Archive for category Pharmacological

[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.

References

  1. 1.

    Meador KJ, Baker GA, Browning N, et al. Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years. Neurology. 2012;78:1207–14.

  2. 2.

    Teramo K, Hiilesmaa V. Pregnancy and fetal complications in epileptic pregnancies. In: Janz D, Dam M, Bossi L, Helge H, Richens A, Schmidt D, editors. Epilepsy, pregnancy, child. New York: Raven Press; 1982. p. 53–9.

  3. 3.

    Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding. Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73:142–9.

  4. 4.

    Voinescu PE, Park S, Chen LQ, et al. Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy. Neurology. 2018;91(13):e1228–36. https://doi.org/10.1212/WNL.0000000000006240.

  5. 5.

    Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia. 2013;54:405–14.

  6. 6.

    Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs: best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49:1239–76.

  7. 7.

    Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10:609–17.

  8. 8.

    Tomson T, Battino D, Bonizzoni E, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17:530–8.

  9. 9.

    Briggs GG, Freeman RK, Towers CV. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Philadelphia: Lippincott Williams and Wilkins; 2017.

  10. 10.

    Campbell E, Kennedy F, Russell A. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry. 2014;85:1029–34.

  11. 11.

    Holmes L, Harvey E, Coull B. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344:1132–8.

  12. 12.

    Güveli BT, Rosti RO, Güzeltas A, et al. Teratogenicity of antiepileptic drugs. Clin Psychopharmacol Neurosci. 2017;15:19–27.

  13. 13.

    Meador KJ, Baker GA, Browning N, et al. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age. Brain. 2011;134:396–404.

  14. 14.

    uptodate.com. Available from: https://www.uptodate.com/contents/search. Accessed 21 June 2018.

  15. 15.

    Johnson EL, Stowe ZN, Ritchie JC, et al. Carbamazepine clearance and seizure stability during pregnancy. Epilepsy Behav. 2014;33:49–53.

  16. 16.

    Reisinger TL, Newman M, Loring DW, et al. Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy. Epilepsy Behav. 2013;29:13–8.

  17. 17.

    Battino D, Tomson T, Bonizzoni E, et al. Seizure control and treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry. Epilepsia. 2013;54:1621–7.

  18. 18.

    Thomas S, Syan U, Devi J. Predictors of seizures during pregnancy in women with epilepsy. Epilepsia. 2012;53:2010–3.

  19. 19.

    Öhman I, Sabers A, de Flon P, et al. Pharmacokinetics of topiramate during pregnancy. Epilepsy Res. 2009;87:124–9.

  20. 20.

    Patsalos PN, Gougoulaki M, Sander JW. Perampanel serum concentrations in adults with epilepsy: effect of dose, age, sex and concomitant anti-epileptic drugs. Ther Drug Monit. 2016;38:358–64.

  21. 21.

    López-Fraile IP, Cid AO, Juste AO, et al. Levetiracetam plasma level monitoring during pregnancy, delivery, and postpartum: clinical and outcome implications. Epilepsy Behav. 2009;15:372–5.

  22. 22.

    Sabers A, Buchholt J, Uldall P, et al. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47:151–4.

  23. 23.

    Sabers A, Ohman I, Christensen J, et al. Oral contraceptives reduce lamotrigine plasma levels. Neurology. 2003;61:570–1.

  24. 24.

    Vajda F, O’Brien T, Lander C, et al. The efficacy of the newer antiepileptic drugs in controlling seizures in pregnancy. Epilepsia. 2014;55:1229–34.

  25. 25.

    Öhman I, Beck O, Vitols S. Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy. Epilepsia. 2008;49:1075–80.

  26. 26.

    Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency. Neurology. 2008;70:2130–6.

  27. 27.

    Wegner I, Edelbroek P, De Haan GJ, et al. Drug monitoring of lamotrigine and oxcarbazepine combination during pregnancy. Epilepsia. 2010;51:2500–2.

  28. 28.

    Sabers A, Petrenaite V. Seizure frequency in pregnant women treated with lamotrigine monotherapy. Epilepsia. 2009;50:2163–6.

  29. 29.

    Reimers A, Brodtkorb E. Second-generation antiepileptic drugs and pregnancy: a guide for clinicians. Expert Rev Neurother. 2012;12:707–17.

  30. 30.

    Polepally AR, Pennell PB, Brundage RC, et al. Model-based lamotrigine clearance changes during pregnancy: clinical implication. Ann Clin Transl Neurol. 2014;1:99–106.

  31. 31.

    Fotopoulou C, Kretz R, Bauer S, et al. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res. 2009;85:60–4.

  32. 32.

    Tomson T, Battino D. Pharmacokinetics and therapeutic drug monitoring of newer antiepileptic drugs during pregnancy and the puerperium. Clin Pharmacokinet. 2007;46:209–19.

  33. 33.

    Novy J, Hubschmid M, Michel P, et al. Impending status epilepticus and anxiety in a pregnant woman treated with levetiracetam. Epilepsy Behav. 2008;13:564–6.

  34. 34.

    Westin A, Reimers A, Helde G, et al. Serum concentration/dose ratio of levetiracetam before, during and after pregnancy. Seizure. 2008;17:192–8.

  35. 35.

    Garrity LC, Turner M, Standridge SM. Increased levetiracetam clearance associated with a breakthrough seizure in a pregnant patient receiving once/day extended-release levetiracetam. Pharmacotherapy. 2014;34:e128–32.

  36. 36.

    Cappellari AM, Cattaneo D, Clementi E, et al. Increased levetiracetam clearance and breakthrough seizure in a pregnant patient successfully handled by intensive therapeutic drug monitoring. Ther Drug Monit. 2015;37:285–7.

  37. 37.

    Tomson T, Palm R, Källén K, et al. Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation. Epilepsia. 2007;48:1111–6.

  38. 38.

    Petrenaite V, Sabers A, Hansen-Schwartz J. Seizure deterioration in women treated with oxcarbazepine during pregnancy. Epilepsy Res. 2009;84:245–9.

  39. 39.

    Westin AA, Nakken KO, Johannessen SI, et al. Serum concentration/dose ratio of topiramate during pregnancy. Epilepsia. 2009;50:480–5.

  40. 40.

    Ornoy A, Zvi N, Arnon J, et al. The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies. Reprod Toxicol. 2008;25:388–9.

  41. 41.

    Johannessen Landmark C, Huuse Farmen A, Larsen Burns M, et al. Pharmacokinetic variability of valproate during pregnany: implications for the use of therapeutic drug monitoring. Epilepsy Res. 2018;141:31–7.

  42. 42.

    Reimers A, Helde G, Becser Andersen N, et al. Zonisamide serum concentrations during pregnancy. Epilepsy Res. 2018;144:25–9.

  43. 43.

    Oles KS, Bell WL. Zonisamide concentrations during pregnancy. Ann Pharmacother. 2008;42:1139–41.

  44. 44.

    Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44:989–1008.

  45. 45.

    Wegner I, Edelbroek P, Bulk S, et al. Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives. Neurology. 2009;73:1388–93.

  46. 46.

    Herzog AG, Blum AS, Farina EL, et al. Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use. Neurology. 2009;72:911–4.

  47. 47.

    Thangaratinam S, Marlin N, Newton S, et al. AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies. Health Technol Assess. 2018;22:1–152.

  48. 48.

    FDA, CDER, CVM. Bioanalytical method validation guidance for industry. Silver Spring: Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) and Center for Veterinary Medicine (CVM); 2018.

  49. 49.

    EMA. Guideline on bioanalytical method validation. Eur Med Agency Comm Med Prod Hum Use. 2015;44:1–23.

  50. 50.

    Art. 3 van het Besluit Geneesmiddelenwet. 2018. Available from: http://wetten.overheid.nl/BWBR0021672/2018-01-01#Paragraaf2. Accessed 22 Nov 2019.

  51. 51.

    Sabers A. Algorithm for lamotrigine dose adjustment before, during, and after pregnancy. Acta Neurol Scand. 2012;126:e1–4.

  52. 52.

    European Medicines Agency. New measures to avoid valproate exposure in pregnancy endorsed. London: European Medicines Agency (EMA); 2018. p. 1–4.

  53. 53.

    International League Against Epilepsy (ILAE) and European Academy of Neurology (EAN). Valproate in the treatment of epilepsy in women and girls. Pre-publication summary of recommendations from a joint Task Force of ILAE-Commission on European Affairs and European Academy of Neurology (EAN). 2018. Available from: https://www.ilae.org/files/ilaeGuideline/ValproateCommentILAE-0315.pdf. Accessed 22 Nov 2019.

  54. 54.

    Hernandez-Diaz S, Smith C, Shen A. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78:1692–9.

  55. 55.

    Patsalos PN, Zugman M, Lake C, et al. Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: a comparison of free non-protein-bound concentrations. Epilepsia. 2017;58:1234–43.

  56. 56.

    Kacirova I, Grundmann M, Brozmanova H. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in maternal and umbilical cord blood at birth: influence of co-administration of valproic acid or enzyme-inducing antiepileptic drugs. Epilepsy Res. 2016;122:84–90.

  57. 57.

    de Leon J, Spina E, Diaz FJ. Clobazam therapeutic drug monitoring: a comprehensive review of the literature with proposals to improve future studies. Ther Drug Monit. 2013;35:30–47.

  58. 58.

    Burns M, Baftiu A, Opdal M, et al. Therapeutic drug monitoring of clobazam and its metabolite: impact of age and comedication on pharmacokinetic variability. Ther Drug Monit. 2016;38:350–7.

  59. 59.

    Shorvon S, Perucca E, Engel J Jr. The treatment of epilepsy. 4th ed. Chichester: Wiley; 2016.

  60. 60.

    Kacirova I, Grundmann M, Brozmanova H. Serum levels of lamotrigine during delivery in mothers and their infants. Epilepsy Res. 2010;91:161–5.

  61. 61.

    Lyseng-Williamson K, Yang L. Spotlight on topiramate in epilepsy. CNS Drugs. 2008;22:171–4.

  62. 62.

    Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia. 2007;48:435–41.

  63. 63.

    Kawada K, Itoh S, Kusaka T, et al. Pharmacokinetics of zonisamide in perinatal period. Brain Dev. 2002;24:95–7.

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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.

 

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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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[WEB PAGE] What are the benefits of increased GABA levels in the brain?

Gamma-aminobutyric acid (GABA) is a neurotransmitter, or chemical messenger, in the brain. It blocks specific signals in the central nervous system, slowing down the brain. This provides a protective and calming effect on the brain and body.

The body produces GABA, and it may also be present in some fermented foods, such as kimchi, miso, and tempeh. These are not foods that most people include in their daily diets, so some people take GABA supplements to achieve the benefits.

In this article, we examine how increased levels of GABA may impact the brain and body, and whether taking GABA supplements could have the same benefits.

What is GABA?

a couple looking relaxed because of gaba activity.

GABA activity can relieve stress, reduce stress, and improve sleep.

GABA is a neurotransmitter that inhibits or slows the brain’s functions. This activity produces effects such as:

  • relieving anxiety
  • reducing stress
  • improving sleep
  • preventing brain damage

The brain naturally releases GABA at the end of a day to promote sleepiness and allow a person to rest. Some of the medications doctors prescribe to induce sleep and reduce anxiety may also increase the action of GABA.

Medical benefits of increased GABA

Some experts have suggested that increased levels of GABA may have benefits, but the evidence is not clear. According to a 2019 review, GABA has anti-microbial, anti-seizure, and antioxidant properties and may help treat and prevent conditions such as:

Medications to increase GABA

Doctors may prescribe medicines that increase the amount of GABA or stimulate the same neurotransmitters in the brain to treat some medical conditions, such as epilepsy.

For example, benzodiazepines (Valium, Xanax) act on many of the same neurotransmitter receptors as GABA. According to one study, people who have depression may have reduced GABA levels in the brain. The use of benzodiazepines may be beneficial in those instances.

Doctors also prescribe the medication gabapentin (Neurontin), which is chemically similar to GABA to reduce seizures and muscle pain.

However, doctors are not clear whether the therapeutic effects of these medications are related to their effect on GABA receptors or whether they work in other ways.

GABA as a supplement

a woman enjoying the benefits of taurine in an energy drink she is drinking

Many sports drinks contain GABA.

Some people take supplements of GABA for their supposed stress- and anxiety-relieving benefits.

The Food and Drug Administration (FDA) has approved GABA for use as a supplement and as a food additive. Manufacturers may add GABA to:

  • sports drinks
  • snack bars
  • chewing gum
  • candies, and more

Manufacturers produce GABA supplements by fermenting a form of lactic acid bacteria.

However, the FDA do not regulate dietary supplements in the same way as medications. Therefore, consumers should exercise caution as to where they purchase the product from and only buy from reputable vendors and companies.

How to use GABA supplements

Some people may take a supplement in pill form, while others may add it to foods, such as protein drinks.

Researchers have not established a daily recommended intake or a suggested upper limit for GABA. Anyone wanting to take GABA as a supplement should consider talking to their doctor first.

At present, there is not enough research to evaluate the possible side effects of taking GABA supplements. However, if a person does experience side effects that might be GABA-related, they should discontinue the use of the supplement and contact their doctor.

Benefits of taking GABA supplements

Some researchers have voiced concerns about the supposed positive benefits of taking GABA supplements. An article in the journal Frontiers in Psychology notes that experts remain unclear whether GABA offers real benefits or whether the effects that people report experiencing are a placebo response.

Other researchers do not believe that GABA supplements cross the blood-brain barrier, which they would have to do to have any effect on the body.

However, some studies report positive effects from taking GABA supplements. These include:

Enhanced thinking and task performance abilities

study from 2015 found that taking 800 milligrams (mg) of GABA supplementation per day enhanced a person’s ability to prioritize and plan actions. Although the study was small, involving just 30 healthy volunteers, it showed how GABA supplementation might promote enhanced thinking.

Stress reduction

An older study from 2012 found that taking 100 mg of GABA daily helped reduce stress due to mental tasks. Like many other studies related to GABA, the study was small and involved just 63 participants.

Workout recovery and muscle building

a man and a woman working out together outside.

GABA supplements may improve workout recovery and muscle building.

The participants performed the same resistance training exercises twice a week, and the researchers measured the results. The researchers found that the combination of whey protein and GABA increased levels of growth hormone compared to whey protein alone.

Although this was another small study, the researchers concluded that GABA supplements might help to build muscle and assist in workout recovery. They recommended that researchers conduct more studies.

Summary

GABA naturally plays an essential role in promoting sleep, relieving anxiety, and protecting the brain.

Scientists have not been able to prove the positive effects of GABA supplementation on a large scale, and their use may have limited effectiveness.

If a person has received a diagnosis for conditions such as depression, anxiety, or attention deficit hyperactivity disorder, they may wish to talk to their doctor about medically-proven treatment before taking GABA supplements.

via What are the benefits of increased GABA levels in the brain?

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[ARTICLE] Follow-up after 5.5 years of treatment with methylphenidate for mental fatigue and cognitive function after a mild traumatic brain injury – Full Text

Objective: Prolonged mental fatigue and cognitive impairments are common after a mild traumatic brain injury (TBI). This sets limits for rehabilitation and for regaining the capacity for work and participation in social life.

Method: This follow-up study, over a period of approximately 5.5 years was designed to evaluate the effect and safety of methylphenidate treatment for mental fatigue after a mild TBI. A comparison was made between those who had continued, and those who had discontinued the treatment. The effect was also evaluated after a four-week treatment break.

Results: Significant improvement in mental fatigue, depression, and anxiety for the group treated with methylphenidate (p < .001) was found, while no significant change was found for the group without methylphenidate. The methylphenidate treatment group also improved their processing speed (p = .008). Withdrawal produced a pronounced and significant deterioration in mental fatigue, depression, and anxiety and a slower processing speed. This indicates that the methylphenidate effect is reversible if discontinued and that continued methylphenidate treatment can be a prerequisite for long-term improvement. The effect was found to be stable and safe over the years.

Conclusion: We suggest methylphenidate to be a possible treatment option for patients with post-TBI symptoms including mental fatigue and cognitive symptoms.

Introduction

Long-term mental fatigue and cognitive impairment are common after a mild, moderate or severe traumatic brain injury (TBI) and these can have a significant impact on work, well-being and quality of life (1). Fatigue and concentration deficits are acknowledged as being one of the most distressing and long-lasting symptoms following mild TBI (1). There is currently no approved treatment (2), although the most widely used research drug for cognitive impairments after TBI is methylphenidate (3). A few studies have used methylphenidate for mental fatigue after TBI with promising results including our own (4,5). Other clinical trials of drugs have reported improvements in mental fatigue ((−)-osu6162 (6)) or none ((−)-osu616, modafinil (79)).

In our feasibility study of methylphenidate (not placebo controlled) we reported decreased mental fatigue, improved processing speed and enhanced well-being with a “normal” dose of methylphenidate compared to no methylphenidate for people suffering from post-traumatic brain injury symptoms (4). We tested methylphenidate in two different dosages and found that the higher dose (20 mg three times/day) had the better effect compared to the lower dose. We also found methylphenidate to be well tolerated by 80% of the participants. Adverse events were reported as mild and the most commonly reported side-effects included restlessness, anxiety, headache, and increased heart rate; no dependence or misuse were detected (10). However, a careful monitoring for adverse effects is needed, as many patients with TBI are sensitive to psychotropic medications (11).

Participants who experienced a positive effect with methylphenidate were allowed to continue the treatment. We have reported the long-term positive effects on mental fatigue and processing speed after 6 months (12) and 2 years (13). No serious adverse events were reported (13)(Figure 1). In a 30-week double-blind-randomized placebo-controlled trial, Zhang et al. reported that methylphenidate decreased mental fatigue and improved cognitive function in the participants who had suffered a TBI. Moreover, social and rehabilitation capacity and well-being were improved (5). Other studies evaluating methylphenidate treatment after TBI have focused only on cognitive function reporting improved cognitive function with faster information processing speed and enhanced working memory and attention span (1421). A single dose of methylphenidate improved cognitive function and brain functionality compared to placebo in participants suffering from post-TBI symptoms (22,23). Most of these have been short-term studies covering a period between 1 day and 6 weeks and included participants suffering from mild or more severe brain injuries.

This clinical follow-up study was designed to evaluate the long-term effect and safety of methylphenidate treatment. We also evaluated the effect after a four-week treatment break and compared the subjective and objective effects with and without methylphenidate. Patients who had discontinued methylphenidate during this long-term study were also included in this follow-up, as it was our intention to compare the long-term effects on mental fatigue in patients with and without methylphenidate treatment.

[…]

 

Continue —->  Follow-up after 5.5 years of treatment with methylphenidate for mental fatigue and cognitive function after a mild traumatic brain injury: Brain Injury: Vol 0, No 0

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[NEWS] Botox is Now Approved for Lower-Limb Spasticity in Children

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The US Food and Drug Administration (FDA) has approved onabotulinumtoxinA (Botox, Allergan) to ease lower-limb spasticity in children and adolescents aged 2 years to 17 years, excluding spasticity caused by cerebral palsy (CP), Allergan announces.

“Lower limb spasticity can impact many aspects of a child’s life and have a drastic influence on their overall development and quality of life,” David Nicholson, Allergan’s chief research and development officer, says in a news release.

The FDA approved Botox for lower-limb spasticity on the basis of safety and efficacy data from a phase 3 study involving more than 300 children aged 2 years or older with lower-limb spasticity.

Participants in the trial had CP, but the approved indication excludes lower-limb spasticity caused by CP, owing to marketing exclusivity by another company, according to Allergan.

The approved recommended dose per treatment session is 4 to 8 units/kg divided among affected muscles of the lower limb. The total dose for pediatric patients should not exceed 8 units/kg body weight, or 300 units, whichever is lower.

When treating both lower limbs or upper and lower limbs in combination, the total dose for pediatric patients should not exceed 10 units/kg, or 340 units, whichever is lower, in a 3-month interval, the company states.

“Pediatric lower limb spasticity inhibits normal muscular movement and function and can result in delayed or impaired motor development, as well as difficulty with posture and positioning,” Mark Gormley, Jr, MD, of Gillette Children’s Specialty Healthcare–St. Paul, comments, in the release.

“Botox has a well-established safety and efficacy profile, and supports children and adolescents successfully manage both their upper and lower limb spasticity,” said Gormley.

Botox was approved for pediatric upper-limb spasticity in June.

[Source: Medscape]

 

via Botox is Now Approved for Lower-Limb Spasticity in Children – Rehab Managment

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[WEB PAGE] Dysport is Now Approved for Upper Limb Spasticity as Well

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The United States Food and Drug Administration (FDA) has expanded the use of Dysport (abobotulinumtoxinA) for injection to include the treatment of upper limb spasticity in children two years of age and older, excluding spasticity caused by cerebral palsy (CP), Ipsen Biopharmaceuticals, an affiliate of Ipsen, announces in a news release.

This approval makes Dysport the first botulinum toxin approved by the FDA for both pediatric spasticity indications, following the previous approval to treat children with lower limb spasticity aged two and older received in July 2016.

“For physicians, it is reassuring to have a botulinum toxin treatment in Dysport which demonstrated sustained symptom relief for spasticity, which can be physically challenging for children,” says Ann Tilton, MD, study investigator and Professor of Clinical Neurology at the Louisiana State University Health Sciences Center New Orleans, in the release.

“This FDA decision for Dysport means we now have an approved therapy to offer children and adolescents seeking improvements in mobility in both upper and lower limbs.”

The approval is based on a Phase 3 study with children aged two to 17 years old being treated for upper limb spasticity. Due to Orphan Drug Exclusivity, this approval excludes use in children with upper limb spasticity caused by CP. Dysport demonstrated statistically significant improvements from baseline at Week 6 with doses of 8 Units/kg and 16 Units/kg vs. 2 Units/kg, as measured by the Modified Ashworth Scale (MAS) in the elbow or wrist flexors.

Dysport demonstrated a reduction in spasticity symptoms through 12 weeks for most children for both upper and lower limbs. In the upper limb study, a majority of patients were retreated between 16-28 weeks; however, some patients had a longer duration of response (ie, 34 weeks or more). The most frequent adverse reactions observed were upper respiratory tract infection and pharyngitis, the release explains.

“This approval is a testament to Ipsen’s legacy in neurotoxin research and continued commitment to advancing patient care,” states Kimberly Baldwin, Vice President, Franchise Head, Neuroscience Business Unit, Ipsen. “We believe the data for both pediatric upper and lower limb spasticity underscore the role of Dysport as an important treatment option for patients seeking long-lasting spasticity symptom relief.”

For more information, visit Ipsen.

[Source(s): Ipsen, Business Wire]

 

via Dysport is Now Approved for Upper Limb Spasticity as Well – Rehab Managment

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[BLOG POST] Benefits Of Magnesium For Traumatic Brain Injury treatment

magnesium tabletMagnesium is a vital nutrient that the human body requires in order to function healthily. It’s important for a range of bodily processes, including regulating nerve functions, blood sugar levels, blood pressure, and making protein, bone, and DNA. It’s one of the 24 essential vitamins and minerals critical for a healthy body.

Magnesium cannot be produced by the body itself – in other words, it needs to be sourced elsewhere, such as from food or supplements. The levels of magnesium needed for each person varies on gender, age and size. However, when a Traumatic Brain Injury occurs, magnesium becomes a nutrient you should strive for with its many mental and physical health benefits.

Many ordinary people today use Magnesium supplements to help with their energy, flexibility, muscle strength, and even sleep or stress management. In particular, people who have a love for fitness or sports take regular Magnesium tablets to assist with recovery and performance.

 

So, what could it do for TBI?

Magnesium For TBI
Following a traumatic brain injury, the side effects of anxiety, stress, brain swelling, cramping and tightening of muscles, stiff muscles, and insomnia are quite possible.

That’s where magnesium comes in to save the day.

Increase Flexibility, Decrease Tone, Reduce
Considering magnesium can assist with flexibility and loosening tight muscles, increasing your magnesium intake after a traumatic brain injury can likely help alleviate your stiff, cramped muscles.

Low magnesium levels can also cause a large build-up of lactic acid, which results in workout pain and tightness.

Taking magnesium for this particular problem allows your muscles to relax correctly before and after exercise.

 

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Stress & Anxiety
Magnesium can also help to control stress hormones. Serotonin, in particular, depends on magnesium for production.

This is responsible for relaxing your nervous system and encouraging positive moods, thus stabilizing you mentally.

Low magnesium levels are linked with anxiety behaviours and heightened stress – all the more reason to ensure you are taking in adequate amounts after your injury.

Brain Swelling
Magnesium is an anti-inflammatory, and as such, it can help to reduce brain swelling from a traumatic brain injury.

It increases cardiac output and cerebral blood flow. When the body has appropriate levels of it circulating throughout the body, people can experience improved neurological and cognitive outcomes.

It has also shown to possibly reduce pain intensity and headache severity.

Insomnia
Serotonin also helps encourage a good night sleep. Low magnesium levels can affect the sleep-regulating hormone melatonin, too.

Insomnia is indeed a common symptom of magnesium deficiency seen in many people today. They experience restless sleep and constant waking during the night, which leads to unhealthy sleep.

By maintaining the correct magnesium levels, people can enjoy deep, undisturbed sleep. Along with the melatonin, magnesium plays a role in maintaining healthy levels of “GABA” which is a neurotransmitter that promotes optimal sleep quality.

How To Take Magnesium

Magnesium can be taken in the form of a tablet supplement, but there are many magnesium-rich foods that can be incorporated into your daily diet, as well.

Try this list of power foods to hit your daily magnesium intake.

Dark leafy green vegetables
Flax seeds and pumpkin seeds
Almonds
Seaweed
Brown rice
Avocado’s
Walnuts, cashews, pecans

 

Other Sources of Magnesium

Magnesium Cream: Magnesium cream delivers the nutrients full spectrum of benefits, soothes muscle tension and increases flexibility in the applied area.

Magnesium Oil: Magnesium oil is  a no mess, easy-to-absorb, form of magnesium that may be able to raise levels of this nutrient within the body when applied topically to the skin.

 

In Conclusion

Ensuring that you have optimal levels of magnesium is the first step towards a healthy recovery following TBI.

It will help your muscles improve in flexibility, reduce pain, balance hormone levels, encourage positive moods, and sleep more soundly.

via Benefits Of Magnesium For Traumatic Brain Injury – treatment

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