Archive for category Pharmacological

[Abstract] Composite active range of motion (CXA) and relationship with active function in upper and lower limb spastic paresis

The aim of this study is to evaluate a novel composite measure of active range of motion (XA) and determine whether this measure correlates with active function.

Post hoc analysis of two randomized, placebo-controlled, double-blind studies with open-label extensions exploring changes in active function with abobotulinumtoxinA.

Tertiary rehabilitation centers in Australia, Europe, and the United States.

Adults with upper (n = 254) or lower (n = 345) limb spastic paresis following stroke or brain trauma.

AbobotulinumtoxinA (⩽5 treatment cycles) in the upper or lower limb.

XA was used to calculate a novel composite measure (CXA), defined as the sum of XA against elbow, wrist, and extrinsic finger flexors (upper limb) or soleus and gastrocnemius muscles (lower limb). Active function was assessed by the Modified Frenchay Scale and 10-m comfortable barefoot walking speed in the upper limb and lower limb, respectively. Correlations between CXA and active function at Weeks 4 and 12 of open-label cycles were explored.

CXA and active function were moderately correlated in the upper limb (P < 0.0001–0.0004, r = 0.476–0.636) and weakly correlated in the lower limb (P < 0.0001–0.0284, r = 0.186–0.285) at Weeks 4 and 12 of each open-label cycle. Changes in CXA and active function were weakly correlated only in the upper limb (Cycle 2 Week 12, P = 0.0160, r = 0.213; Cycle 3 Week 4, P = 0.0031, r = 0.296). Across cycles, CXA improvements peaked at Week 4, while functional improvements peaked at Week 12.

CXA is a valid measure for functional impairments in spastic paresis. CXA improvements following abobotulinumtoxinA injection correlated with and preceded active functional improvements.

via Composite active range of motion (CXA) and relationship with active function in upper and lower limb spastic paresis – Nicolas Bayle, Pascal Maisonobe, Romain Raymond, Jovita Balcaitiene, Jean-Michel Gracies,

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[Abstract] Pharmacological and Non-Pharmacological Interventions for Depression after Moderate-to-Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis

The objective of this study was to systematically review the literature and perform a meta-analysis of randomized controlled trials (RCTs) on the effectiveness of pharmacological and non-pharmacological interventions for depression in patients with moderate-to-severe traumatic brain injury.

Databases searched were: Embase, PubMed, PsycInfo, Cochrane Central, Web of Science, and Google Scholar. Depression score on a self-report questionnaire was the outcome measure. Outcomes were collected at baseline and at the first follow-up moment. Data extraction was executed independently by two researchers. Thirteen RCTs were identified: five pharmacological and eight non-pharmacological. Although not all individual studies had significant results, the overall standardized mean difference (SMD) was −0.395, p ≤ 0.001, indicating that interventions improved the depression scores in patients with TBI.

The difference in effectiveness between pharmacological interventions and non-pharmacological interventions was not significant (ΔSMD: 0.203, p = 0.238). Further subdivision into methylphenidate, sertraline, psychological, and other interventions showed a significant difference in effectiveness between methylphenidate (ΔSMD: −0.700, p = 0.020) and psychological interventions (reference). This difference was not found if other depression outcomes in four of the included studies were analyzed. The SMD of low-quality studies did not differ significantly from moderate- and high-quality studies (ΔSMD: 0.321, p = 0.050).

Although RCTs targeting interventions for depression after TBI are scarce, both pharmacological and non-pharmacological interventions appear to be effective in treating depressive symptoms/depression after moderate-to-severe TBI. There is a need for high-quality RCTs in which the add-on effects of pharmacological and non-pharmacological interventions are investigated.

via Pharmacological and Non-Pharmacological Interventions for Depression after Moderate-to-Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis | Journal of Neurotrauma

 

 

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[Abstract] Does Casting After Botulinum Toxin Injection Improve Outcomes in Adults With Limb Spasticity? A Systematic Review – Full Text PDF

Abstract

Objective: To determine current evidence for casting as an adjunct therapy following botulinum toxin injection for adult limb spasticity.

Design: The databases MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials were searched for English language studies from 1990 to August 2018. Full-text studies using a casting protocol following botulinum toxin injection for adult participants for limb spasticity were included. Studies were graded according to Sackett’s levels of evidence, and outcome measures were categorized using domains of the International Classification of Disability, Functioning and Health. The review was prepared and reported according to PRISMA guidelines.

Results: Five studies, involving a total of 98 participants, met the inclusion criteria (2 randomized controlled trials, 1 pre-post study, 1 case series and 1 case report). Casting protocols varied widely between studies; all were on casting of the lower limbs. There is level 1b evidence that casting following botulinum toxin injection improves spasticity outcomes compared with stretching and taping, and that casting after either botulinum toxin or saline injections is better than physical therapy alone.

Conclusion: The evidence suggests that adjunct casting of the lower limbs may improve outcomes following botulinum toxin injection. Casting protocols vary widely in the literature and priority needs to be given to future studies that determine which protocol yields the best results.

Full Text PDF

via Does Casting After Botulinum Toxin Injection Improve Outcomes in Adults With Limb Spasticity? A Systematic Review – PubMed

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[NEWS] Brain-wave pattern can identify people likely to respond to antidepressant, study finds.

Researchers used electroencephalography and artificial intelligence to identify individuals who would likely respond to sertraline, the antidepressant marketed as Zoloft.

brain wave graphic

Researchers used electroencephalography and an algorithm to identify a brain-wave signature in individuals with depression who will most likely respond to a medication.
Andrea Danti/Shutterstock.comA new method of interpreting brain activity could potentially be used in clinics to help determine the best treatment options for depression, according to a study led by researchers at the Stanford School of Medicine.      

Stanford researchers and their collaborators used electroencephalography, a tool for monitoring electrical activity in the brain, and an algorithm to identify a brain-wave signature in individuals with depression who will most likely respond to sertraline, an antidepressant marketed as Zoloft.

paper describing the work was published today in Nature Biotechnology.

The study emerged from a decades-long effort funded by the National Institute of Mental Health to create biologically based approaches, such as blood tests and brain imaging, to help personalize the treatment of depression and other mental disorders. Currently, there are no such tests to objectively diagnose depression or guide its treatment.

“This study takes previous research showing that we can predict who benefits from an antidepressant and actually brings it to the point of practical utility,” said Amit Etkin, MD, PhD, professor of psychiatry and behavioral sciences at Stanford. “I will be surprised if this isn’t used by clinicians within the next five years.”

Instead of functional magnetic resonance imaging, an expensive technology often used in studies to image brain activity, the scientists turned to electroencephalography, or EEG, a much less costly technology.

Etkin shares senior authorship of the paper with Madhukar Trivedi, MD, professor of psychiatry at the University of Texas-Southwestern. Wei Wu, PhD, an instructor of psychiatry at Stanford, is the lead author.

The paper is one of several based on data from a federally funded depression study launched in 2011 — the largest randomized, placebo-controlled clinical trial on antidepressants ever conducted with brain imaging — which tested the use of sertraline in 309 medication-free patients. The multicenter trial was called Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care, or EMBARC. Led by Trivedi, it was designed to advance the goal of improving the trial-and-error method of treating depression that is still in use today.

“It often takes many steps for a patient with depression to get better,” Trivedi said. “We went into this thinking, ‘Wouldn’t it be better to identify at the beginning of treatment which treatments would be best for which patients?’”

Most common mental disorder

Major depression is the most common mental disorder in the United States, affecting about 7% of adults in 2017, according to the National Institute of Mental Health. Among those, about half never get diagnosed. For those who do, finding the right treatment can take years, Trivedi said. He pointed to one of his past studies that showed only about 30% of depressed patients saw any remission of symptoms after their first treatment with an antidepressant.

Amit Etkin

Amit Etkin

Current methods for diagnosing depression are simply too subjective and imprecise to guide clinicians in quickly identifying the right treatment, Etkin said. In addition to a variety of antidepressants, there are several other types of treatments for depression, including psychotherapy and brain stimulation, but figuring out which treatment will work for which patients is based on educated guessing. 

    

To diagnose depression, clinicians rely on a patient reporting at least 5 of 9 common symptoms of the disease. The list includes symptoms such as feelings of sadness or hopelessness, self-doubt, sleep disturbances — ranging from insomnia to sleeping too much — low energy, unexplained body aches, fatigue, and changes in appetite, ranging from overeating to undereating. Patients often vary in both the severity and types of symptoms they experience, Etkin said.

“As a psychiatrist, I know these patients differ a lot,” Etkin said. “But we put them all under the same umbrella, and we treat them all the same way.” Treating people with depression often begins with prescribing them an antidepressant. If one doesn’t work, a second antidepressant is prescribed. Each of these “trials” often takes at least eight weeks to assess whether the drug worked and symptoms are alleviated. If an antidepressant doesn’t work, other treatments, such as psychotherapy or occasionally transcranial magnetic stimulation, may also be tried. Often, multiple treatments are combined, Etkin said, but figuring out which combination works can take a while.

“People often feel a lot of dejection each time a treatment doesn’t work, creating more self-doubt for those whose primary symptom is most often self-doubt,” Trivedi said.

Looking for a biomarker

The EMBARC trial enrolled 309 people with depression who were randomized to receive either sertraline or a placebo.

For their study, Etkin and his colleagues set out to find a brain-wave pattern to help predict which depressed participants would respond to sertraline. First, the researchers collected EEG data on the participants before they received any drug treatment. The goal was to obtain a baseline measure of brain-wave patterns.

Next, using insights from neuroscience and bioengineering, the investigators analyzed the EEG using a novel artificial intelligence technique they developed and identified signatures in the data that predicted which participants would respond to treatment based on their individual EEG scans. The researchers found that this technique reliably predicted which of the patients did, in fact, respond to sertraline and which responded to placebo. The results were replicated at four different clinical sites.

Further research suggested that participants who were predicted to show little improvement with sertraline were more likely to respond to treatment involving transcranial magnetic stimulation, or TMS, in combination with psychotherapy.

“Using this method, we can characterize something about an individual person’s brain,” Etkin said. “It’s a method that can work across different types of EEG equipment, and thus more apt to reach the clinic.”

Etkin is on leave from Stanford, working as the founder and CEO of the startup Alto Neuroscience, a company based in Los Altos, California, that aims to build on these findings and develop a new generation of biologically based diagnostic tests to personalize mental health treatments with a high degree of clinical utility. “Part of getting these study results used in clinical care is, I think, that society has to demand it,” Trivedi said. “That is the way things get put into practice. I don’t see a downside to putting this into clinical use soon.”

Broad effort

When EMBARC was launched, it was part of a broader effort by the NIMH to push for improvements in mental health care by using advances in fields such as genetics, neuroscience and biotechnology, said Thomas Insel, MD, who served as director of that institute from 2002 to 2015.

“We went into EMBARC saying anything is possible,” Insel said. “Let’s see if we can come up with clinically actionable techniques.” He didn’t think it would take this long, but he remains optimistic.

“I think this study is a particularly interesting application of EMBARC,” he said. “It leverages the power of modern data science to predict at the individual level who is likely to respond to an antidepressant.”

In addition to improving care, the researchers said they see a possible side benefit to the use of biologically based approaches: It could reduce the stigma associated with depression and other mental health disorders that prevents many people from seeking appropriate medical care.

“I’d love to think scientific evidence will help to counteract this stigma, but it hasn’t so far,” said Insel. “It’s been over 160 years since Abraham Lincoln said that melancholy ‘is a misfortune, not a fault.’ We still have a long way to go before most people will understand that depression is not someone’s fault.” (President Lincoln suffered bouts of depression.)

Other Stanford co-authors of the paper are postdoctoral scholars Yu Zhang, PhD, and Jing Jiang, PhD; former postdoctoral scholar Gregory Fonzo, PhD; neuroscience graduate students Molly Lucas and Camarin Rolle; research assistants Carena Cornelssen and Kamron Sarhadi; clinical research coordinator Trevor Caudle; former clinical research coordinators Rachael Wright, Karen Monuszko and Hersh Trivedi; and former neuroscience graduate student Russell Toll. All Stanford authors, including Etkin, are affiliated with Veterans Affairs Palo Alto Healthcare System and the Sierra Pacific Mental Illness, Research, Education and Clinical Center in Palo Alto.

Etkin is a member of the Wu Tsai Neurosciences Institute at Stanford.

Researchers at South China University of Technology, the Netherlands Research Institute, Harvard Medical School, the New York State Psychiatric Institute, Columbia University and the Netherlands neuroCare Group also contributed to the work.

Insel is an investor in Alto Neuroscience.

The EMBARC study data are publicly available through the NIMH Data Archive.

The study was funded by the National Institutes of Health (U01MH092221, U01MH092250, R01MH103324, DP1 MH116506), the Stanford Neurosciences Institute, the Hersh Foundation, the National Key Research and Development Plan of China, and the National Natural Science Foundation of China.


Stanford Medicine integrates research, medical education and health care at its three institutions – Stanford University School of MedicineStanford Health Care (formerly Stanford Hospital & Clinics), and Lucile Packard Children’s Hospital Stanford. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu.

via Brain-wave pattern can identify people likely to respond to antidepressant, study finds | News Center | Stanford Medicine

 

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[WEB PAGE] The ABCs of CBD: Separating fact from fiction – NIH MedlinePlus Magazine

CBD. Cannabidiol. No matter what you call it, you may have heard health claims about this little-known part of the marijuana plant, which comes from the plant’s flowers. Some say it treats muscle aches, anxiety, sleeping troubles, chronic pain, and more.

But what does the science say?

We spoke to NIH expert Susan Weiss, Ph.D., to learn more and find out why consumers should be careful. Dr. Weiss is the director of the division of extramural research at the National Institute on Drug Abuse (NIDA).

What is CBD?

CBD (or cannabidiol) comes from the cannabis (or marijuana) plant.

The chemical compound THC [tetrahydrocannabinol] is the part of the cannabis plant that most people are familiar with because that is the part that makes people “high.” Most effects of marijuana that people think of are caused by THC.

Most recreational marijuana has very little CBD in it. CBD products are available through dispensaries, health food and convenience stores, and the internet. It’s a widely used product that’s not regulated—and is not legal to sell for its largely unproven health benefits.

How does CBD work?

Nobody really knows what is responsible for the mental and physical health benefits that have been attributed to it. CBD affects the body’s serotonin system, which controls our moods. It also affects several other signaling pathways, but we really don’t understand its mechanisms of action yet.

How much do we know about CBD as a potential treatment?

There are over 50 conditions that CBD is claimed to treat.

We do know that CBD can help control serious seizure disorders in some children (e.g., Dravet and Lennox-Gastaut syndromes) that don’t respond well to other treatments. Epidiolex is an FDA [Food and Drug Administration] approved medication containing CBD that can be used for this purpose.

There’s also data to suggest the potential of CBD as a treatment for schizophrenia and for substance use disorders. But these potential uses are in extremely early stages of development.

Are there side effects?

We don’t know of any severe side effects at this time. But there were mild side effects reported in the epilepsy studies, mostly gastrointestinal issues like diarrhea. There were also some reported drug-to-drug interactions. That’s why, for safety reasons, it’s important that CBD or any cannabis product go through the FDA review process.

Are there any specific CBD studies that you are focused on?

We are interested in CBD as a potential treatment of substance use disorders.

There is some research looking at it for opioid, tobacco, and alcohol use disorders. If CBD can help prevent relapse in those areas, that would be really interesting. We’re also interested in it for pain management. Trying to find less addictive medications for pain would help a lot of people.

What else would you like people to know?

Buyer beware.

We are concerned about the health claims being exaggerated or incorrect. The FDA issued warning letters to several companies because of untested health claims. And the CBD products themselves didn’t always contain the amount of CBD that they were reported to have—some actually had THC in them.

Another concern is that people are using CBD to treat ailments for which we have FDA-approved medications. Thus, they may be missing out on better treatments. And when they’re using CBD or other cannabis products for conditions we don’t know very much about, that’s worrisome.

via The ABCs of CBD: Separating fact from fiction | NIH MedlinePlus Magazine

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[Abstract + References] Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy – Review

Abstract

During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine’s active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15–25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.

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[ARTICLE] Endocannabinoids: A Promising Impact for Traumatic Brain Injury – Full Text

Abstract

The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.

 

Introduction

Traumatic brain injury accounts for approximately 10 million deaths and/or hospitalizations annually in the world, and approximately 1.5 million annual emergency room visits and hospitalizations in the US (). Young men are consistently over-represented as being at greatest risk for TBI (). While half of all traumatic deaths in the USA are due to brain injury (), the majority of head injuries are considered mild and often never receive medical treatment (). Survivors of TBI are at risk for lowered life expectancy, dying at a 3⋅2 times more rapid rate than the general population (). Survivors also face long term physical, cognitive, and psychological disorders that greatly diminish quality of life. Even so-called mild TBI without notable cell death may lead to enduring cognitive deficits (). A 2007 study estimated that TBI results in $330,827 of average lifetime costs associated with disability and lost productivity, and greatly outweighs the $65,504 estimated costs for initial medical care and rehabilitation (), demonstrating both the long term financial and human toll of TBI.

The development of management protocols in major trauma centers () has improved mortality and functional outcomes (). Monitoring of intracranial pressure is now standard practice (), and advanced MRI technologies help define the extent of brain injury in some cases (). Current treatment of major TBI is primarily managed through surgical intervention by decompressive craniotomy () which involves the removal of skull segments to reduce intracranial pressure. Delayed decompressive craniotomy is also increasingly used for intractable intracranial hypertension (). The craniotomy procedure is associated with considerable complications, such as hematoma, subdural hygroma, and hydrocephalus (). At present, the pathology associated with TBI remains refractive to currently available pharmacotherapies () and as such represents an area of great research interest and in need of new potential targets. Effective TBI drug therapies have yet to be proven, despite promising preclinical data () plagued by translational problems once reaching clinical trials ().

The many biochemical events that occur in the hours and months following TBI have yielded preclinical studies directed toward a single injury mechanism. However, an underlying premise of the present review is an important need to address the multiple targets associated with secondary injury cascades following TBI. A growing body of published scientific research indicates that the endogenous cannabinoid (endocannabinoid; eCB) system possesses several targets uniquely positioned to modulate several key secondary events associated with TBI. Here, we review the preclinical work examining the roles that the different components of the eCB system play in ameliorating pathologies associated with TBI.

The Endocannabinoid (eCB) System

Originally, “Cannabinoid” was the collective name assigned to the set of naturally occurring aromatic hydrocarbon compounds in the Cannabis sativa plant (). Cannabinoid now more generally refers to a much more broad set of chemicals of diverse structure whose pharmacological actions or structure closely mimic that of plant-derived cannabinoids. Three predominant categories are currently in use; plant-derived phytocannabinoids (reviewed in ), synthetically produced cannabinoids used as research () or recreational drugs (), and the endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) () and 2-AG ().

These three broad categories of cannabinoids generally act through cannabinoid receptors, two types of which have so far been identified, CB1 () and CB2 (). Both CB1 and CB2 receptors are coupled to signaling cascades predominantly through Gi/o-coupled proteins. CB1 receptors mediate most of the psychomimetic effects of cannabis, its chief psychoactive constituent THC, and many other CNS active cannabinoids. These receptors are predominantly expressed on pre-synaptic axon terminals (), are activated by endogenous cannabinoids that function as retrograde messengers, which are released from post-synaptic cells, and their activation ultimately dampens pre-synaptic neurotransmitter release (). Acting as a neuromodulatory network, the outcome of cannabinoid receptor signaling depends on cell type and location. CB1 receptors are highly expressed on neurons in the central nervous system (CNS) in areas such as cerebral cortex, hippocampus, caudate-putamen (). In contrast, CB2 receptors are predominantly expressed on immune cells, microglia in the CNS, and macrophages, monocytes, CD4+ and CD8+ T cells, and B cells in the periphery (). Additionally, CB2 receptors are expressed on neurons, but to a much less extent than CB1 receptors (). The abundant, yet heterogeneous, distribution of CB1 and CB2 receptors throughout the brain and periphery likely accounts for their ability to impact a wide variety of physiological and psychological processes (e.g., memory, anxiety, and pain perception, reviewed in ) many of which are impacted following TBI.

Another unique property of the eCB system is the functional selectivity produced by its endogenous ligands. Traditional neurotransmitter systems elicit differential activation of signaling pathways through activation of receptor subtypes by one neurotransmitter (). However, it is the endogenous ligands of eCB receptors which produce such signaling specificity. Although several endogenous cannabinoids have been described () the two most studied are anandamide () and 2-AG (). 2-AG levels are three orders of magnitude higher than those of anandamide in brain (). Additionally, their receptor affinity () and efficacy differ, with 2-AG acting as a high efficacy agonist at CB1 and CB2 receptors, while anandamide behaves as a partial agonist (). In addition, anandamide binds and activates TRPV1 receptors (), whereas 2-AG also binds GABAA receptors (). As such, cannabinoid ligands differentially modulate similar physiological and pathological processes.

Distinct sets of enzymes, which regulate the biosynthesis and degradation of the eCBs and possess distinct anatomical distributions (see Figure Figure11), exert control over CB1 and CB2 receptor signaling. Inactivation of anandamide occurs predominantly through FAAH (), localized to intracellular membranes of postsynaptic somata and dendrites (), in areas such as the neocortex, cerebellar cortex, and hippocampus (). Inactivation of 2-AG proceeds primarily via MAGL (), expressed on presynaptic axon terminals (), and demonstrates highest expression in areas such as the thalamus, hippocampus, cortex, and cerebellum (). The availability of pharmacological inhibitors for eCB catabolic enzymes has allowed the selective amplification of anandamide and 2-AG levels following brain injury as a key strategy to enhance eCB signaling and to investigate their potential neuroprotective effects.

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FIGURE 1
Endocannabinoid system cell localization by CNS cell type. Endocannabinoid functional specialization among CNS cell types is determined by the cellular compartmentalization of biosynthetic and catabolic enzymes (biosynthesis by NAPE and DAGL-α, -β, catabolism by FAAH and MAGL). Cellular level changes in eCB biosynthetic and catabolic enzymes as a result of brain injury have yet to be investigated, though morphological and molecular reactivity by cell type is well documented.

[…]

 

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[Abstract] Exploratory Randomized Double-Blind Placebo-Controlled Trial of Botulinum Therapy on Grasp Release After Stroke (PrOMBiS)

Background. OnabotulinumtoxinA injections improve upper-limb spasticity after stroke, but their effect on arm function remains uncertain.

Objective. To determine whether a single treatment with onabotulinumtoxinA injections combined with upper-limb physiotherapy improves grasp release compared with physiotherapy alone after stroke.

Methods. A total of 28 patients, at least 1 month poststroke, were randomized to receive either onabotulinumtoxinA or placebo injections to the affected upper limb followed by standardized upper-limb physiotherapy (10 sessions over 4 weeks). The primary outcome was time to release grasp during a functionally relevant standardized task. Secondary outcomes included measures of wrist and finger spasticity and strength using a customized servomotor, clinical assessments of stiffness (modified Ashworth Scale), arm function (Action Research Arm Test [ARAT], Nine Hole Peg Test), arm use (Arm Measure of Activity), Goal Attainment Scale, and quality of life (EQ5D).

Results. There was no significant difference between treatment groups in grasp release time 5 weeks post injection (placebo median = 3.0 s, treatment median = 2.0 s; t(24) = 1.20; P = .24; treatment effect = −0.44, 95% CI = −1.19 to 0.31). None of the secondary measures passed significance after correcting for multiple comparisons. Both groups achieved their treatment goals (placebo = 65%; treatment = 71%), and made improvements on the ARAT (placebo +3, treatment +5) and in active wrist extension (placebo +9°, treatment +11°).

Conclusions. In this group of stroke patients with mild to moderate spastic hemiparesis, a single treatment with onabotulinumtoxinA did not augment the improvements seen in grasp release time after a standardized upper-limb physiotherapy program.

 

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[Abstract] Update on pharmacotherapy for stroke and traumatic brain injury recovery during rehabilitation

Abstract

PURPOSE OF REVIEW:

This article evaluates whether specific drugs are able to facilitate motor recovery after stroke or improve the level of consciousness, cognitive, or behavioral symptoms after traumatic brain injury.

RECENT FINDINGS:

After stroke, serotonin reuptake inhibitors can enhance restitution of motor functions in depressed as well as in nondepressed patients. Erythropoietin and progesterone administered within hours after moderate to severe traumatic brain injury failed to improve the outcome. A single dose of zolpidem can transiently improve the level of consciousness in patients with vegetative state or minimally conscious state.

SUMMARY:

Because of the lack of large randomized controlled trials, evidence is still limited. Currently, most convincing evidence exists for fluoxetine for facilitation of motor recovery early after stroke and for amantadine for acceleration of functional recovery after severe traumatic brain injury. Methylphenidate and acetylcholinesterase inhibitors might enhance cognitive functions after traumatic brain injury. Sufficiently powered studies and the identification of predictors of beneficial drug effects are still needed.

 

via Update on pharmacotherapy for stroke and traumatic brain injury recovery during rehabilitation. – PubMed – NCBI

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[ARTICLE] Pharmacological Therapies for Motor Recovery After Stroke – Full Text

Abstract and Introduction

Abstract

Stroke is the most common serious neurological disorder. To date, the focus for research and trials has been on prevention and acute care. Many patients are left with serious neurological impairments and limitations in activity and participation after stroke. Recent preliminary research and trials suggest that the brain is ‘plastic’ and that the natural history of stroke recovery can be improved by physical therapy and pharmacotherapy. Motor weakness and the ability to walk have been the primary targets for testing interventions that may improve recovery after stroke. Physical therapeutic interventions enhance recovery after stroke; however, the timing, duration and type of intervention require clarification and further trials. Pharmacotherapy, in particular with dopaminergic and selective serotonin-reuptake inhibitors, shows promise in enhancing motor recovery after stroke; however, further large-scale trials are required.

Introduction

This review is a framework around an emerging and exciting area of stroke care – maximizing recovery after stroke. Stroke care is a continuum from prevention to hyperacute care to acute care to rehabilitation to community reintegration and back (Figure 1). The traditional medical model of care artificially divides care across multiple healthcare providers and locations. Prevention is most often in the hands of general and primary care medicine with the goal of maximizing stroke risk reduction strategies such as controlling hypertension. Hyperacute stroke care is in the hands of neurologists with a primary goal of providing thrombolysis to as many patients as possible and as quickly as possible. Acute stroke care is in the hands of neurologists and very often in the hands of internal medicine specialists who manage patients according to best practices on acute stroke units in acute care hospitals. Rehabilitation is under the care of physical medicine and rehabilitation physicians and allied health professionals usually in rehabilitation hospitals. Reintegration into the community is in the hands of home care and out-patient providers in the community. One patient, one neurological disorder and so many different care providers and locations.

Figure 1.The continuum of stroke care.

Recent research suggests that we are at the edge of major advances in post-stroke care. Animal and human studies show that the brain is ready to heal immediately after a stroke. The brain is ‘plastic’ and responds to external influences, such as physical therapy. The timing, the intensity and the exact external influence may all be important factors in maximizing recovery. Pharmacotherapy may influence how the injured brain recovers. This complex array of influences and recent research addressing these areas will be elaborated on in this review (Figure 2).

Figure 2.
Multiple factors may influence recovery after stroke.

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