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Toxicology Letters Dec 2023Many xenobiotics are non-genotoxic carcinogens (NGC) in rodent liver. Their mode of action (MoA) and health risks for humans are unclear and no in-vitro tests are...
Many xenobiotics are non-genotoxic carcinogens (NGC) in rodent liver. Their mode of action (MoA) and health risks for humans are unclear and no in-vitro tests are available to predict NGC. Human HepaRG™ cells in the differentiated (d-HepaRG) and non-differentiated state (nd-HepaRG) were studied as new approach methodology (NAM) for NGC. Cell-biological assays were performed with d-/nd-HepaRG and human hepatoma/hepatocarcinoma cell lines to characterize the benign/malignant phenotype. Reaction of d-/nd-HepaRG to several liver growth factors and NGC (phenobarbital, PB; cyproterone acetate, CPA; WY-14643) was compared to unaltered and premalignant rat hepatocytes in ex-vivo culture. Enzyme induction by NGC was checked by RT-qPCR/oligo-arrays. Growth, anchorage-independency, migration, clonogenicity, and in-vivo tumorigenicity of nd-HepaRG ranged between benign d-HepaRG and malignant hepatoma/hepatocarcinoma cells. All growth factors elevated DNA replication of d-/nd-HepaRG cells, similarly to unaltered/premalignant rat hepatocytes. NGC induced their prototypical enzymes in the rat and human cells, but elicited a growth response only in the unaltered/premalignant rat hepatocytes and not in human d-/nd-HepaRG cells. To conclude, a benign/premalignant phenotype of d-/nd-HepaRG cells and a reactivity towards several hepatic growth factors and NGC, as known from human hepatocytes, are essential components for an in-vitro model for early stage human hepatocarcinogenesis.The potential value as new approach methodology (NAM) for NGC is discussed.
Topics: Humans; Rats; Animals; Carcinoma, Hepatocellular; Carcinogens; Hepatocytes; Liver Neoplasms
PubMed: 37890683
DOI: 10.1016/j.toxlet.2023.10.014 -
Epilepsy & Behavior : E&B Nov 2023To assess the impact of epilepsy and antiseizure medications (ASMs) on sleep quality in people with epilepsy (PWE).
OBJECTIVE
To assess the impact of epilepsy and antiseizure medications (ASMs) on sleep quality in people with epilepsy (PWE).
METHODS
An online survey was conducted in France, Germany, Italy, Spain and the UK among PWE taking >1 ASM and matched controls. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Associations between sleep quality (global PSQI) and overall quality of life (QoL; assessed using the 12-Item Short Form Survey [SF-12]) and sleep quality and depressive symptoms (assessed using the Neurological Disorders Depression Inventory for Epilepsy [NDDI-E]) were also evaluated.
RESULTS
Overall, 500 PWE and 500 matched controls were included. PWE had significantly greater mean global PSQI scores than controls (9.32 vs 7.56; p < 0.0001), with 80% reporting a score >5 versus 66% of controls (p < 0.001). PWE experienced significantly more problems with most PSQI components than controls. Mean global PSQI scores in PWE receiving 2 versus ≥3 ASMs were 9.03 and 10.18, respectively (p < 0.004); global PSQI scores >5 were reported in 76% versus 90%, respectively (p = 0.001). Regimens containing lamotrigine or phenobarbital were associated with poorer sleep quality than those without these ASMs. In PWE, negative correlations were identified between global PSQI scores and both the SF-12 physical and mental components (Pearson's correlation coefficient [PCC], -0.61 and -0.40, respectively); NDDI-E and global PSQI scores were positively correlated (PCC, 0.6).
CONCLUSIONS
PWE experience significantly worse sleep quality than people without epilepsy, with some ASMs contributing to poorer sleep. QoL and physical and mental health were all affected by sleep quality in PWE.
Topics: Adult; Humans; Quality of Life; Epilepsy; Anticonvulsants; Sleep; Surveys and Questionnaires
PubMed: 37862873
DOI: 10.1016/j.yebeh.2023.109481 -
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 -
Epilepsy & Behavior : E&B Nov 2023This study evaluated the impact of a newly established clinic for the diagnosis of pediatric epilepsy in a resource-limited center (Ifakara, Tanzania). (Observational Study)
Observational Study
PURPOSE
This study evaluated the impact of a newly established clinic for the diagnosis of pediatric epilepsy in a resource-limited center (Ifakara, Tanzania).
METHODS
Patients aged 0-18 years referred to the Pediatric Epilepsy Unit of Saint Francis Referral Hospital were recruited. Demographic and clinical data were collected through Kobo Toolbox and analyzed through a descriptive analysis..
RESULTS
143 patients were evaluated, and for 48 of them an EEG was recorded (abnormalities were detected in 80.85% of the cases). The diagnosis of epilepsy was confirmed in 87 patients. Focal epilepsy was diagnosed in 57 patients, generalized epilepsy in 24 patients, and forms of unknown onset in 6 patients. Epilepsy was excluded for 9 children. Etiologies included hypoxic-ischemic encephalopathy (39%), central nervous system infections (3.4%), and genetic diseases (3.4%). A specific epilepsy syndrome was diagnosed in 16 patients. 74 patients were under treatment; the most used antiseizure medication (ASM) was phenobarbital (43.36%), followed by carbamazepine (16.08%), sodium valproate (11.19%), phenytoin (2.8%), and lamotrigine (0.7%). Therapeutic changes were proposed to 95 patients, more frequently consisting of withdrawing phenobarbital (39.16%), switching to sodium valproate (27.97%), switching to or adjusting carbamazepine dosage (27.27%), and starting prednisone (2.8%). 76% of the patients with confirmed epilepsy achieved complete seizure freedom at the fourth follow-up consultation.
CONCLUSIONS
Our data depicted the epilepsy spectrum and highlighted the prognostic implications of improving the availability of ASMs such as sodium valproate and second- and third-generation ones in resource-limited countries.
Topics: Child; Humans; Valproic Acid; Tanzania; Epilepsy; Anticonvulsants; Carbamazepine; Phenobarbital; Benzodiazepines
PubMed: 37776594
DOI: 10.1016/j.yebeh.2023.109454 -
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 -
Journal of Feline Medicine and Surgery Sep 2023Phenobarbital (PB) q12h is the most common treatment recommendation for cats with recurrent epileptic seizures. Medicating cats may be challenging and result in...
OBJECTIVES
Phenobarbital (PB) q12h is the most common treatment recommendation for cats with recurrent epileptic seizures. Medicating cats may be challenging and result in decreased quality of life for both cat and owner. The aim of this retrospective study was to evaluate treatment with oral PB q24h in cats with presumptive idiopathic epilepsy.
METHODS
Nine cats with presumptive idiopathic epilepsy, receiving oral PB q24h, were included in a retrospective descriptive study.
RESULTS
Seizure remission was achieved in 88% (8/9) of the cats and good seizure control in 12% (1/9) of the cats, treated with a mean dose of oral PB of 2.6 mg/kg q24h (range 1.4-3.8 mg/kg). No cats required an increase of their PB frequency at any time during a mean follow-up period of 3.5 years (range 1.1-8.0 years). No cats displayed side effects or issues with compliance at the last recorded follow-up.
CONCLUSIONS AND RELEVANCE
Once-a-day administration of PB for feline epilepsy was safe and resulted in satisfactory seizure control for the nine cats included in this study. The results of this study justify exploring this topic further in larger prospective studies.
Topics: Cats; Animals; Retrospective Studies; Prospective Studies; Quality of Life; Epilepsy; Seizures; Phenobarbital; Cat Diseases
PubMed: 37747329
DOI: 10.1177/1098612X231196806 -
Frontiers in Oncology 2023Phenobarbital (PB) is an archetypal substance used as a mouse hepatocellular carcinoma (HCC) promotor in established experimental protocols. Our previous results showed...
Phenobarbital (PB) is an archetypal substance used as a mouse hepatocellular carcinoma (HCC) promotor in established experimental protocols. Our previous results showed CAR is the essential factor for PB induced HCC promotion. Subsequent studies suggested Gadd45β, which is induced by PB through CAR activation, is collaborating with CAR to repress TNF-α induced cell death. Here, we used Gadd45β null mice (Gadd45β KO) treated with N-diethylnitrosamine (DEN) at 5 weeks of age and kept the mice with PB supplemented drinking water from 7 to 57 weeks old. Compared with wild type mice, Gadd45β KO mice developed no HCC in the PB treated group. Increases in liver weight were more prominent in wild type mice than KO mice. Microarray analysis of mRNA derived from mouse livers found multiple genes specifically up or down regulated in wild type mice but not null mice in DEN + PB groups. Further qPCR analysis confirmed two genes, Tgfbr2 and irisin/Fndc5, were up-regulated in PB treated wild type mice but no significant increase was observed in Gadd45β KO mice. We focused on these two genes because previous reports showed that hepatic Irisin/Fndc5 expression was significantly higher in HCC patients and that irisin binds to TGF-β receptor complex that includes TGFBR2 subunit. Our results revealed irisin peptide in cell culture media increased the growth rate of mouse hepatocyte-derived AML12 cells. Microarray analysis revealed that irisin-regulated genes in AML12 cells showed a significant association with the genes in the TGF-β pathway. Expression of irisin/Fndc5 and Tgfbr2 induced growth of human HCC cell line HepG2. Thus, Gadd45β plays an indispensable role in mouse HCC development regulating the irisin/Fndc5 and Tgfbr2 genes.
PubMed: 37746289
DOI: 10.3389/fonc.2023.1217847 -
Journal of Veterinary Internal Medicine 2023We describe a case of presumptive acquired systemic lupus erythematosus secondary to phenobarbital administration in a dog, which resolved with withdrawal of the drug.
CASE DESCRIPTION
We describe a case of presumptive acquired systemic lupus erythematosus secondary to phenobarbital administration in a dog, which resolved with withdrawal of the drug.
CLINICAL FINDINGS
A 3.5 year-old poodle presented to a veterinary teaching hospital for Tier 1 idiopathic epilepsy and was treated with phenobarbital. The dog experienced fever, multiple cytopenias, and proteinuria in conjunction with a positive antinuclear antibody (ANA) titer.
DIAGNOSTICS
Serial CBCs, urine protein : creatinine ratios, and sternal bone marrow aspirates were performed to evaluate improvement.
TREATMENT AND OUTCOME
Phenobarbital was withdrawn and levetiracetam initiated. All abnormalities resolved with supportive care, without initiation of immunosuppressive drugs. All cytopenias and proteinuria resolved and ANA test results became negative within 3 months. The patient recovered and did well clinically.
CLINICAL RELEVANCE
Systemic lupus erythematosus is a disease of multiple autoimmune syndromes occurring concurrently or sequentially in conjunction with the presence of circulating ANA. It has been well described in dogs as an idiopathic condition, but in human medicine may occur secondary to drug reactions (drug-associated lupus) including as a reaction to phenobarbital. The findings in our case are consistent with the criteria for drug-induced lupus in humans and we suggest it as the first report of phenobarbital-induced lupus in a dog.
Topics: Dogs; Humans; Animals; Hospitals, Animal; Hospitals, Teaching; Lupus Erythematosus, Systemic; Phenobarbital; Proteinuria; Dog Diseases
PubMed: 37737539
DOI: 10.1111/jvim.16882