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Children (Basel, Switzerland) Aug 2023Crigler-Najjar Syndrome (CNS) with residual activity of UDP-glucuronosyltransferase 1A1 () and no need for daily phototherapy is called mild Crigler-Najjar Syndrome....
Crigler-Najjar Syndrome (CNS) with residual activity of UDP-glucuronosyltransferase 1A1 () and no need for daily phototherapy is called mild Crigler-Najjar Syndrome. Most of these patients need medical treatment for enzyme induction (phenobarbital) to lower blood levels of unconjugated bilirubin (UCB). Apart from this, no long-term problems have been described so far. The phenotype of patients with the homozygous pathogenic variant c.115C>G p.(His39Asp) in UGT1A1 is described as variable. Clinical observations of our patients led to the assumption that patients with variant c.115C>G have a mild CNS phenotype while having a high risk of developing progressive liver disease. For mild CNS disease, progressive liver disease has not been described so far. Therefore, we conducted a retrospective multicenter analysis of 14 patients with this particular variant, aiming for better characterization of this variant. We could confirm that patients with variant c.115C>G have a high risk of progressive liver disease (seven of fourteen), which increases with age despite having a very mild CNS phenotype. Earlier predictors and causes for an unfavorable disease course are not detectable, but close follow-up could identify patients with progressive liver disease at the beginning. In conclusion, these patients need close and specialized follow-up. Our study questions whether fibrosis in the CNS is really driven by high amounts of UCB or phototherapy.
PubMed: 37761392
DOI: 10.3390/children10091431 -
Pharmaceutical Research Nov 2023The unbound brain extracelullar fluid (brain) to plasma steady state partition coefficient, K, values provide steady-state information on the extent of blood-brain...
INTRODUCTION
The unbound brain extracelullar fluid (brain) to plasma steady state partition coefficient, K, values provide steady-state information on the extent of blood-brain barrier (BBB) transport equilibration, but not on pharmacokinetic (PK) profiles seen by the brain targets. Mouse models are frequently used to study brain PK, but this information cannot directly be used to inform on human brain PK, given the different CNS physiology of mouse and human. Physiologically based PK (PBPK) models are useful to translate PK information across species.
AIM
Use the LeiCNS-PK3.0 PBPK model, to predict brain extracellular fluid PK in mice.
METHODS
Information on mouse brain physiology was collected from literature. All available connected data on unbound plasma, brain PK of 10 drugs (cyclophosphamide, quinidine, erlotonib, phenobarbital, colchicine, ribociclib, topotecan, cefradroxil, prexasertib, and methotrexate) from different mouse strains were used. Dosing regimen dependent plasma PK was modelled, and Kpuu,BBB values were estimated, and provided as input into the LeiCNS-PK3.0 model to result in prediction of PK profiles in brain.
RESULTS
Overall, the model gave an adequate prediction of the brain PK profile for 7 out of the 10 drugs. For 7 drugs, the predicted versus observed brain data was within two-fold error limit and the other 2 drugs were within five-fold error limit.
CONCLUSION
The current version of the mouse LeiCNS-PK3.0 model seems to reasonably predict available information on brain from healthy mice for most drugs. This brings the translation between mouse and human brain PK one step further.
Topics: Humans; Blood-Brain Barrier; Brain; Extracellular Fluid; Models, Biological; Pharmacokinetics; Quinidine; Animals; Mice
PubMed: 37442882
DOI: 10.1007/s11095-023-03554-5 -
Journal of Veterinary Internal Medicine Jun 2024Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy.
BACKGROUND
Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy.
HYPOTHESIS/OBJECTIVES
Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs.
ANIMALS
Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam.
METHODS
Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction.
RESULTS
The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 μg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified.
CONCLUSION AND CLINICAL IMPORTANCE
Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital.
PubMed: 38888491
DOI: 10.1111/jvim.17128 -
Iranian Journal of Allergy, Asthma, and... Apr 2024There are limited data on severe cutaneous adverse reactions (SCARs) associated with antiepileptic medications. The current study aims to investigate the clinical and...
BACKGROUND
There are limited data on severe cutaneous adverse reactions (SCARs) associated with antiepileptic medications. The current study aims to investigate the clinical and epidemiological characteristics of antiepileptic medication-induced SCARs in hospitalized children.
MATERIALS AND METHODS
The current five-year retrospective study was conducted at Isfahan University of Medical Sciences, Iran. This study included all children with a definite diagnosis of SCARs secondary to the use of antiepileptic medications based on the world health organization (WHO) definition. In our study SCARs were categorized into three fields: Hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).
RESULTS
Among 259 children with SCARs induced by antiepileptic medications, 199 (76.83%), 42 (16.22%), and 18 (6.95%) had hypersensitivity syndrome, DRESS, and SJS/TEN, respectively. Phenobarbital was the most common offending drug in all types of SCARs. The multinomial logistic regression model revealed that lymphadenopathy increased the occurrence of DRESS by 35 times compared to hypersensitivity syndrome (P < 0.001). Girls were at risk of SJS/TEN approximately 6 times more than boys (P = 0.027). Age (P = 0.021), weight (P = 0.036), and mucosal involvement (P < 0.001) affected the hospitalization duration in children with SCARs related to antiepileptic medication.
CONCLUSION
There are some similarities and differences in the clinical and epidemiological features of Iranian children suffering from antiepileptic medication-induced SCARs.
Topics: Humans; Anticonvulsants; Female; Male; Child; Retrospective Studies; Child, Preschool; Iran; Stevens-Johnson Syndrome; Drug Hypersensitivity Syndrome; Adolescent; Infant; Child, Hospitalized; Hospitalization; Risk Factors
PubMed: 38822509
DOI: 10.18502/ijaai.v23i2.15320 -
Molecules (Basel, Switzerland) Apr 2024Two series, "" and "", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their...
Two series, "" and "", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, - and -, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "" series, particularly for compound .
Topics: Anticonvulsants; Animals; Mice; Seizures; Receptors, GABA-A; Pentylenetetrazole; Quinazolinones; Molecular Docking Simulation; Male; Structure-Activity Relationship; Molecular Dynamics Simulation; Computer Simulation; Disease Models, Animal; Molecular Structure; Allosteric Site
PubMed: 38731442
DOI: 10.3390/molecules29091951 -
Arquivos de Neuro-psiquiatria Aug 2023Epilepsy is a common neurological disease that affects people all over the world, but it is rarely described in indigenous peoples.
BACKGROUND
Epilepsy is a common neurological disease that affects people all over the world, but it is rarely described in indigenous peoples.
OBJECTIVE
To study the epilepsy characteristics and risk factors for seizure control in people from an isolated indigenous population.
METHODS
This is a retrospective and historical cohort study conducted from 2003 to 2018 (15 years), at a neurology outpatient clinic, of 25 Waiwai tribes' indigenous individuals with epilepsy, inhabitants of an isolated forest reserve in the Amazon. Clinical aspects, background, comorbidities, exams, treatment, and response were studied. Factors that impacted seizure control over 24 months were identified using Kaplan-Meier curves and Cox and Weibull regression models.
RESULTS
The majority of cases started in childhood, with no difference regarding gender. Focal epilepsies were predominant. Most patients had tonic-clonic seizures. A quarter of them had a family history, and 20% had referred febrile seizures. There was intellectual disability in 20% of patients. Neurological examination and psychomotor development were altered in one third of the participants. The treatment controlled 72% of the patients (monotherapy in 64%). Phenobarbital was the most prescribed anti-seizure medication, followed by carbamazepine and valproate. The most relevant factors that impacted seizure control over time were abnormal neurological exam and family history.
CONCLUSION
Family history and abnormal neurological exam were predicted risk factors for refractory epilepsy. Even in an isolated indigenous tribe, the partnership between the indigenous people and the multidisciplinary team ensured treatment adherence. The public healthcare system must guarantee modern anti-seizure medications, mainly for this vulnerable population, which has no other source of treatment.
Topics: Humans; Anticonvulsants; Epilepsy, Generalized; Brazil; Cohort Studies; Follow-Up Studies; Retrospective Studies; Epilepsy
PubMed: 37402399
DOI: 10.1055/s-0043-1769125 -
Journal of the Neurological Sciences Feb 2024Nodding Syndrome is a poorly understood epilepsy disorder in sub-Saharan Africa. The cause(s) of the disease, risk factors and long-term outcomes are unknown or... (Observational Study)
Observational Study
Nodding Syndrome is a poorly understood epilepsy disorder in sub-Saharan Africa. The cause(s) of the disease, risk factors and long-term outcomes are unknown or controversial. The objectives of this study were to describe the long-term clinical course and treatment outcomes of individuals suffering from Nodding Syndrome. In addition, we aimed to provide a comprehensive characterization of the epileptological and social features of patients with Nodding Syndrome. From 11/2014 to 4/2015, we conducted a hospital-based, cross-sectional and observational study in Mahenge, Tanzania. Seventy-eight individuals (female:male ratio: 40:38, age at examination: 21.1 ± 6.39 (SD) years) have been enrolled, of whom 38 (49%) had also been examined in 2005 and in 2009. The 10-year clinical course analysis of this revisited subgroup revealed a calculated case fatality of 0.8-2.3%. Progressive physical or cognitive deterioration has not been observed in any of the 78 individuals and more than half of the people studied (38/69; 55%) managed to live and work independently. 14/78 individuals (18%) were seizure-free, (no head nodding, no other seizure types), 13 of whom were taking antiseizure medication. Phenytoin was more effective against head nodding seizures (14/19 (74%)) than monotherapy with other available antiseizure medication (phenobarbitone 12/25 (48%) and carbamazepine 7/22 (32%), p = 0.02, chi-square test). Our ten-year clinical outcome data show that Nodding Syndrome is not a fatal disease, however, the response to treatment is worse than in epilepsy patients in general. Phenytoin may be more effective than carbamazepine and phenobarbitone, but further studies are needed to confirm this observation.
Topics: Humans; Male; Female; Anticonvulsants; Phenytoin; Nodding Syndrome; Cross-Sectional Studies; Epilepsy; Phenobarbital; Carbamazepine; Treatment Outcome; Benzodiazepines; Disease Progression
PubMed: 38278097
DOI: 10.1016/j.jns.2024.122893 -
Indian Journal of Pharmacology 2023The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain...
Study of fingolimod, nitric oxide inhibitor, and P-glycoprotein inhibitor in modulating the P-glycoprotein expression via an endothelin-sphingolipid pathway in an animal model of pharmacoresistant epilepsy.
BACKGROUND
The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present study explored the effect of fingolimod (FTY720) acting through an endothelin-sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats.
MATERIALS AND METHODS
PTZ kindling (30 mg/kg; i.p.) and PB (40 mg/kg; orally) were used to develop an animal model of refractory epilepsy. The effect of Fingolimod on seizure score (Racine scale), plasma and brain levels of PB (high-performance liquid chromatography), and blood-brain barrier permeability (Evans blue dye) was determined. Further, Fingolimod's neuroprotective effect was determined by measuring the levels of various inflammatory cytokines, oxidative stress parameters, and neurotrophic factors in rat brain homogenate. The Fingolimod's effect on P-gp expression was estimated by reverse transcriptase-polymerase chain reaction and immunohistochemistry in rat brain. The H and E staining was done to determine the neuronal injury.
RESULTS
Fingolimod significantly (P < 0.001) reduced the seizure score in a dose-dependent manner and alleviated the blood-brain barrier permeability. It decreased the P-gp expression, which further increased the brain PB concentration. Fingolimod significantly (P < 0.01) reduced oxidative stress as well as inflammation. Moreover, it attenuated the raised neuronal injury score in a resistant model of epilepsy.
CONCLUSION
The modulation of the P-gp expression by Fingolimod improved drug delivery to the brain in an animal model of refractory epilepsy. Therefore, S1P signaling could serve as an additional therapeutic target to overcome refractoriness.
Topics: Animals; Humans; Rats; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistant Epilepsy; Endothelins; Fingolimod Hydrochloride; Models, Animal; Nitric Oxide; Pentylenetetrazole; Seizures; Sphingolipids
PubMed: 37929409
DOI: 10.4103/ijp.ijp_100_23 -
BMC Pediatrics Nov 2023Empyema as a rare cause of respiratory distress in neonatal period has not yet been reported after Corona virus disease 2019 (COVID-19) and even rarely in the context of...
BACKGROUND
Empyema as a rare cause of respiratory distress in neonatal period has not yet been reported after Corona virus disease 2019 (COVID-19) and even rarely in the context of bacterial infections is age group.
CASE PRESENTATION
The first neonate of quadruplets, resulting from Cesarean-Section of a 30-year-old mother without a history of previous illness, born at 34 weeks of gestation with a birth weight of 1600 gram. All four newborns were hospitalized; while the first one underwent nasal continuous positive airway pressure (N-CPAP) with a positive end-expiratory pressure of 6 and fractional inspired oxygen of 0.6, due to respiratory distress, noting a respiratory score of five out of 12.She was resuscitated one hour later due to bradycardia and underwent ventilator support. She received a single dose of pulmonary surfactant, intravenous paracetamol, and phenobarbital due to respiratory distress syndrome, Pectus Ductus Arteriosus, and unilateral clonic movements, respectively. In the lack of positive blood culture, she extubated two days later and breast-feeding was started. On day eight, she underwent high flow nasal cannula. On day 12, she suddenly developed respiratory distress, mottling, and abdominal distension, leading to N-CPAP and re-evaluation. The nasopharyngeal sampling for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) real time Polymerase chain reaction and the blood culture for staphylococcus aurous became positive. A large volume pleural effusion including septa and loculation in right hemi-thorax on chest computerized tomography scan and ultrasound was seen, necessitating to thoracotomy, which was not possible due to her general condition. Remdesivir was started and antibiotics changed to a more broad-spectrum coverage. Chest tube was inserted and Alteplase was injected for three consecutive days with beneficial effects. She had no problem for six-month follow up.
CONCLUSION
This was a case of empyema thoracic in the context of SARS-CoV-2 and Staphylococcus arouses co-infection. In our experience, it can be treated by chest drainage and fibrinolysis in neonatal period.
Topics: Pregnancy; Female; Humans; Infant, Newborn; Adult; SARS-CoV-2; COVID-19; Fibrinolysis; Staphylococcus; Continuous Positive Airway Pressure; Empyema; Pleural Effusion; Respiratory Distress Syndrome; Dyspnea
PubMed: 37923992
DOI: 10.1186/s12887-023-04375-6 -
Pharmacological Reports : PR Dec 2023Overwhelming evidence indicates that some naturally occurring coumarins and terpenes are widely used in folk medicine due to their various therapeutic effects affecting...
Anticonvulsant effects of isopimpinellin and its interactions with classic antiseizure medications and borneol in the mouse tonic-clonic seizure model: an isobolographic transformation.
BACKGROUND
Overwhelming evidence indicates that some naturally occurring coumarins and terpenes are widely used in folk medicine due to their various therapeutic effects affecting the brain. Antiseizure medications (ASMs) are the principal treatment option for epilepsy patients, although some novel strategies based on naturally occurring substances are intensively investigated. This study was aimed at determining the influence of isopimpinellin (ISOP-a coumarin) when administered either separately or in combination with borneol (BOR-a monoterpenoid), on the antiseizure potencies of four classic ASMs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA)) in the mouse model of maximal electroshock-induced (MES) tonic-clonic seizures.
MATERIALS
Tonic-clonic seizures were evoked experimentally in mice after systemic (ip) administration of the respective doses of ISOP, BOR, and classic ASMs. Interactions for two-drug (ISOP + a classic ASM) and three-drug (ISOP + BOR + a classic ASM) mixtures were assessed isobolographically in the mouse MES model.
RESULTS
ISOP (administered alone) had no impact on the anticonvulsant potencies of four classic ASMs. Due to the isobolographic transformation of data, the combination of ISOP + VPA exerted an antagonistic interaction, whereas the two-drug mixtures of ISOP + CBZ, ISOP + PHT, and ISOP + PB produced additive interactions in the mouse MES model. The three-drug combinations of ISOP + BOR with CBZ and PHT produced additive interactions, while the three-drug combinations of ISOP + BOR with PB and VPA exerted synergistic interactions in the mouse MES model.
CONCLUSIONS
The most intriguing interaction was that for ISOP + VPA, for which the addition of BOR evoked a transition from antagonism to synergy in the mouse MES model.
Topics: Humans; Animals; Mice; Anticonvulsants; Drug Interactions; Seizures; Carbamazepine; Phenobarbital; Phenytoin; Electroshock; Drug Combinations; Disease Models, Animal; Dose-Response Relationship, Drug
PubMed: 37821793
DOI: 10.1007/s43440-023-00532-x