS-CoV-2 Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
B. Nobile ◽  
M. Durand ◽  
E. Olié ◽  
S. Guillaume ◽  
J. P. Molès ◽  
...  
Keyword(s):  
Tricyclic Antidepressant ◽  
High Penetration ◽  
Good Target ◽  
Long Term Consequences ◽  
Anti Inflammatory ◽  
Neuro Inflammation ◽  
The Brain

At the time of writing (December 2020), coronavirus disease 2019 (COVID-19) has already caused more than one million deaths worldwide, and therefore, it is imperative to find effective treatments. The “cytokine storm” induced by Severe Acute Respiratory Syndrome-Coronavirus type 2 (SARS-CoV-2) is a good target to prevent disease worsening, as indicated by the results obtained with tocilizumab and dexamethasone. SARS-CoV-2 can also invade the brain and cause neuro-inflammation with dramatic neurological manifestations, such as viral encephalitis. This could lead to potentially incapacitating long-term consequences, such as the development of psychiatric disorders, as previously observed with SARS-CoV. Several pathways/mechanisms could explain the link between viral infection and development of psychiatric diseases, especially neuro-inflammation induced by SARS-CoV-2. Therefore, it is important to find molecules with anti-inflammatory properties that penetrate easily into the brain. For instance, some antidepressants have anti-inflammatory action and pass easily through the blood brain barrier. Among them, clomipramine has shown very strong anti-inflammatory properties in vitro, in vivo (animal models) and human studies, especially in the brain. The aim of this review is to discuss the potential application of clomipramine to prevent post-infectious mental complications. Repositioning and testing antidepressants for COVID-19 management could help to reduce peripheral and especially central inflammation and to prevent the acute and particularly the long-term consequences of SARS-CoV-2 infection.

scholarly journals Update on Antiviral Strategies Against COVID-19: Unmet Needs and Prospects

2021 ◽  
Vol 11 ◽  
Author(s):  
Ching-Hsuan Liu ◽  
Cheng-Hua Lu ◽  
Shu Hui Wong ◽  
Liang-Tzung Lin
Keyword(s):  
Unmet Needs ◽  
Future Prospect ◽  
Current Status ◽  
Effective Control ◽  
Research Focus ◽  
The Past ◽  
Current Outbreak

By December 2020, the COVID-19 pandemic had caused more than 74 million confirmed cases and 1.6 million related deaths around the world. However, only a few drugs have been approved in certain areas and for use in conditional patients, and the vaccine candidates were only recently approved or authorized for emergency use without being fully implemented worldwide, suggesting that we are yet to reach effective control of the current outbreak as its uninhibited transmission continues precariously. Over the past few months, several therapeutic candidates have been proven ineffective in large clinical trials, while some other agents exhibited promising preliminary results. Meanwhile, the investigation of SARS-CoV-2-specific antivirals is underway. Despite still being preclinical, these agents could be beneficial for the long-term control of COVID-19 and deserve more research focus. In this article, we update the current status of therapeutic candidates that have been examined for COVID-19 management, including the virus-targeting inhibitors and host-targeting agents, with their antiviral efficacy in vitro, in vivo, and in clinical studies. Finally, we highlight the current challenges and future prospect of developing potent therapeutic agents against COVID-19.

Fever: A Hot Topic

Physiology ◽  
1986 ◽  
Vol 1 (1) ◽  
pp. 25-27
Author(s):  
MJ Kluger
Keyword(s):  
Body Temperature ◽  
Interleukin 1 ◽  
White Blood Cells ◽  
Point Contact ◽  
In Vivo Studies ◽  
Set Point ◽  
The Past ◽  
The Brain

Fever is the regulation of body temperature at an elevated "set point." Contact with a variety of pathogens, such as viruses or bacteria, will result in the release of a small protein, endogenous pyrogen or interleukin 1, from the host's white blood cells. This protein circulates to the brain where it is thought to raise the temperature set point via the production of a prostaglandin. Fevers occur throughout the vertebrates. The cold-blooded vertebrates (fishes, amphibians, reptiles) raise their body temperature by behaviorally selecting a warmer microhabitat. Warm-blooded vertebrates (birds and mammals) use both physiological and behavioral means to raise core temperature. Over the past decade data from both in vitro and in vivo studies support the hypothesis that moderate fevers are beneficial to the host;that is, fever as evolved as an adaptation to reduce the severity of infection.

Long-term therapy with glatiramer acetate in multiple sclerosis: effect on T-cells

2001 ◽  
Vol 7 (1) ◽  
pp. 43-47 ◽  
Author(s):  
Samia Ragheb ◽  
Sarah Abramczyk ◽  
Deena Lisak ◽  
Robert Lisak
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Glatiramer Acetate ◽  
Mechanisms Of Action ◽  
Term Therapy ◽  
In Vitro Proliferation ◽  
Long Term Therapy

Glatiramer acetate (GA) is an immunotherapeutic drug for multiple sclerosis (MS). Several mechanisms of action have been demonstrated which target and affect T-cells that are specific for myelin antigen epitopes. We measured the in vitro proliferation of GA-responsive T-cells from untreated MS patients and from normal healthy subjects; in addition, we determined the effect of prolonged GA therapy or interferon-b therapy on the in vitro proliferation of GA-responsive T-cells of MS patients. We found that GA induces the proliferation of T-cells isolated from individuals who have not been previously exposed to GA, and that long-term in vivo therapy of MS patients with GA abrogates the GA-induced proliferative response of T-cells. In GA-treated patients, there is no evidence of generalized immunosuppression; both tetanus toxoid and anti-CD3 induced proliferative responses remain unaffected. We propose that prolonged in vivo exposure to GA may result in the eventual induction of anergy or deletion of a population of GA-responsive cells that may also be T-cells that are pathogenic in MS. This mechanism of action, in addition to other mechanisms that have been demonstrated, suggests that GA has pleiotropic effects on the immune system in MS.

REGENERATING ADULT COCKROACH DORSAL UNPAIRED MEDIAN NEURONES IN VITRO RETAIN THEIR IN VIVO MEMBRANE CHARACTERISTICS

1993 ◽  
Vol 179 (1) ◽  
pp. 323-329
Author(s):  
N. L. Newland ◽  
P. J. S. Smith ◽  
E. A. Howes
Keyword(s):  
Culture Conditions ◽  
Regenerative Process ◽  
Extrinsic Factors ◽  
Insect Central Nervous System ◽  
Physical And Chemical ◽  
The Brain ◽  
Dorsal Unpaired Median

The ability of differentiated neurones to recover from disease or injury depends upon both intrinsic and extrinsic factors. Whereas most mammalian neurones have a limited capacity for regeneration, regulated, in part, by physical and chemical cues in the brain microenvironment (Bray et al. 1987; Caroni and Schwab, 1988, 1989), invertebrates, and in particular insects, exhibit a far greater capacity for repair of central neurones and circuits (Treherne et al. 1988). Studies of the cues that regulate the regenerative process are made easier by the use of individual, identified neurones, cultured under controlled conditions. Invertebrates are particularly useful in this regard; neurones from mature nervous systems of both annelids and molluscs have been grown successfully in culture and their growth can be influenced by changes in the culture conditions (Acklin and Nicholls, 1990; Dagan and Levitan, 1981; Ready and Nicholls, 1979; Syed et al. 1990). Routine and long-term culture of identified neurones from the insect central nervous system (CNS) has proved more elusive, preventing the use of neurones from these well-studied systems. Recently, however, cultures of cockroach (Howes et al. 1991), locust (Kirchoff and Bicker, 1992) and moth (Hayashi and Levine, 1992) adult neurones have been described.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

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