Archive for category Pharmacological

[ARTICLE] Paired Associative Stimulation as a Tool to Assess Plasticity Enhancers in Chronic Stroke – Full Text

Background and Purpose: The potential for adaptive plasticity in the post-stroke brain is difficult to estimate, as is the demonstration of central nervous system (CNS) target engagement of drugs that show promise in facilitating stroke recovery. We set out to determine if paired associative stimulation (PAS) can be used (a) as an assay of CNS plasticity in patients with chronic stroke, and (b) to demonstrate CNS engagement by memantine, a drug which has potential plasticity-modulating effects for use in motor recovery following stroke.

Methods: We examined the effect of PAS in fourteen participants with chronic hemiparetic stroke at five time-points in a within-subjects repeated measures design study: baseline off-drug, and following a week of orally administered memantine at doses of 5, 10, 15, and 20 mg, comprising a total of seventy sessions. Each week, MEP amplitude pre and post-PAS was assessed in the contralesional hemisphere as a marker of enhanced or diminished plasticity. Strength and dexterity were recorded each week to monitor motor-specific clinical status across the study period.

Results: We found that MEP amplitude was significantly larger after PAS in baseline sessions off-drug, and responsiveness to PAS in these sessions was associated with increased clinical severity. There was no observed increase in MEP amplitude after PAS with memantine at any dose. Motor threshold (MT), strength, and dexterity remained unchanged during the study.

Conclusion: Paired associative stimulation successfully induced corticospinal excitability enhancement in chronic stroke subjects at the group level. However, this response did not occur in all participants, and was associated with increased clinical severity. This could be an important way to stratify patients for future PAS-drug studies. PAS was suppressed by memantine at all doses, regardless of responsiveness to PAS off-drug, indicating CNS engagement.

Introduction

The capacity of the brain to make structural, physiological, and genetic adaptations following stroke, otherwise known as plasticity, is likely to be critical for improving sensorimotor impairments and functional activities. Promotion of adaptive plasticity in the central nervous system (CNS) leading to sustained functional improvement is of paramount importance, given the personal suffering and cost associated with post-stroke disability (Ma et al., 2014). In addition to rehabilitation therapies to retrain degraded motor skills, animal and human studies have tried to augment recovery with neuropharmacologic interventions. Unfortunately, few if any have had a notable effect in patients or have come into routine use (Martinsson et al., 2007Chollet et al., 2011Cramer, 2015Simpson et al., 2015). Methods to screen drugs based on their presumed mechanism of action on plasticity in human motor systems could speed translation to patients. However, there is currently no accepted method in stroke patients for evaluating the potential effectiveness or individual responsiveness to putative “plasticity enhancing” drugs in an efficient, low-cost, cross-sectional manner, in order to establish target engagement in humans and to avoid the extensive time and cost of protracted clinical trials.

Paired associative stimulation (PAS) is a safe, painless, and non-invasive technique known to result in short-term modulation of corticospinal excitability in the adult human motor system, lasting ∼90 min (Stefan et al., 2000Wolters et al., 2003). Post-PAS excitability enhancement has been considered an LTP-like response thought to relate to transient changes in synaptic efficacy in the glutamatergic system at the N-methyl-D-aspartate (NMDA) receptor, since both human NMDA receptor deficiency (Volz et al., 2016) and pharmacological manipulation with dextromethorphan (Stefan et al., 2002) can block the effect. While PAS has been explored as a potential therapeutic intervention in patients with residual motor deficits after stroke (Jayaram and Stinear, 2008Castel-Lacanal et al., 2009), it has not previously been investigated for its potential use as an assay of motor system plasticity in this context. Prior studies have suggested that motor practice and PAS share the same neuronal substrates, modulating LTP and LTD-like plasticity in the human motor system (Ziemann et al., 2004Jung and Ziemann, 2009); therefore, as an established non-invasive human neuromodulation method (Suppa et al., 2017), we reasoned that PAS would be a suitable assay in the present study to examine the effect of a drug on motor system plasticity.

Here, we examine the effect of memantine, a drug used for treatment of Alzheimer’s disease, on the PAS response in patients with chronic stroke. Memantine is described pharmacologically as a low affinity, voltage dependent, non-competitive, NMDA antagonist (Rogawski and Wenk, 2003). At high concentrations, like other NMDA-R antagonists, it can inhibit synaptic plasticity. At lower, clinically relevant concentrations, memantine can, under some circumstances, promote synaptic plasticity by selectively inhibiting extra-synaptic glutamate receptor activity while sparing normal synaptic transmission, and hence may have clinical utility for rehabilitation (Xia et al., 2010). Interest in specifically using the drug for its interaction with stroke pathophysiology stems from animal models of both prevention (Trotman et al., 2015), in which pre-conditioning reduced infarct size, as well as for functional recovery, in which chronic oral administration starting >2 h post-stroke resulted in improved function through a non-neuroprotective mechanism (López-Valdés et al., 2014). In humans, memantine taken over multiple days has been used to demonstrate that the NMDA receptor is implicated in specific transcranial magnetic paired-pulse measures (Schwenkreis et al., 1999), and short-term training-induced motor map reorganization (Schwenkreis et al., 2005). In studies of neuromodulation, memantine blocked the facilitatory effect of intermittent theta-burst stimulation (iTBS) (Huang et al., 2007). Similarly, LTP-like plasticity induced by associative pairing of painful laser stimuli and TMS over primary motor cortex (M1) can also be blocked by memantine (Suppa et al., 2013). The effects of memantine on the PAS response have not yet been demonstrated, including examination of potential dose-response effects, which would be important for the potential clinical application of memantine for stroke recovery.

In our study, we set out to determine whether PAS might be a useful tool to probe the potential for plasticity after stroke in persons with chronic hemiparesis and apply PAS as an assay to look at drug effects on motor system plasticity using memantine. We hypothesized that (a) PAS would enhance corticospinal excitability in the contralesional hemisphere of stroke patients, and that (b) since PAS-induced plasticity is thought to involve a short-term change in glutamatergic synaptic efficacy, memantine would have a dose-dependent effect on PAS response. We predicted that at low doses, memantine would enhance PAS-induced plasticity through selective blockade of extrasynaptic NMDA receptors, whereas higher doses would inhibit PAS-induced plasticity.[…]

 

Continue —> Frontiers | Paired Associative Stimulation as a Tool to Assess Plasticity Enhancers in Chronic Stroke | Neuroscience

Figure 1. Axial MR/CT images for individual patients illustrating the stroke lesion. Images are displayed in radiological convention. Images are labeled by participant number.

 

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[WEB SITE] Marijuana could be effective against traumatic brain injury

Although the lives of patients dealing with a traumatic brain injury have improved manifold in recent years, they find themselves vulnerable to a host of side-effects that come with the modern-day medicine such as opioid painkillers, antidepressants, mood stabilizers and anti-seizure medicines.

The good news, however, is that we can now make use of legal cannabis to treat a traumatic brain injury, without the fear of death and other side-effects (recall, marijuana consumption has never resulted in a single death thus far).

A study published in 2014 found that testing positive for THC while sustaining a traumatic brain injury was associated with decreased mortality – from 11.5% to down to just 2.4%. In this post, we’ll take a look at the available research and scientific evidence that may help us determine if (and how) marijuana could help improve the condition of a person battling TBI.

Symptoms of a traumatic brain injury

TBIs occur because of a severe blow to the head, typically during an athletic event or a road accident. The common symptoms include:

  • Mood swings
  • Headaches
  • Seizures
  • Difficulties while speaking
  • Loss of motor control
  • Loss of memory

How cannabis could prove to be a breakthrough

1) Relieving Symptoms

Cannabis-derived medicines are known to drastically reduce the intensity and frequency of some types of seizures, while at the same time also displaying potent anti-anxiety and antidepressant effects, and that too without any serious side-effects.

Interestingly, a 2017 survey of 271 medical marijuana patients found that nearly 63% of participants preferred cannabis over prescription medications for the management of pain and anxiety.

2) Protection against a TBI

In order to understand this point well, you first need to have a clear understanding of the term ‘endocannabinoids’. Just like a cannabis plant produces phytocannabinoids (CBD, THC), the human body naturally produces similar molecules named endocannabinoids, which are used by the nervous and immune system to communicate.

A number of pre-clinical studies like this have shown that endocannabinoids have neuroprotective properties, which helps the brain and nervous system to recover after a blow.

It has been seen in animal models that CBD works by boosting levels of the body’s own endocannabinoids; while THC — the compound responsible for the “high” — works by taking the place of natural endocannabinoids itself in the body.

Growth of new brain cells

A study from the University of Saskatchewan (2005) found that when rodents were administered with synthetic THC, the cannabinoid apparently boosted the growth of new brain cells in a region known as the hippocampus.

The hippocampus region is responsible for memory, learning and the autonomic nervous system; research has shown that patients battling anxiety and depression often have this portion of their brain adversely affected.

Hence, the growth of new cells, courtesy of cannabis, may help in tackling the situation.

Reduced Brain inflammation

It is a well-known fact that CBD has anti-inflammatory properties. Preclinical research has found that CBD treatment immediately after a loss of oxygen can significantly reduce brain damage.

This 2011 study found that CBD treatment administered to newborn pigs after an injury effectively reduced brain edema, seizures and improved overall motor skills and behavior within just 72 hours after the injury.

Conclusion

The power of cannabinoids should never be underestimated. It’s only a matter of time before cannabis replaces most of the opioid medicines in use for traumatic brain injury treatment.

 

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[Abstract + References] Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy

Abstract

Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

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[Abstract] Pharmacological interventions and rehabilitation approach for enhancing brain self-repair and stroke recovery

Abstract

Neuroplasticity is a natural process occurring in the brain for entire life. Stroke is the leading cause of long term disability and huge medical and financial problem throughout the world. Research conducted over the past decade focused mainly on neuroprotection in the acute phase of stroke while very little studies targets chronic stage. Recovery after stroke depends on the ability of our brain to reestablish structural and functional organization of neurovascular networks. Combining adjuvant therapies and drugs may enhance the repair processes and restore impaired brain functions. Currently, there are some drugs and rehabilitative strategies that can facilitate brain repair and improve clinical effect even years after stroke onset. Moreover, some of compounds such as citicoline, fluoxetine, niacin, levodopa etc. are already in clinical use or are being trial in clinical issues. Many studies testing also cell therapies, in our review we will focused on studies where cells have been implemented at the early stage of stroke. Next, we discuss pharmaceutical interventions. In this section selected methods of cognitive, behavioral and physical rehabilitation as well as adjuvant interventions for neuroprotection including non invasive brain stimulation and extremely low frequency electromagnetic field. The modern rehabilitation represents new model of physical interventions with limited therapeutic window up to six months after stroke. However, last studies suggest, that time window for stroke recovery is much longer than previous thought. This review attempts to present the progress in neuroprotective strategies, both pharmacological and non-pharmacological that can stimulate the endogenous neuroplasticity in post stroke patients.

 

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[ARTICLE] Pharmacological management of long-term aggression secondary to traumatic brain injuries

Abstract
Aggression is common after traumatic brain injuries (TBI) in acute and chronic settings. However, there is limited guidance regarding its assessment and effective management. Whilst a number of pharmacological options are available for long term treatment, the evidence base is not of an adequate strength to support a unified practice. This article will explore the currently available guidelines and recommendations for treating chronic aggression after TBIs and evaluate the evidence for its pharmacological management.


Introduction

Aggression is a long term neurobehavioural sequelae of TBIs with incidences quoted from 11.5-33.7%.1 In TBI patients, aggressive behaviour tends to be impulsive rather than premeditated and can manifest as episodic dyscontrol syndrome, disinhibition or exacerbated premorbid antisocial traits.2 The underlying mechanisms of aggression are complex allowing numerous and diverse interventions targeting various pathways.

In acute settings, Lombard and Zafonte (2005) describe non-pharmacological measures to manage aggression including environmental alterations and ensuring minimal or non-contact restraints. Screening for systemic causes, optimising pain control and patients’ sleep-wake cycle are also advocated. In the event of failed non-pharmacological treatment, Lombard and Zafonte (2005) recommend that medication choice should be tailored to individuals; with side effect profiles taken into consideration.3

For chronic aggression, psychological therapies are used as a first line with pharmacological interventions trialled in later stages.4 Psychological therapy options include cognitive behavioural therapy (CBT), behavioural management utilising operant learning theory and contingency management. However, a review by Alderman (2013) concluded that further evidence using scientific methods is needed to analyse these approaches.5  Comparatively, there is a diverse body of literature addressing long term pharmacological treatment although quality among studies are varied. This article will focus on the aetiology for chronic post TBI aggression, current management guidelines and the evidence for long term pharmacological interventions.

Aetiology

Post TBI aggression has been associated with lesions affecting the prefrontal cortex – particularly the orbitofrontal and ventromedial areas – causing a loss of behavioural regulation. Disruption to inhibitory pathways between the prefrontal cortex and limbic system also results in limbic kindling and inappropriate emotional responses to negative stimuli thus facilitating aggressive behaviour.2 Associated neurotransmitter abnormalities include low cortical serotonin and impaired gamma amino-butyric acid (GABA)/ glutamate levels.6 Altered catecholamine and cholinergic levels are associated with cognitive impairment2 thus distorting information processing and predisposing patients to aggression.6 In TBI patients, underlying anxiety, affective disorders, seizures and frontal lobe dysfunction also increase susceptibility.10

Differentials for aggression

When identifying a cause for chronic aggressive behaviour, a patient’s previous experiences, comorbid psychiatric conditions and alcohol and/or substance abuse must be established with a collateral history.2,7  McAllister (2008) highlights the importance of determining pre-injury behaviour in order to exclude the possibility of symptoms being an exaggeration of pre-injury personality traits.8 Additionally, psychosocial factors must be deduced to identify possible triggers.2,7

Clinicians must be aware that aggression can be a presenting feature of other psychiatric disorders. Depression has a prevalence of 18.5% to 61% in post-TBI patients  and is linked with aggression due to their shared association with frontal lobe lesions and serotonin level imbalance.9 Other differentials include manic disorders (which can involve a more marked aggressive component if secondary to TBIs), anxiety disorders and alcohol and/or substance abuse. Personality and behavioural disorders such as affective lability, behavioural disinhibition and acquired antisocial behaviour should also be considered.8

Management guidelines

The National Institute for Health and Care Excellence (NICE) refers to the Scottish Intercollegiate Guidelines Network (SIGN) for rehabilitating patients with acquired brain injuries (ABIs). Psychological treatments advocated by SIGN include CBT, contingency management procedures, music therapy and comprehensive neurobehavioural rehabilitation (CNR).10 Family involvement appears to be associated with better outcomes2 and is also recommended.10

Of the studies quoted by SIGN, CNR was found to cause a positive effect in ABI patients in one systematic review although inconsistent results were obtained for the other three methods. Regarding pharmacological treatment, SIGN advises propranolol and pindolol as first line options.10

Pharmacological treatment

The aberrant neurotransmitter changes in the cortex and limbic areas as a result of TBIs2 provide targets for pharmacological therapy (as summarised in Table 1). Theoretically, cortical behavioural regulation can be enhanced by serotonergic agents and antagonists of dopaminergic and noradrenergic neurotransmission. Limbic hyperactivity can be dampened by the use of gamma aminobutyric acid (GABA) agonists, glutamatergic antagonists and anticholinergics.6

Impaired behavioural regulation

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are indicated for their increase in dopamine and serotonin availability and the treatment of depression contributing to aggressive behaviour. In a trial conducted by Kant et al (1998), sertraline reduced aggression within one week of treatment although TBI severities were variable within the population.11 These results are mirrored in other trials presenting sertraline as a viable treatment option.12 Citalopram used in conjunction with carbamazepine successfully treated behavioural symptoms in a clinical trial of 22 patients conducted by Perino et al (2001)13 although the separate effects of both drugs are impossible to differentiate. A case study by Sloan et al (1992) found that fluoxetine improved emotional lability in one patient within a week.13

Tricyclic antidepressants have been shown to be useful for managing both post-traumatic and chronic aggression. Amitriptyline has reduced aggression with good tolerability despite its strong anticholinergic side effects in several studies and is suggested as the best option for treating behavioural disorders secondary to frontal lobe injuries without impairing cognition.13

Antipsychotics

There is a wide body of literature advocating antipsychotics for managing aggression due to their sedative effects.13 Nevertheless, the cognitive and extrapyramidal side effects of typical antipsychotics limit their value for chronic use. Comparatively, atypical antipsychotics have a milder side effect profile and are preferred although their cognitive impact in TBI patients is unclear.2 Furthermore, unlike older generations, atypical antipsychotics antagonise 5HT2 receptors and are therefore implicated in reduced aggression.9

Of the typical antipsychotics, chlorpromazine reduced explosiveness in one case study conducted by Sandel et al (1993). Various case studies also report haloperidol improving chronic agitation in TBI patients although significant side effects were encountered.13 Of the atypical antipsychotics the level of evidence is low. Quetiapine reduced aggression and irritability in seven patients in a trial conducted by Kim and Bijlani (2006).11 Olanzapine significantly reduced aggression within six months in a case study conducted by Umansky and Geller (2000). Clozapine was associated with varying levels of improvement in six case studies conducted by Michals et al (1993) however seizures were experienced in two patients.13

Overall, there is no reliable evidence advocating antipsychotic use for managing chronic post-TBI aggression. If antipsychotics are commenced for this purpose, it is suggested that their use is restricted to patients with psychosis.13

Beta blockers

Beta blockers are useful for cases where aggression is caused by underlying anxiety13 due to its inhibition of noradrenergic levels.9 A Cochrane review of four RCTs found that pindolol and propranolol reduced aggression within two to six weeks of starting treatment in ABI patients however no recommendations were made due to heterogeneity between samples, a small number of trials and small sample sizes.  The authors acknowledge that the trials involved high doses and so recommend caution when prescribing beta blockers for aggression.4

Methylphenidate

Methylphenidate is a psychostimulant indicated for its enhancement of dopamine and noradrenaline in the frontal lobe improving arousal and alertness.13 Mooney (1993) found in a single RCT that methylphenidate significantly improved anger scores in TBI patients.4 However other studies have yielded mixed results12,13 and no firm conclusion can be made.

Amantadine

Amantadine increases dopamine availability and acts on glutamatergic pathways. An advantage of its use is its non-sedating qualities however there is contradicting evidence for its efficacy.13 An RCT conducted by Schneider (1999) found no significant improvement4 however the trial was limited by a small sample size and large heterogeneity. Interestingly, studies of a lower level of evidence demonstrate favourable results.13 Due to this variability, its efficacy is still in question.

Buspirone

Buspirone – a serotonergic agonist licensed for treating anxiety13 – has also reduced aggression in several case studies2,12,14 warranting further research. Its side effects are amenable for use in TBIs although one disadvantage is its delayed onset.13

Hyperactive limbic drive

Anticonvulsants

The mood stabilising effects of anticonvulsants are mediated through their enhancement of GABA transmission.2 Carbamazepine has been demonstrated in studies to be effective for managing acute and chronic post- TBI aggression.12,13 Its side effects include impaired balance, sedation13 and cognitive impairment particularly in brain injured patients2 due to their heightened sensitivity. In a trial conducted by Mattes (2005), Oxcarbazepine reduced impulsive aggression however the number of TBI participants in the sample was unclear. Nine of the 48 participants also dropped out due to adverse effects11 suggesting more research is needed into its tolerability in TBI patients. Valproate has also been demonstrated to effectively manage behavioural and affective disorders13 with a milder cognitive impact compared to carbamazepine.2 Regarding other anticonvulsants, the evidence is of a lower standard. Pachet et al (2003) found that lamotrigine reduced aggression with good tolerability in one case study.11 Topiramate has been demonstrated to effectively treat manic symptoms but due to its side effects of psychosis and cognitive impairment,2 may be inappropriate for TBI patients. Case reports reference lithium to reduce post – TBI agitation however it may be unsuitable as a first line option due to its neurotoxicity.13

Benzodiazepines

Benzodiazepines are indicated for their anticonvulsive, anti-anxiety and sedative qualities facilitated by stimulation of the GABA receptor.13 There is limited literature on their chronic use in TBI patients due to their side effects of agitation, cognitive impairment and tolerance2 thus they are recommended to be more appropriate for cases of acute agitation or anxiety.11

Conclusion

There are many challenges in assessing and managing chronic aggression due to its complex aetiology. Previous literature presents a selection of pharmacological options however, their effect on TBI patients has not been confirmed resulting in limited guidance. The heterogeneity between samples also renders it impossible to predict treatment outcomes in the TBI population warranting the need for low doses, slow titration and frequent monitoring.13 A six-week trial period is advised by Fleminger et al (2006) to ascertain effects of treatment before trialling a new medication.4 Patient and family education regarding realistic treatment outcomes and side effects of treatments is also necessary to ensure treatment compliance.2 In future, a clarification of the underlying neurochemical changes is needed to identify further treatment targets. Additional larger scale RCTs are also needed to guide decision making and predict treatment outcomes. Table 2 offers a practical guide on medication choice in relation to aggressive behaviour in ABI.

References

  1. Tateno A, Jorge RE, Robinson RG. Clinical correlates of aggressive behaviour after traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2003;15(2):155-60.
  2. Kim E. Agitation, aggression and disinhibition syndromes after traumatic brain injury. NeuroRehabilitation 2002;17:297-310.
  3. Lombard LA, Zafonte RD. Agitation after traumatic brain injury: considerations and treatment options. Am J Phys Med Rehabil. 2005;84(10):797-812.
  4. Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev. 2006;18(4):CD003299.
  5. Alderman N, Knight C, Brooks J. Rehabilitation Approaches to the Management of Aggressive Behaviour Disorders after Acquired Brain Injury. Brain Impairment. 2013;14(1):5-20.
  6. Siever LJ. Neurobiology of Aggression and Violence. Am J Psychiatry. 2008;165(4):429-42.
  7. McAllister TW. Neurobehavioral sequelae of traumatic brain injury: evaluation and management. World Psychiatry. 2008;7(1):3-10.
  8. Schwarzbold M, Diaz A, Martins ET, Rufino A, Amante LN, Thais ME et al. Psychiatric disorders and traumatic brain injury. Neuropsychiatr Dis Treat. 2008;4(4):797-816.
  9. Coccaro EF, Siever LJ. Pathophysiology and treatment of aggression. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropsychopharmacology: The Fifth Generation of Progress. 5th ed. Pennsylvania: Lipincott, Williams & Wilkins; 2002:1709-23.
  10. Scottish Intercollegiate Guidelines Network. Brain injury rehabilitation in adults. Edinburgh: SIGN; 2013. 68 p. Report no.:130.
  11. Luauté J, Plantier D, Wiart L, Tell L, the SOFMER group. Care management of the agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and practice recommendations. Ann Phys Rehabil Med 2016;59(1):58-67.
  12. Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, Bruns J, et al. Guidelines for the Pharmacological Treatment of Neurobehavioral Sequelae of Traumatic Brain Injury. J Neurotrauma 2006;23(10):1468-501.
  13. Levy M, Berson A, Cook T, Bollegala N, Seto E, Tursanski S, et al. Treatment of agitation following traumatic brain injury: A review of the literature. NeuroRehabilitation 2005;20(4):279-306.
  14. Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury – a state-of-the-art review. J Rehabil Res Dev 2009;46(6):851-79.

Anum Bhatti is currently in her final year of training for her MBchB at Keele University. She is interested in pursuing psychiatry as a career choice.

 

Dr George El-Nimr, MBChB, MSc (Neuropsych), MRCPsych, MSc (Psych), MMedEd, is a Consultant Neuropsychiatrist and Academic Secretary of the Faculty of Neuropsychiatry at the Royal College of Psychiatrists.

 

Correspondence to: Dr El-Nimr, Consultant Neuropsychiatrist, Neuropsychiatry Services, Bennett Centre, Richmond Terrace, Shelton, Stoke-on-Trent ST1 4ND. Tel: 01782 441614
Conflict of interest statement: None declared
Provenance and peer review: Submitted and externally reviewed
Date first submitted: 18/4/18
Date submitted after peer review: 21/9/18
Acceptance date: 15/5/19
To cite: Bhatti A, El-Nimr G. 
ACNR 2019;18(4);15-17
Published online: 1/8/19

via Pharmacological management of long-term aggression secondary to traumatic brain injuries | ACNR | Online Neurology Journal

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[WEB SITE] Prozac vs. Zoloft: What are the differences?

Prozac and Zoloft are common antidepressant drugs. Although they have similar effects on the body, their specific uses, side effects, and dosages are different.

Prozac and Zoloft are both selective serotonin reuptake inhibitors (SSRIs). This class of medication is among the first options for treating major depressive disorder, which people usually call depression.

Fluoxetine is the generic drug name for Prozac, and sertraline is the generic name for Zoloft.

In this article, we discuss the differences between Prozac and Zoloft.

What do they treat?

prozac vs zoloft

Taking either Prozac or Zoloft will increase the levels of serotonin in the brain.

The Food and Drug Administration (FDA) have approved both Prozac and Zoloft for treating:

In addition, the FDA have approved Prozac for the treatment of:

Doctors may also use Zoloft to treat post-traumatic stress disorder (PTSD) and social anxiety disorder.

Some doctors prescribe Prozac for social anxiety disorder in adults, borderline personality disorderRaynaud’s phenomenon, and selective mutism, but the FDA have not approved these uses.

Other SSRIs include:

  • escitalopram (Lexapro)
  • vortioxetine (Trintellix)
  • citalopram (Celexa)
  • fluvoxamine (Luvox)
  • paroxetine (Paxil)
  • vilazodone (Viibryd)

Forms

Both Prozac and Zoloft are available in the forms of a liquid oral solution, a tablet, and a capsule.

The following table lists the different forms of each drug along with the available dosages in milligrams (mg) and milligrams per milliliter (mg/ml).

Prozac Zoloft
Capsule 10 mg, 20 mg, 40 mg, 90 mg 25 mg, 50 mg, 100 mg
Tablet 60 mg 25 mg, 50 mg, 100 mg
Liquid 20 mg/5 ml 20 mg/ml

How to take and dosage

When a person first starts taking antidepressants, they will typically begin on a smaller dosage and increase this over time. Doing this makes it possible to test how well the drug works and monitor its side effects, as the effectiveness and adverse effects can differ among individuals.

American Psychiatric Association guidelines report the following starting dosages and the usual effective dosages when treating MDD:

Prozac Zoloft
Starting dosage 20 mg/day 50 mg/day
Usual effective dosages 20–60 mg/day 50–200 mg/day

Some people may see improvements in their symptoms in the first 1–2 weeks of treatment, whereas it may take 2–4 weeks for others to notice changes.

Some studies have shown that all antidepressants require at least 4–6 weeks before they reach their maximal clinical effectiveness.

There are three phases of MDD therapy:

  • The acute phase. The goal of the acute phase is for the person to recover from depressive symptoms and return to their baseline of functioning. This phase will last about 6–12 weeks.
  • The continuation phase. During the continuation phase, doctors will recommend that people continue treatment for 4–9 months to prevent symptoms from returning.
  • The maintenance phase. Some people may need to continue their medication for longer and complete a maintenance phase. The goal is to protect at-risk people from recurring depressive symptoms.

Doctors will usually recommend a maintenance phase for people with recurrent MDD or chronic depression.

If a person does not have a satisfactory response to medication, the doctor may try increasing the dosage. However, a higher dosage may cause more side effects, so doctors need to evaluate the risks and benefits of increasing it.

Another strategy to increase the effectiveness of the therapy is to add another medicine. A doctor may advise a person to combine Prozac or Zoloft with certain other antidepressants and other types of medication to improve their symptoms.

The doctor will determine which combinations are the most appropriate for each person while keeping in mind the possibility of drug interactions.

Doctors may also adjust medication dosages and regimens for people who are combining medication therapy and psychotherapy.

Side effects

As Prozac and Zoloft are both SSRIs, people may experience similar side effects with these drugs.

Zoloft is more likely than Prozac to cause gastrointestinal tract side effects, such as nausea and diarrhea. Men taking Zoloft may also report more sexual dysfunction side effects, such as failure to ejaculate, than those using Prozac.

However, people taking Prozac more often experience headaches, nervousness, and a lack of energy.

The following table lists the most common side effects of Prozac and Zoloft, which occur in at least 5% of people.

Prozac Zoloft
nausea 22% 26%
diarrhea 11% 20%
constipation 5% 6%
decreased appetite no data available 7%
anorexia 10% no data available
acid reflux 8% 8%
dry mouth 9% 14%
sweating 7% 7%
insomnia 19% 20%
drowsiness 12% 11%
anxiety 12% no data available
agitation no data available 8%
nervousness 13% no data available
dizziness 9% 12%
tremor 9% 9%
headache 21% no data available
weakness/lack of energy 11% no data available
flu-like symptoms 5% no data available
decreased sex drive no data available 6%
failure to ejaculate no data available 8%

Warnings

When people are ready to come off their antidepressant medications, they should do so gradually. Stopping Prozac, Zoloft, or any other antidepressant abruptly can cause discontinuation symptoms.

Discontinuation symptoms may include:

  • dysphoria, or general unease and dissatisfaction
  • irritability
  • agitation
  • dizziness
  • electric shock sensations
  • anxiety
  • confusion
  • headaches
  • lethargy
  • emotional lability, or rapid and exaggerated changes in mood
  • sleeplessness

Several short-term studies have shown that children, adolescents, and young adults under 24 years old have an increased risk of suicidal thoughts and behaviors when taking any antidepressants.

Doctors will monitor people taking Prozac, Zoloft, or any other antidepressant for worsening of depressive symptoms, suicidal thoughts, and unusual behaviors.

People with glaucoma and a history of seizures should use Prozac, Zoloft, and other SSRIs with caution because the drugs can make these conditions worse.

Suicide prevention

  • If you know someone at immediate risk of self-harm, suicide, or hurting another person:
  • Call 911 or the local emergency number.
  • Stay with the person until professional help arrives.
  • Remove any weapons, medications, or other potentially harmful objects.
  • Listen to the person without judgment.
  • If you or someone you know is having thoughts of suicide, a prevention hotline can help. The National Suicide Prevention Lifeline is available 24 hours a day at 1-800-273-8255.

Interactions

SSRIs, including Prozac and Zoloft, have similar drug interactions.

Serotonin syndrome

prozac vs zoloft agitated

Feelings of agitation and restlessness can indicate serotonin syndrome.

Serotonin syndrome is a potentially life-threatening interaction that occurs as a result of combining drugs that increase serotonin in the body.

Doctors should avoid prescribing Prozac, Zoloft, and other SSRIs alongside the following drugs:

  • triptans
  • tricyclic antidepressants (TCAs)
  • fentanyl
  • lithium
  • tramadol
  • tryptophan
  • buspirone
  • amphetamines
  • St. John’s wort
  • monoamine oxidase inhibitors (MAOIs)

Some of the signs and symptoms of serotonin syndrome include:

  • agitation
  • anxiety
  • restlessness
  • disorientation
  • sweating
  • a high body temperature
  • increased heart rate
  • nausea
  • vomiting
  • shaking
  • muscle rigidity
  • overactive reflexes
  • abnormal muscle contractions
  • dilated pupils
  • abnormal eye movements
  • dry mucous membranes
  • flushed skin
  • increased bowel sounds

MAOIs

People cannot take MAOIs, another type of antidepressant, with Prozac, Zoloft, or any other SSRIs because the risk of developing serotonin syndrome is very high.

Anyone taking an MAOI must stop taking it at least 2 weeks before starting SSRI treatment.

QT prolongation

Doctors have reported QT prolongation in people taking Prozac and Zoloft. QT prolongation is a potentially fatal heart rhythm dysfunction.

This heart condition is more common in people who take other drugs that can prolong the QT interval on an electrocardiograph. These include certain antipsychotics, antibiotics, and anti-arrhythmic medications.

Abnormal bleeding

Some people can experience abnormal bleeding when combining Prozac, Zoloft, and other SSRIs with drugs that can increase bleeding, such as:

  • aspirin
  • nonsteroidal anti-inflammatories (NSAIDs)
  • warfarin
  • anticoagulants

Cost

The following table compares the lowest available prices of Prozac and Zoloft:

fluoxetine Prozac sertraline Zoloft
Capsule (30 capsules) 10 mg: $3.00
20 mg: $3.00
40 mg: $3.00
10 mg: $461.85
20 mg: $474.70
40 mg: $947.40
no information available no information available
Tablet (30 tablets) 10 mg: $4.00
20 mg: $26.76
60 mg: $96.35
no information available 25 mg: $3.99
50 mg: $7.17
100 mg: $6.52
25 mg: $313.61
50 mg: $313.61
100 mg: $313.61
Liquid oral solution (1 bottle) 120 ml: $12.81 no information available 60 ml: $25.10 60 ml: $216.18

Can you take Prozac and Zoloft together?

People should not take Prozac and Zoloft together. These drugs are in the same drug class and have the same actions. Taking both drugs will not improve symptoms but can cause additional side effects.

When people are not feeling the intended effects of either Prozac or Zoloft, the doctor may increase the dosage or alter the treatment regimen by adding another antidepressant or antipsychotic drug that has different actions on the brain.

Summary

Prozac and Zoloft are part of the same family of antidepressants, and both raise the levels of serotonin in the brain. Both drugs have FDA approval for the treatment of MDD, and they also have other approved and nonapproved uses.

The safe warnings relating to taking Prozac or Zoloft are similar, as are many of the side effects, although these can vary from person to person. Zoloft may be harsher on the stomach, while Prozac is more likely to cause headaches.

Both drugs are generally effective and safe, but people taking Prozac or Zoloft should follow up with their doctor to discuss their symptoms and side effects to ensure that they are taking the most effective dosage.

If treatment is successful, the doctor will slowly reduce the dosage if possible to eventually stop the medication. People should not abruptly stop taking Prozac or Zoloft.

via Prozac vs. Zoloft: What are the differences?

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[WEB SITE] Amitriptyline: Uses, side effects, warnings, and interactions

Amitriptyline is an antidepressant drug that doctors prescribe to treat depression. It also has off-label uses for other mental and physical health conditions.

Amitriptyline is a drug in the tricyclic antidepressant (TCA) family.

TCAs were introduced in the late 1950s as a treatment for depression. Since then, other less toxic drugs have become available. Among them are selective serotonin reuptake inhibitors, better known as SSRIs.

Doctors prescribe amitriptyline to people with depression who have not responded to other antidepressants. There are additional uses for amitriptyline that the Food and Drug Administration (FDA) have not approved.

Read on to learn more about the uses, side effects, warnings, and potential interactions of amitriptyline.

What is amitriptyline?

amitriptyline

Amitriptyline is a prescription antidepressant drug.

The structure of amitriptyline allows it to attach to receptors in the brain called alpha-adrenergic, histaminic, and muscarinic receptors. This means that amitriptyline can cause more side effects than some other TCAs.

Some examples of other drugs in the TCA class include:

  • clomipramine
  • desipramine
  • doxepin
  • imipramine
  • nortriptyline
  • protriptyline
  • trimipramine

There are six dosages of amitriptyline: 10 milligrams (mg), 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg.

Amitriptyline was once manufactured under the brand Elavil, but only generic forms of the drug are currently available.

Uses

Doctors prescribe amitriptyline to treat depression in adults.

They may also use the drug in ways that the FDA has not approved, known as off-label uses. For example, a doctor may recommend amitriptyline as an off-label treatment for:

amitriptyline headache

Taking amitriptyline can cause dizziness and drowsiness.

Amitriptyline may also cause blurred vision, urinary retention, a rapid heartbeat, and acute-angle glaucoma when it binds to muscarinic receptors in the body.

When amitriptyline attaches to histaminic receptors, it may cause sedation, confusion, and delirium.

People who have seizures should use amitriptyline with caution because it can lower the seizure threshold.

Serious cardiac side effects can occur when amitriptyline binds to alpha-adrenergic receptors in the heart. Low blood pressure upon standing and heart rate fluctuations and irregularities are some of these effects.

How to take and dosage

When treating depression with amitriptyline, doctors usually prescribe a starting dosage of 25 mg per day — at bedtime because it can cause drowsiness. For off-label uses, doctors may prescribe dosages of 10–20 mg per day.

Depending on a person’s response to the medication, the doctor may increase the dosage by 25 mg every 3–7 days. The effective dosage of amitriptyline is one that controls symptoms without causing too many side effects.

The maximum daily dosage of amitriptyline is 150–300 mg per day.

When the dosage is correct, people should notice their symptoms improving within 2–4 weeks. The doctor will recommend maintaining an effective dosage for at least 3 months to prevent symptoms from returning.

If a person wants to stop taking amitriptyline, it is important to develop a tapering schedule with a doctor to prevent withdrawal symptoms. Stopping amitriptyline abruptly can cause side effects.

What happens when you stop taking it?

It is important to gradually reduce the dosage of amitriptyline to prevent withdrawal symptoms.

Withdrawal symptoms can include:

  • nausea
  • headache
  • general discomfort

A doctor will recommend a tapering schedule. An individual approach is key because each person may have a different reaction to stopping the drug.

Keeping track of any symptoms and informing the doctor can help them judge whether to speed up or slow down the tapering.

Warnings

Short-term studies have shown that antidepressants can increase the risk of suicidal thoughts and behaviors in children, adolescents, and young adults. Research has not shown that people older than 24 years experience these or similar effects.

Before prescribing amitriptyline to a child, adolescent, or young adult, the doctor should weigh the benefits and risks carefully. During treatment, doctors and caregivers need to monitor people taking amitriptyline for worsening symptoms of depression, suicidal thoughts, and unusual behaviors.

Anyone who has experienced an allergic reaction to amitriptyline should refrain from using this drug.

If a person has a history of cardiac problems, such as arrhythmiaheart failure, or a recent heart attack, a doctor should not prescribe amitriptyline.

Anyone over 50 and anyone with a history of heart trouble will undergo an electrocardiogram before beginning amitriptyline treatment. They will repeat this test during treatment so a doctor can check for new or worsening heart conditions.

Amitriptyline can worsen existing angle-closure glaucoma, urinary retention, and seizures. It is important to discuss any symptoms with a doctor, who can rule out these issues, before beginning treatment.

Doctors should prescribe lower doses of amitriptyline to people with liver or kidney failure.

Suicide prevention

  • If you know someone at immediate risk of self-harm, suicide, or hurting another person:
  • Call 911 or the local emergency number.
  • Stay with the person until professional help arrives.
  • Remove any weapons, medications, or other potentially harmful objects.
  • Listen to the person without judgment.
  • If you or someone you know is having thoughts of suicide, a prevention hotline can help. The National Suicide Prevention Lifeline is available 24 hours a day at 1-800-273-8255.

Interactions

When a person takes amitriptyline and certain other drugs, three critical interactions can occur: monoamine oxidase inhibitor (MAOI) interactions, QT prolongation interactions, and serotonin syndrome interactions.

MAOI interactions

amitriptyline overheating fan

A person may experience an increased body temperature when taking amitriptyline.

MAOIs work by blocking the effect of the enzyme monoamine oxidase. This enzyme is responsible for breaking down monoamines in the body.

Monoamines include epinephrine, norepinephrine, dopamine, serotonin, and tyramine. When levels of these chemicals rise in the body, a person may experience:

  • increased heart rate
  • increased body temperature
  • muscle twitching
  • high blood pressure
  • agitation

MAOI drugs include :

  • isocarboxazid
  • phenelzine
  • tranylcypromine
  • selegiline

QT prolongation

The QT interval on an electrocardiogram is an important measure of the electrical conduction of the heart. When this interval lengthens, a person may experience an abnormal heart rhythm, which can lead to arrhythmia.

Amitriptyline can prolong the QT interval. Combining this drug with others that have the same effect puts a person at risk of developing arrhythmia.

Some examples of other drugs that can prolong the QT interval include:

  • astemizole
  • cisapride
  • disopyramide
  • ibutilide
  • indapamide
  • pentamidine
  • pizomide
  • procainamide
  • quinidine
  • sotalol
  • terfenadine

Serotonin syndrome

Serotonin syndrome occurs when there is too much serotonin in the body. This can cause symptoms that can range in severity from mild-to-life-threatening.

Serotonin syndrome symptoms include:

  • dilated pupils
  • flushed skin
  • dry mucous membranes
  • increased bowel sounds
  • excessive sweating
  • increased body temperature
  • a rapid heartbeat
  • muscle rigidity
  • muscle twitching
  • abnormal reflexes agitation
  • anxiety
  • restlessness
  • nausea
  • vomiting
  • tremor
  • disorientation
  • an altered mental status

Amitriptyline increases the amount of serotonin in the brain. When a person also takes other drugs that have this effect, it puts them at risk of developing serotonin syndrome.

Some other drugs that can increase the amount of serotonin in the brain include:

  • isocarboxazid
  • phenelzine
  • procarbazine
  • safinamide
  • selegiline
  • tranylcypromine

Cost

The manufacturer has discontinued the Elavil brand of amitriptyline, so only generic forms are available.

The following list shows the prices for 30 tablets of amitriptyline by dosage.

  • Amitriptyline 10 mg: $4.00
  • Amitriptyline 25 mg: $4.00
  • Amitriptyline 50 mg: $4.00
  • Amitriptyline 75 mg: $4.00
  • Amitriptyline 100 mg: $16.82
  • Amitriptyline 150 mg: $23.50

Summary

Doctors usually prescribe amitriptyline to treat depression. In addition, some off-label uses include treating anxiety, IBS, and chronic pain.

People taking amitriptyline may experience drowsiness, headaches, and dizziness, among other side effects, some of which are more severe.

Anyone taking any antidepressant should remain watchful for worsening of symptoms. Some people have experienced suicidal thoughts and behaviors while taking amitriptyline, and this requires immediate medical attention.

Also, some drugs can interact with amitriptyline. It is crucial that doctors and pharmacists carefully weigh the benefits and risks of adding amitriptyline to a person’s care plan.

 

via Amitriptyline: Uses, side effects, warnings, and interactions

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[ARTICLE] The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury – Full Text

Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4–8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing.

Therapeutic Time Window is a Key Element of Drugs to Treat TBI

Despite decades of research, there are currently no treatments for TBI other than palliative care (Diaz-Arrastia et al., 2014). The reasons for the lack of therapeutics are many; drug may have failed in clinical trials since most preclinical studies dose drugs immediately or soon after experimental TBI (Diaz-Arrastia et al., 2014). This experimental design fails to take into account the well-documented clinical phenomenon of treatment gap: the time individuals wait before seeking medical care after head trauma (Tanielian and Jaycox, 2008Demakis and Rimland, 2010). In 1991, one quarter of an estimated 1.5 million patients in America did not seek medical care after receiving a TBI that did not result in death or long-term institutionalization (Sosin et al., 1996). The multiple reasons given to postpone or avoid treatment include perceived symptom resolution, as well as the time and cost of treatment (Demakis and Rimland, 2010). Military personnel are particularly at risk for TBI. Lack of access to safe and accessible transportation for deployed military personnel can delay treatment up to 72 h after TBI (Farmer et al., 2017). Thus, treatment gap likely contributes to negative outcomes after TBI. Despite the importance of treatment gap, we know relatively little about the time course of pathophysiological events that can be successfully targeted with drugs first dosed many hours to days following TBI.

The treatment of thromboembolic stroke using tissue plasminogen activator illustrates the importance of time window in neurodegenerative diseases with a rapid onset. Thromboembolic stroke produces a complex and rapidly evolving injury with an overlapping, yet distinct, pathophysiology to TBI. Tissue plasminogen activator (t-PA) is highly effective if dosed within 4.5 h of a stroke, yet its utility drops sharply after 4.5 h due to the increased probability of hemorrhage (Ahmed et al., 2013). Despite its established ability to prevent injury, only 2–5% of stroke patients receive t-PA (Miller et al., 2011). A major reason for the limited use of t-PA is its short time window (Miller et al., 2011). The experience of clinicians with t-PA to treat stoke suggests similar difficulties will arise if drugs to treat TBI have similarly short therapeutic time windows that fall off sharply.

Since no drug has received FDA-approval, a key unanswered question is: what is a clinically relevant therapeutic window for a TBI drug? Clinical trials at designated trauma centers have enrolled patients 4–7 h after a moderate to severe TBI. Even with the high skill of the clinical staff at these trauma centers; many patients could not be enrolled because treatment could not be initiated within 4–7 h. Less specialized hospitals are likely to have even longer treatment delays. To treat the largest number of patients, a drug or drug combination will likely need to retain high efficacy when first dosed 12 h after moderate to severe TBI. In contrast to those with severe or moderate TBI, patients with mild TBI often delay seeking medical help for days after injury until their symptoms do not abate (Sosin et al., 1996Tanielian and Jaycox, 2008Demakis and Rimland, 2010). Thus, drugs will need to retain efficacy when dosed days after injury to treat large numbers of patients with mild TBI.

Traumatic brain injury has a complex pathophysiology whether initiated by a blunt impact, penetration through the skull into the brain, or exposure to explosive blast (Dixon, 2017). TBI produces mechanical injury within seconds to neurons, glia, and vessels. This primary injury rapidly triggers a secondary injury that evolves for weeks to months (Dixon, 2017). Both primary and secondary injury damages both gray and white matter. Within minutes after primary injury, neurons lose the ability to control ion homeostasis, which results in accumulation of intracellular calcium, cell depolarization, excitotoxic release of glutamate and additional disruptions of ionic gradients (Weber, 2012Guerriero et al., 2015). Impaired mitochondrial function leads to energy failure; calcium accumulation and elevated reactive oxygen species are additional early events in secondary injury (Bains and Hall, 2012Weber, 2012Hill et al., 2017). Damage to vessels reduces cerebral blood flow resulting in hypoxia, hypoglycemia, and breakdown of the blood-brain barrier (Price et al., 2016). Inflammation rapidly follows TBI and persists for weeks to months after injury (Hinson et al., 2015). Acute inflammation is initiated by release by necrotic cells of damage associated molecular patterns (DAMPS) that activate astrocytes and microglia. Release of proinflammatory cytokines and chemokines lead to further breakdown of the blood brain barrier and recruitment of peripheral inflammatory cells. Microglia and astrocyte activation occurs rapidly in both gray and white matter; neuroinflammation may become chronic and continue to injure brain for months or years after injury. Later events in secondary injury include induction of cytogenic and vasogenic edema, increased intracerebral pressure, oxidative damage and necrotic and apoptotic cell loss (Bains and Hall, 2012Hill et al., 2017). Early events in white matter include damage to axons, impaired transport and swelling. Damage to oligodendrocytes leads to demyelination and oligodendrocyte loss (Narayana, 2017). White matter damage evolves for weeks resulting in Wallerian axonal degeneration.

The pathophysiological events of secondary injury are highly interconnected. If dosed before, or soon after TBI, a variety of drugs with diverse modes of action (anti-oxidants, glutamate receptor antagonists, and anti-inflammatories) greatly limit the scope of secondary injury (Diaz-Arrastia et al., 2014). These drugs are effective despite targeting only one component of secondary injury. This suggests that, early after TBI, multiple pathophysiological events trigger the spread of secondary injury. Thus, early blockade of any one of these many injury mechanisms results in a substantial, long-term therapeutic effect. As secondary injury evolves, the efficacy of most drugs rapidly diminish through loss of drug targets; the intensification of secondary injury greatly diminishes the therapeutic effect of inhibiting one injury mechanism. Drugs that retain efficacy when dosed at longer intervals after injury may target pathophysiological events that initiate slowly after injury. Alternatively, drugs with good therapeutic windows have multiple targets that can still reduce secondary injury even after its intensification over time.

The importance of therapeutic time window in treating TBI is illustrated by comparing the preclinical testing of progesterone and CDP-choline with the design of Phase III clinical trials testing the same drugs. Progesterone was tested in two recent Phase III trials for TBI. The PROTECT III trial (NCT00822900) recruited patients with moderate to severe TBI (Glasgow Coma Score 4–12) within 4 h post-injury while the SYNAPSE trial (NCT01143064) recruited patients with severe TBI (Glasgow Coma Score < 7) within 7 h (Skolnick et al., 2014Wright et al., 2014). Both trials were unable to demonstrate a therapeutic effect for progesterone. Prior to Phase III testing, numerous laboratories demonstrated a diverse set of therapeutic effects of progesterone in multiple rodent TBI models (Stein and Sayeed, 2018). Progesterone reduced glutamate release, prevented vasogenic edema, restored the blood brain barrier, improved aerobic respiration, and increased myelin and neurotrophin synthesis. Most importantly, progesterone reduced brain damage and improved multiple functional outcomes. Few drugs have had such wide preclinical testing on so many therapeutic outcomes. Virtually all of these studies, however, first dosed progesterone within 1 h or less after injury (Stein and Sayeed, 2018). Only three studies dosed progesterone between 4 and 6 h after injury and none of these studies performed a careful analysis of how the efficacy of progesterone changed after injury (Peterson et al., 20122015). A first dose of progesterone 4 h after experimental TBI decreased gray matter damage, improved motor function and limited astrocyte activation (Peterson et al., 20122015). A first dose at 6 h produced small improvements on expression of Nogo-A, GFAP, and GAP-43 (Liu et al., 2014). None of these studies examined multiple therapeutic time windows so it remains unknown how the efficacy of progesterone changed with increasingly longer times to first dose. A study of a first dose of progesterone 1 or 6 h post-stroke showed good retention of drug efficacy in a rat cerebral ischemia model (Yousuf et al., 2014). Little is understood, however, of how the analysis of therapeutic time window in animal models of stroke tells us whether an equivalent therapeutic window exists for TBI. The PROTECT III and SYNAPSE trials provided important information of how rapidly we could recruit and treat patients after moderate to severe TBI, however, due to the lack of appropriate preclinical testing, we do not know if progesterone retained sufficient potency to treat TBI when first dosed at 4–7 h after injury.

The Phase 3 COBRIT study tested the efficacy of CDP-choline on mild, moderate and severe TBI (Zafonte et al., 2012). Most patients (86%) received drugs within the first 24 h after injury. The COBRIT study did not show improvement in any outcome measures. Compared to progesterone, there was relatively little preclinical testing of CHP-choline. Dixon et al. showed that a first dose of CDP-choline beginning 24 h after injury produced mild improvements on beam balance and beam walk, and on acquisition of Morris water maze (Dixon et al., 1997). Two additional studies that dosed CDP-choline immediately after injury reported decreased lesion volume, increased neuroprotection, improvements in neurological tests, edema and protection of the blood brain barrier (Başkaya et al., 2000Dempsey and Raghavendra Rao, 2003). A potential hypothesized mechanism of action of CDP-choline was to improve lipid metabolism, yet no study examined whether CDP-choline limited white matter injury. As with progesterone, there are no studies examining the efficacy of CDP-choline at different therapeutic time windows. Thus, inadequate drug potency at the time when patients were treated may have contributed to the futility of the PROTECT III, SYNAPSE, and COBRIT trials.

TBI Pathophysiology is a Major Determinant of Therapeutic Time Window

The speed of secondary injury after TBI results in the rapid appearance and disappearance of drug targets (Dixon, 2017). Studies of the therapeutic time windows of methyl-d-aspartate (NMDA) receptor agonists and antagonists illustrate how therapeutic time windows arise from the interaction of drugs with changes in TBI pathophysiological changes over time (Guerriero et al., 2015). Excessive glutamate release activates NMDA receptors within minutes after the onset of TBI (Guerriero et al., 2015). NMDA receptor activation produces calcium overload and activation of calcium-activated catabolic enzymes (Weber, 2012). If dosed soon after injury, NMDA antagonists prevent this calcium overload and prevent neuronal loss (Shohami and Biegon, 2013). The short therapeutic time window of NMDA receptor antagonists is the consequence of the speed of the calcium overload after TBI (Shohami and Biegon, 2013Campos-Pires et al., 2015). Ongoing secondary injury subsequently produces a long-lasting downregulation of NMDA receptor expression. The loss of NMDA receptor function impairs synaptic plasticity and results in cognitive and memory deficits. The partial NMDA receptor agonist D-cycloserine when first dosed at 24 or 72 h post-injury improves Neurological Severity Score (NSS). A first dose of d-cycloserine at 24 h PI also improved performance of hippocampal-dependent tasks (Temple and Hamm, 1996Adeleye et al., 2010Sta Maria et al., 2017). A first dose of cycloserine at 24 h post-injury was also effective in rat model of pediatric TBI (Sta Maria et al., 2017). D-cycloserine improved performance on Novel Object Recognition and produced a mild improvement in acquisition, but not retention of Morris Water Maze (Sta Maria et al., 2017). Earlier dosing of d-cycloserine was ineffective at 8 or 16 h post-injury when NMDA receptors were downregulated (Adeleye et al., 2010). Thus, the different therapeutic time windows of NMDA receptor antagonists and agonists results from the differential consequences of NMDA receptor activation after TBI (Shohami and Biegon, 2013).

Are Studies of Therapeutic Time Window in Animal Models Relevant to Human TBI?

Animal models of TBI have been invaluable for our understanding of TBI pathophysiology (Xiong et al., 2013). Most of the secondary injury events that occur in clinical TBI also occur in animal models. This has validated the use of animal models to find drug targets to treat TBI. Virtually all studies of therapeutic time window have used rodent TBI models (Table 1 and Supplementary Table 1). Studies of therapeutic time window in rodents not only assume similar TBI pathophysiology in animals and people, but that these pathophysiological events occur with similar kinetics. Both humans and rodents rapidly develop edema, elevated extracellular glutamate, excitotoxicity and elevated intracellular Ca++2 after TBI or experimental TBI (Palmer et al., 1993Bullock et al., 1995Vespa et al., 1998Markgraf et al., 2001Hutchinson, 2005Weber, 2012). The increase in reactive oxygen species and its accompanying oxidative damage also occurs rapidly in animals and people (Bains et al., 2013Cornelius et al., 2013). A variety of plasma biomarkers (GFAP, UCh-1, Tau, and S100β) show similar kinetics in rodent TBI models and clinical TBI (Mondello et al., 2016Caprelli et al., 2017Korley et al., 2018Shahjouei et al., 2018). In both human TBI and TBI animal models, there is an acute and rapid increase in the levels of pro-inflammatory markers (Clausen et al., 2018Huie et al., 2018). These data suggest that studies using rodent TBI model can provide important insights into the therapeutic window of a drug to treat clinical TBI.

Table 1. Drugs with a therapeutic time window of 12 h or greater in animal models of TBI.

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Continue —>  Frontiers | The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury | Neuroscience

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[WEB SITE] Botox® Injection: Not Just for Celebrities’ Furrows and Wrinkles – Lower Extremity Review Magazine

Not at all: Plantar fasciitis is now a proven therapeutic target for onabotulinumtoxinA. Consider its potential value for your patients.

By Benn Jason Scott Boshell, MSc, BSc (Hons)

When people hear the word “Botox,”a their immediate associations might be with facial injection as an anti-wrinkle treatment or magazine gossip on the latest celebrity to suffer a “botch job” from one-too-many injections. Prior to the modern use of this acetylcholine-blocking neurotoxin, no one other than medical professionals who used it to treat their patients really knew what Botox is. Injections were originally used to treat neurological conditions that result in spastic paralysis, such as cerebral palsy.

In addition to managing neurological conditions and, more recently, for aesthetic enhancement, Botox is now being used to treat musculoskeletal disorders. One of these conditions is plantar fasciitis, the subject of this narrative review of the literature.b

a. Botox, the registered trade name of onabotulinumtoxinA, is used in this article for ease of reading.

b. Treatment of plantar fasciitis is not a US Food and Drug Administration-approved indication for Botox®.

How can Botox injection treat plantar fasciitis?

Botox is a neurotoxin that blocks release of the neurotransmitter acetylcholine in overactive muscles. Motor neurons release acetylcholine to activate muscles at the neuromuscular junction; Botox, when injected, causes relaxation of muscles and other local soft tissue.

A body of evidence identifies tightness in calf muscles as a causative factor in plantar fasciitis.1-5 Botox injection into the calf aims to relax contracture in calf muscles, thus reducing tensile strain on the plantar fascia as a result of muscle relaxation. Additionally, Botox can be injected into the muscles of the foot to achieve the same effect.

What is the evidence for Botox injection?

Key Messages

  • Botox injection into the calf aims to relax contracture in calf muscles, thus reducing tensile strain on the plantar fascia. Botox can also be injected into muscles of the foot for the same effect.
  • Improvement in plantar fasciitis pain after Botox injection has been reported to be sustained over the long term.
  • Major adverse effects of Botox are uncommon when injections are administered by a qualified clinician.

Several clinical studies have looked at the effectiveness of Botox injection for treating plantar fasciitis.

Botox injection compared with corticosteroid injection (2013). Elizondo-Rodriguez and co-workers’ level-1, double-blind, randomized controlled trial compared Botox injection to corticosteroid injection for the treatment of plantar fasciitis.6The study randomized participants into 2 groups:

  • Group 1 (19 participants) received a Botox injection and were instructed on performing plantar fascia stretching exercises.
  • Group 2 (17 partcipants) received a corticosteroid injection and the same instructions on plantar fascia stretching exercises.

Results of treatment were recorded at 2 weeks and at 1, 2, 4, and 6 months. No significant improvement was seen in either group after the initial 2-week review. However, both groups showed significant improvement in pain scores at 1 month. At 2-, 4-, and 6-months follow-up, the Botox group had significantly better pain scores than the corticosteroid group. At the final, 6-month review, the average pain score in the Botox group was 1.1 (on a scale of 1 to 10, with 10 the “worst pain”), a reduction from 7.1 (difference of 6 points); in the corticosteroid group, the average pain score was 3.8, a reduction from 7.7 (difference of 3.9 points).

Elizondo-Rodriguez therefore concluded that Botox injection is superior to corticosteroid injection for the treatment of plantar fasciitis over the short term and mid-term. A limitation of this study is that patients were not followed over a longer period; it is not known, therefore, whether participants would have maintained their improved pain scores 12 months’ posttreatment. Longer follow-up would help ascertain whether Botox is also successful in the long-term management of plantar fasciitis.

A particular point of interest from the Elizondo-Rodriguez study is that Botox was not injected into or around the plantar fascia but into the gastrocnemius and soleus muscles. Following injection, calf muscles went into a state of relaxation, due to the effect of Botox. It is believed that this relaxation reduced additional strain on the plantar fascia that results from increased calf-muscle tension. One could argue that this approach seeks to address the purported cause of plantar fasciitis—unlike corticosteroid injection, which aims to treat symptoms.

Figure 1: Medial (a) and plantar (b) views of the injection entry point for study patients. This is at the distal aspect of the plantar-medial aspect of the calcaneus where the plantar fascia is proximal and the flexor digitorum brevis is adjacent. The X marks the most common spot injected for patients based on their maximum point tenderness. The circle around the X is a 1.5-cm radius where some patients received their injection based on their maximum point of tenderness (used with permission from reference 12).

Botox injection compared with corticosteroid injection (2012). Díaz-Llopis and colleagues also compared Botox injection with corticosteroid injection.7 Their study was likewise a randomized, controlled trial, with 28 patients in each group. As in the Elizondo-Rodriguez study,6 Díaz-Llopis found both that Botox and corticosteroid injections were successful at 1-month review; however, the difference between the 2 treatments grew at 6 months, with the Botox group continuing to improve while the steroid group grew slightly worse.

Long-term follow-up of sustained effects of Botox injection (2013). The lead Díaz-Llopis investigator and a different group of co-workers8 returned to the findings of the original Díaz-Llopis study,7 conducting a 12-month follow-up of the 2012 Botox group to determine whether reported improvements were sustained over the long term, which they were. Their findings provide evidence to support the use of Botox injection as a long-term treatment option.

(Notably, the site of the Botox injection in the 2012 Díaz-Llopis study differed from the site used in the Elizondo-Rodriguez study. Instead of injecting into calf muscles, Díaz-Llopis injected Botox into the plantar fascia attachment to the heel bone and further along the arch of the foot; they decided to use this technique based on a 2005 study by Babcock and co-workers.9 By using the same injection technique that Babcock used, Díaz-Llopis and colleagues were able to determine whether they would achieve similar success.)

Botox injection compared with corticosteroid injection (2018). In a randomized, controlled trial reported this year, Roca and co-workers found Botox superior to corticosteroid injection.10

Botox injection compared with placebo. Babcock and colleagues compared Botox injection and placebo in a double-blind, randomized, placebo-controlled study in 27 patients with plantar fasciitis.9 Results were recorded at 3 weeks and 8 weeks; improvement observed in the Botox group was significantly greater than in the placebo group. The strength of the study was limited by short-term follow-up.

Other studies have also compared Botox injection with placebo and found Botox to be significantly more effective.11,12 Ahmad and colleagues,12 in a double-blind, randomized, controlled trial of 50 patients (25 in each group) found Botox injection to be significantly superior to placebo at 6-month and 12-month reviews (Figure 1). The Botox group also showed significant reduction in plantar fascia thickness, which demonstrated healing of the degenerative plantar fascia—a finding not seen in the control group. A further benefit of Botox injection in this study was that it did not reduce heel fat-pad thickness, a commonly reported complication of corticosteroid injection.

Conversely, a similar study that compared Botox injection and placebo found only a marginal difference in improvement between the 2 groups:13 63.1% of the Botox group perceived improvement compared to 55% of the placebo group.

Botox injection compared with extracorporeal shockwave therapy (ESWT). Roca and co-workers’ study14 is interesting because ESWT has become an established, successful treatment option for plantar fasciitis.15 Because Botox injection is considered a novel treatment with less evidence of effectiveness, comparing it with an established treatment can be considered a good test of its effectiveness.

The Roca study randomized patients to 2 groups, 36 in each group. The researchers found both treatments effective—i.e., both demonstrated improved pain scores after treatment. However, ESWT came out on top, producing a greater reduction in pain than Botox injection.

A limitation of this study is that the researchers reviewed patients only 1 to 2 months after treatment. As noted, previous studies of Botox injection demonstrate continued improvement in pain score with more time. It is possible that the Botox group would have seen greater improvement in pain score if the researchers had reviewed that group at 6 and 12 months (although the same possibility can be considered for the ESWT group).

Are there risks to Botox injection?

Botox injection is generally safe; major adverse effects are uncommon when injection is administered by a suitably qualified clinician. There is a possibility (although highly unlikely) that the effect of botulinum toxin will spread to other parts of the body and cause botulism-like signs and symptoms, including:

  • muscle weakness all over the body
  • vision problems
  • difficulty speaking or swallowing
  • difficulty breathing
  • loss of bladder control.

Can a verdict be brought?

Overall, it appears that the evidence for Botox injection as a treatment for plantar fasciitis is sufficiently strong to support its use. Nearly all current studies of moderate- to high-quality  demonstrate significant success with this treatment option.

Despite that conclusion, Botox injection is not a commonly used treatment option and—in the United Kingdom—is not widely available for treating plantar fasciitis; in the United States, Botox injection is not indicated by the Food and Drug Administration for treating plantar fasciitis. Nevertheless, Botox injection deserves greater study and consideration for its applicability to clinical practice for treating plantar fasciitis. This therapy might replace commonly used corticosteroid injection for plantar fasciitis, which has 1) a lower success rate over the long term and 2) an increased risk of harmful effects, including plantar fascia rupture.

The most effective Botox injection technique remains in question. In most studies, plantar fascia and surrounding tissue were injected directly; in some, calf muscles were injected. To determine which technique is better, it will be necessary to conduct a head-to-head trial of these 2 techniques.

Benn Jason Scott Boshell MSc, BSc (Hons) is clinical lead podiatrist at Hatt Health & Movement Clinic, Devizes, United Kingdom.

Source:
https://lermagazine.com/article/botox-injection-not-just-for-celebrities-furrows-and-wrinkles

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[Abstract] Pharmacology and epilepsy : update on the new antiepileptic drugs

New antiepileptic drugs are regularly approved for treatment and offer large therapeutic opportunities. Efficacy of these drugs is relatively similar on-label with different mechanisms to be combined for a synergic effect. Treatments such as cannabidiol have benefitted from large media coverage despite limited clinical evidence so far. The objective of antiepileptic drugs is to stop the recurrence of epileptic seizures with as few adverse events as possible. When confronted to a difficult-to-treat epilepsy, referral to a specialised centre is strongly advised. The aim is to confirm that the diagnosis is correct, that the treatment is well adapted (indication, pharmacokinetic and compliance) and to evaluate the indication for non-pharmacological treatments such as epilepsy surgery.

 

via [Pharmacology and epilepsy : update on the new antiepileptic drugs]. – Abstract – Europe PMC

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