scholarly journals Anticonvulsive Effects and Pharmacokinetic Profile of Cannabidiol (CBD) in the Pentylenetetrazol (PTZ) or N-Methyl-D-Aspartate (NMDA) Models of Seizures in Infantile Rats

2021 ◽  
Vol 23 (1) ◽  
pp. 94
Author(s):  
Libor Uttl ◽  
Tomáš Hložek ◽  
Pavel Mareš ◽  
Tomáš Páleníček ◽  
Hana Kubová
Keyword(s):  
Seizure Activity ◽  
Motor Impairment ◽  
Pharmacokinetic Profile ◽  
Generalized Seizures ◽  
Chemically Induced ◽  
Righting Reflex ◽  
Motor Tests ◽  
Old Rats ◽  
Therapeutic Doses ◽  
Patients With Epilepsy

In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1–2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 hour after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined.

Epilepsy in Nicolaides–Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects

2021 ◽  
Author(s):  
Benedikt Hofmeister ◽  
Celina von Stülpnagel ◽  
Cornelia Betzler ◽  
Francesca Mari ◽  
Alessandra Renieri ◽  
...  
Keyword(s):  
Neurodevelopmental Outcome ◽  
Initial Response ◽  
Clinical Findings ◽  
Generalized Seizures ◽  
Parent Support Group ◽  
Anticonvulsive Drugs ◽  
Epilepsy Classification ◽  
Structural Epilepsy ◽  
Patients With Epilepsy ◽  
Electroencephalogram Eeg

AbstractNicolaides–Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via “Network Therapy of Rare Epilepsies (NETRE)” and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy.

scholarly journals Non-Traditional Administration of Remifentanil in an Experimental Setting

2019 ◽  
pp. S97-S103
Author(s):  
A. KURZOVÁ ◽  
J. MÁLEK ◽  
L. HESS ◽  
M. JAČEK ◽  
J. SLÍVA
Keyword(s):  
Arterial Oxygen Saturation ◽  
Pharmacokinetic Profile ◽  
Rapid Onset ◽  
Arterial Oxygen ◽  
Onset Of Action ◽  
Routes Of Administration ◽  
Arterial Blood ◽  
Pharmacokinetic Properties ◽  
Righting Reflex ◽  
Cardiovascular Functions

Remifentanil is ultrashort-acting opioid with a unique pharmacokinetic profile. It is used exclusively intravenously. While considering its rapid onset of action and other pharmacokinetic properties, we decided to assess its effects following administration via non-traditional routes. Rabbits (n=10 per each group) were randomized into six groups: remifentanil 1 μg/kg and 3 μg/kg IM, 5.0 and 10.0 μg/kg conjunctivally, and 10 μg/kg and 25.0 μg/kg intranasally. Sedating effects were assessed via a loss of the righting reflex. Secondary, mean arterial blood pressure, arterial oxygen saturation of hemoglobin, and pulse rate was monitored in all rabbits. Non-traditional routes of administration were shown to provide a rapid onset of action as well as fast recovery. Importantly, the administration of remifentanil did not result in any deterioration of cardiovascular functions.

Neonatal phenobarbital-induced defects in age- and sex-specific growth hormone profiles regulating monooxygenases

1995 ◽  
Vol 268 (3) ◽  
pp. E439-E445 ◽  
Author(s):  
A. K. Agrawal ◽  
N. A. Pampori ◽  
B. H. Shapiro
Keyword(s):  
Growth Hormone ◽  
Sexually Dimorphic ◽  
Transient Effects ◽  
Neonatal Administration ◽  
Old Rats ◽  
The Mean ◽  
Therapeutic Doses ◽  
Induced Defects ◽  
Hexobarbital Metabolism ◽  
Hepatic Monooxygenases

Growth hormone was secreted in sexually dimorphic patterns in both 65- and 150-day-old rats (i.e., "on-off" pulsatile for males and "continuous" pulsatile for females), but as a result of a 200-400% increase in pulse levels the mean concentration of hormone in the circulation was about two times as great in the younger animals. Neonatal exposure to phenobarbital at anticonvulsant therapeutic doses for the rat reduced the pulse amplitudes of circulating growth hormone in both the 65- and 150-day-old males but only in the 65-day-old females. As expected, neonatal administration of the barbiturate produced an almost immediate increase in the activities of the hepatic monooxygenases, as measured by hexobarbital metabolism, which declined to noninduction levels after treatment ceased. Contrary to the well-known transient effects of phenobarbital, at around the time of sexual maturity when gender-dependent differences in hepatic monooxygenases appear (males > females), we observed a second "round" of enzyme induction that persisted in both sexes for the remainder of the study (180 days). Because growth hormone is the primary regulator of sex-dependent hepatic monooxygenases, we have proposed that the abnormal plasma growth hormone profiles produced by neonatal phenobarbital are responsible for the permanent induction of hepatic monooxygenases.

scholarly journals Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice

2018 ◽  
Vol 115 (36) ◽  
pp. 9002-9007 ◽  
Author(s):  
Te-Chen Tzeng ◽  
Yuto Hasegawa ◽  
Risa Iguchi ◽  
Amy Cheung ◽  
Daniel R. Caffrey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Seizure Activity ◽  
Synaptic Proteins ◽  
Amyloid Peptide ◽  
Spine Density ◽  
Central Neurons ◽  
Chemically Induced ◽  
Neuronal Transmission ◽  
Selective Increase

Alzheimer’s disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD.

A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats

2010 ◽  
Vol 25 (2) ◽  
pp. 92-100 ◽  
Author(s):  
G. Marchese ◽  
B. Pittau ◽  
G. Casu ◽  
G. Peddio ◽  
G.P. Spada ◽  
...  
Keyword(s):  
Motor Impairment ◽  
Receptor Occupancy ◽  
Immediate Release ◽  
Pharmacokinetic Profile ◽  
Continuous Administration ◽  
Release Formulation ◽  
Antipsychotic Efficacy ◽  
Drug Concentrations ◽  
Oral Antipsychotic ◽  
Novel Antipsychotic

AbstractIt is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D2-receptor occupancy by antipsychotics within the striatum must exceed 60−65%. However, at high levels of D2-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D2-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak−trough fluctuations and consistent D2-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.

scholarly journals Spatial Neglect Predicts Upper Limb Use in the Activities of Daily Living

2017 ◽  
Vol 44 (3-4) ◽  
pp. 122-127 ◽  
Author(s):  
Tim Vanbellingen ◽  
Beatrice Ottiger ◽  
Noortje Maaijwee ◽  
Tobias Pflugshaupt ◽  
Stephan Bohlhalter ◽  
...  
Keyword(s):  
Activities Of Daily Living ◽  
Upper Limb ◽  
Daily Living ◽  
Motor Impairment ◽  
Spatial Neglect ◽  
Time Interval ◽  
Observation Scale ◽  
Initial Severity ◽  
Motor Tests ◽  
Time Of Admission

Background and Purpose: Motor tests performed at stroke onset have been shown to predict the recovery of upper limb motor impairment. Less is known about upper limb recovery at the level of functional activity or of participation and how spatial neglect may influence the integration of the upper limb in the activities of daily living (ADL). Our objective was to investigate whether the initial severity of spatial neglect may predict upper limb use in ADL. Methods: Eighty-two patients with a right-hemispheric stroke (RHS) were prospectively included in the study. They were assessed twice in the acute/subacute and in the subacute/chronic phases (mean time interval of 45 days) after stroke. The Catherine Bergego Scale (CBS) was used to quantify the influence of spatial neglect on the ADL. Contralesional upper limb use in the ADL was evaluated with the Lucerne international classification of function, disability and health-based Multidisciplinary Observation Scale. Hand strength was measured using the Jamar, dexterity with the Nine Hole Peg test, and tactile perception using the stereognosis subtest of the Nottingham Sensory Assessment. Cognitive functions were assessed with the Montreal Cognitive Assessment. Results: Regression analyses revealed that spatial neglect is an independent and a significant predictor of upper limb outcome. A CBS score of ≤5 at the time of admission to neurorehabilitation care was highly predictive for good upper limb use in the ADL 45 days later. Conclusions: This study demonstrates that spatial neglect severity, as observed in the ADL, is a significant and an independent predictor of upper limb outcome. Neglect therapy is thus needed to further improve contralesional upper limb use in the ADL in RHS patients.

The Controversy over Generic Antiepileptic Drugs

2010 ◽  
Vol 15 (2) ◽  
pp. 81-93 ◽  
Author(s):  
Susan J. Shaw ◽  
Adam L. Hartman
Keyword(s):  
Antiepileptic Drugs ◽  
Generic Substitution ◽  
Patent Protection ◽  
Cost Savings ◽  
Pharmacokinetic Profile ◽  
Test Procedures ◽  
Rigorous Study ◽  
Clinically Significant ◽  
Few Data ◽  
Patients With Epilepsy

ABSTRACT As patent protection ends for the next generation of antiepileptic drugs (AEDs), a complex debate continues over generic substitution of AEDs. On one hand, generic drug formulations provide cost savings for patients and society. On the other hand, patients with epilepsy and physicians are wary about the adequacy and efficacy of the Food and Drug Administration's (FDA) standards for generics. This article reviews current and proposed bioequivalence test procedures, summarizes new generic AED formulations and their costs, and discusses potential pitfalls in the current standards. These shortcomings include certain pharmacokinetic factors and clinical pharmacologic factors that may affect bioequivalence of generic AEDs, and statistical limitations of the standards. While the drug concentration differences between the brand name drug and each generic formulation are unlikely to be substantial, the differences with generic-to-generic switches will be greater and potentially clinically significant. Conversely, owing to their more favorable pharmacokinetic profile, newer AEDs may be less prone to problems with generic substitution than older ones. Unfortunately, very few data are available to guide decisions regarding what is best for an individual patient. Based on new prediction methods, generic substitution should be safe for many patients but identifying them ultimately requires more rigorous study.

scholarly journals Midline (central) fluid percussion model of traumatic brain injury in pediatric and adolescent rats

2018 ◽  
Vol 22 (1) ◽  
pp. 22-30 ◽  
Author(s):  
Rachel K. Rowe ◽  
Jordan L. Harrison ◽  
Timothy W. Ellis ◽  
P. David Adelson ◽  
Jonathan Lifshitz
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Late Onset ◽  
Human Condition ◽  
Acute Injury ◽  
Behavioral Deficits ◽  
Fluid Percussion ◽  
Skull Size ◽  
Righting Reflex ◽  
Old Rats

OBJECTIVEExperimental traumatic brain injury (TBI) models hold significant validity to the human condition, with each model replicating a subset of clinical features and symptoms. TBI is the leading cause of mortality and morbidity in children and teenagers; thus, it is critical to develop preclinical models of these ages to test emerging treatments. Midline fluid percussion injury (FPI) might best represent mild and diffuse clinical brain injury because of the acute behavioral deficits, the late onset of behavioral morbidities, and the absence of gross histopathology. In this study, the authors sought to adapt a midline FPI to postnatal day (PND) 17 and 35 rats. The authors hypothesized that scaling the craniectomy size based on skull dimensions would result in a reproducible injury comparable to the standard midline FPI in adult rats.METHODSPND17 and PND35 rat skulls were measured, and trephines were scaled based on skull size. Custom trephines were made. Rats arrived on PND10 and were randomly assigned to one of 3 cohorts: PND17, PND35, and 2 months old. Rats were subjected to midline FPI, and the acute injury was characterized. The right reflex was recorded, injury-induced apnea was measured, injury-induced seizure was noted, and the brains were immediately examined for hematoma.RESULTSThe authors’ hypothesis was supported; scaling the trephines based on skull size led to a reproducible injury in the PND17 and PND35 rats that was comparable to the injury in a standard 2-month-old adult rat. The midline FPI suppressed the righting reflex in both the PND17 and PND35 rats. The injury induced apnea in PND17 rats that lasted significantly longer than that in PND35 and 2-month-old rats. The injury also induced seizures in 73% of PND17 rats compared with 9% of PND35 rats and 0% of 2-month-old rats. There was also a significant relationship between the righting reflex time and presence of seizure. Both PND17 and PND35 rats had visible hematomas with an intact dura, indicative of diffuse injury comparable to the injury observed in 2-month-old rats.CONCLUSIONSWith these procedures, it becomes possible to generate brain-injured juvenile rats (pediatric [PND17] and adolescent [PND35]) for studies of injury-induced pathophysiology and behavioral deficits, for which rational therapeutic interventions can be implemented.

Generalized Convulsions in a Patient Receiving Ultrashort-Acting Beta-Blocker Infusion

1988 ◽  
Vol 22 (6) ◽  
pp. 484-485 ◽  
Author(s):  
Gopal Das ◽  
Janine C. Ferris
Keyword(s):  
Heart Disease ◽  
Beta Blocker ◽  
Blocking Agent ◽  
Literature Survey ◽  
Receptor Blocking ◽  
Blocking Agents ◽  
Beta Receptor ◽  
Generalized Seizures ◽  
Beta Blocking ◽  
Therapeutic Doses

Beta-receptor blocking agents are commonly used to treat patients with heart disease, and generalized seizures due to therapy with these agents are rare. All reported cases of seizures due to beta blocking agents have occurred only in those subjects who ingested large doses of the drugs. We observed generalized convulsions in a patient who was receiving therapeutic doses of an ultrashort-acting beta-blocking agent (esmolol hydrochloride) intravenously. A literature survey and possible mechanisms by which these agents induce seizures are presented.

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