RESUMEN
Hypoxic-ischemic encephalopathy is the most common cause of neonatal seizures. Continuous electroencephalographic monitoring is recommended given high rates of subclinical seizures. Prompt diagnosis and treatment of seizures may improve neurodevelopmental outcomes. International League Against Epilepsy guidelines indicate that (1) phenobarbital remains the first-line treatment of neonatal seizures and (2) early discontinuation of antiseizure medications following resolution of acute provoked seizures, and prior to discharge home, is recommended. Long-term follow-up of these infants is necessary to screen for postneonatal epilepsy and support neurodevelopment.
Asunto(s)
Anticonvulsivantes , Electroencefalografía , Hipoxia-Isquemia Encefálica , Fenobarbital , Convulsiones , Humanos , Hipoxia-Isquemia Encefálica/terapia , Recién Nacido , Anticonvulsivantes/uso terapéutico , Convulsiones/tratamiento farmacológico , Fenobarbital/uso terapéuticoRESUMEN
Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy, disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs-midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM)-were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), and hypoxia plus TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (predose) and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, and 24 hours post drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and noncompartmental PK analysis. The study showed a statistically significant decrease in FNT clearance (CL; 66% decrease), with an approximately threefold longer half-life (t1/2) in the TH group. The H+TH group showed a 17% reduction in FNT CL, with a 62% longer t1/2 compared with the C group; however, it was not statistically significant. Although not statistically significant, trends toward lower CL and longer t1/2 were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared with controls. SIGNIFICANCE STATEMENT: The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK using four model drugs. Such insights can subsequently be used to inform and develop a physiologically based pharmacokinetic model, which is useful for drug exposure prediction in human neonates.
Asunto(s)
Animales Recién Nacidos , Asfixia Neonatal , Hipotermia Inducida , Midazolam , Porcinos Enanos , Animales , Porcinos , Hipotermia Inducida/métodos , Asfixia Neonatal/terapia , Asfixia Neonatal/tratamiento farmacológico , Masculino , Midazolam/farmacocinética , Fenobarbital/farmacocinética , Fentanilo/farmacocinética , Modelos Animales de Enfermedad , Recién Nacido , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/metabolismo , HumanosRESUMEN
BACKGROUND: Lacosamide (LCM) is a third-generation antiseizure medication (ASM) currently approved for the treatment of focal seizures in children aged greater than one month. There are limited data on its efficacy in the neonatal age group. We describe our experience with LCM as an adjunct ASM for the treatment of neonatal seizures. METHODS: A retrospective chart review over a five-year period (2018 to 2022) was conducted at Le Bonheur Children's Hospital to identify neonates with electroencephalography (EEG)-proven seizures who were treated with LCM. Data were collected on electroclinical seizure characteristics, underlying etiology, ASMs, treatment response, and any adverse effects. RESULTS: A total of 15 neonates with EEG-confirmed seizures who were treated with LCM were included. Ten neonates achieved seizure cessation after LCM was added to their ASM regimen consisting of phenobarbital, levetiracetam, or both. No new treatment-related adverse effects were noted. CONCLUSIONS: LCM is effective as an adjunct treatment for neonatal seizures. Randomized controlled studies are needed to establish its effectiveness and adequate dosing regimen in this population.
Asunto(s)
Anticonvulsivantes , Electroencefalografía , Lacosamida , Convulsiones , Humanos , Lacosamida/administración & dosificación , Lacosamida/farmacología , Estudios Retrospectivos , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacología , Recién Nacido , Masculino , Convulsiones/tratamiento farmacológico , Femenino , Quimioterapia Combinada , Fenobarbital/administración & dosificación , Fenobarbital/uso terapéutico , Levetiracetam/administración & dosificación , Levetiracetam/farmacologíaRESUMEN
BACKGROUND: Status epilepticus (SE) is potentially life-threatening, however, it is unclear which antiepileptic drugs (AEDs) should be used as second-line AEDs. OBJECTIVE: We conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing multiple second-line AEDs for SE to investigate the efficacy of AEDs. METHODS: We searched MEDLINE, CENTRAL, ClinicalTrials.gov, and World Health Organization International Clinical Trials Platform Search Portal and included RCTs for patients aged ≥15 years with SE on December 31, 2023. We compared multiple second-line AEDs for SE including fosphenytoin (fPHT), lacosamide (LCM), levetiracetam (LEV), phenytoin (PHT), phenobarbital (PHB), and valproate (VPA). The primary and secondly outcomes were termination of seizures integrating the absence of seizure recurrence at 30 min and 60 min, and adverse events associated with AEDs, respectively, with expressing as relative risk (RR) with a 95% confidence interval (CI). We conducted a NMA using frequentist-based approach with multivariate random effects, and assessed the certainty based on the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: Seven RCTs (n = 780) were included, and statistically significant difference was detected between VPA vs. PHB (RR, 0.67; 95% CI, 0.53-0.85; very low certainty), fPHT vs. PHB (RR, 0.66; 95% CI, 0.48-0.90; very low certainty), LCM vs. PHB (RR, 0.62; 95% CI, 0.41-0.93; very low certainty), and LEV vs. PHB (RR, 0.69; 95% CI, 0.51-0.94; very low certainty). Moreover, PHB was the highest in the ranking for termination of seizures. For adverse events, no significant reduction was observed owing to the selection of AEDs, although the ranking of PHB was the lowest. CONCLUSIONS: PHB may have been the most effective for seizure termination as second-line AEDs in adult patients with SE. However, the certainty of almost all comparisons was "very low", and careful interpretation is essential.
Asunto(s)
Anticonvulsivantes , Metaanálisis en Red , Prohibitinas , Estado Epiléptico , Estado Epiléptico/tratamiento farmacológico , Humanos , Anticonvulsivantes/uso terapéutico , Levetiracetam/uso terapéutico , Fenitoína/uso terapéutico , Fenitoína/análogos & derivados , Adulto , Lacosamida/uso terapéutico , Ácido Valproico/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Fenobarbital/uso terapéuticoRESUMEN
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 (R2 = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R2 = 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.
Asunto(s)
Anticonvulsivantes , Enfermedades de los Perros , Epilepsia , Levetiracetam , Levetiracetam/uso terapéutico , Levetiracetam/sangre , Animales , Perros , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/sangre , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/sangre , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Epilepsia/veterinaria , Epilepsia/tratamiento farmacológico , Epilepsia/sangre , Estudios Retrospectivos , Femenino , Masculino , Fenobarbital/uso terapéutico , Fenobarbital/sangre , Estudios de Cohortes , Piracetam/análogos & derivados , Piracetam/uso terapéutico , Piracetam/sangre , Piracetam/administración & dosificación , Relación Dosis-Respuesta a DrogaRESUMEN
Pethoxamid (PXA) is a chloroacetamide herbicide that works by inhibiting the germination of target weeds in crops. PXA is not a genotoxic agent, however, in a two-year chronic toxicity study, incidence of thyroid follicular cell hyperplasia was observed in male rats treated at a high dose. Many non-mutagenic chemicals, including agrochemicals are known to produce thyroid hyperplasia in rodents through a hepatic metabolizing enzyme induction mode of action (MoA). In this study, the effects of oral gavage PXA treatment at 300 mg/kg for 7 days on the disposition of intravenously (iv) administered radio-labeled thyroxine ([125I]-T4) was assessed in bile-duct cannulated (BDC) rats. Another group of animals were treated with phenobarbital (PB, 100 mg/kg), a known enzyme inducer, serving as a positive control. The results showed significant increase (p < 0.01) in the mean liver weights in the PB and PXA-treated groups relative to the control group. The serum total T4 radioactivity Cmax and AUC0-4 values for PB and PXA-treated groups were lower than for the control group, suggesting increased clearance from serum. The mean percentages of administered radioactivity excreted in bile were 7.96 ± 0.38%, 16.13 ± 5.46%, and 11.99 ± 2.80% for the control, PB and PXA groups, respectively, indicating increased clearance via the bile in the treated animals. These data indicate that PXA can perturb the thyroid hormone homeostasis in rats by increasing T4 elimination in bile, possibly through enzyme induction mechanism similar to PB. In contrast to humans, the lack of high affinity thyroid binding globulin (TBG) in rats perhaps results in enhanced metabolism of T4 by uridine diphosphate glucuronosyl transferase (UGT). Since this liver enzyme induction MoA for thyroid hyperplasia by PB is known to be rodent specific, PXA effects on thyroid can also be considered not relevant to humans. The data from this study also suggest that incorporating a BDC rat model to determine thyroid hormone disposition using [125I]-T4 is valuable in a thyroid mode of action analysis.
Asunto(s)
Herbicidas , Hígado , Ratas Sprague-Dawley , Tiroxina , Animales , Tiroxina/sangre , Masculino , Ratas , Hígado/efectos de los fármacos , Hígado/metabolismo , Herbicidas/toxicidad , Radioisótopos de Yodo , Tamaño de los Órganos/efectos de los fármacos , Fenobarbital/farmacología , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Glándula Tiroides/patologíaRESUMEN
BACKGROUND: Alcohol use is frequent in trauma patients and alcohol withdrawal syndrome (AWS) is associated with significant morbidity. Benzodiazepines are commonly used for AWS, but may cause neurologic and respiratory adverse events (AEs). The objective was to evaluate the effectiveness and safety of a phenobarbital-based protocol for the treatment of AWS in non-intensive care unit (ICU) trauma patients. METHODS: Adult non-ICU trauma patients at high risk of or experiencing AWS PRE and POST implementation of a phenobarbital-based protocol were included. Outcomes were AWS-related complications (AWS-RC), benzodiazepine use, adjunctive medication use, hospital length of stay (HLOS), and medication-related AEs. Subgroup analyses were performed on patients with traumatic brain injury (TBI), rib fractures, and at high risk of severe AWS. RESULTS: Overall, 110 patients were included (51 PRE, 59 POST). AWS-RC developed in 17 PRE patients compared to 10 POST patients (33% vs 17%; P = .05). PRE patients were more likely to receive benzodiazepines (88% vs 42%, P < .0001) and higher total dose (11 vs 4 mg lorazepam equivalent; P = .001). No difference noted in HLOS (8 vs 8 days, P = .27), adjunctive medication use (49% vs 54%, P = .60), or AEs (57% vs 39%, P = .06). There was no difference in AWS-RC in the TBI subgroup (P = .19), less AEs in the rib fracture POST subgroup (P = .04), and less AWS-RC in the high risk of severe AWS POST subgroup (P = .03). DISCUSSION: A phenobarbital-based protocol in trauma patients is effective in preventing AWS-RC and decreasing benzodiazepine use without increasing AEs.
Asunto(s)
Benzodiazepinas , Protocolos Clínicos , Fenobarbital , Humanos , Fenobarbital/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Benzodiazepinas/uso terapéutico , Estudios Retrospectivos , Heridas y Lesiones/complicaciones , Síndrome de Abstinencia a Sustancias , Hipnóticos y Sedantes/uso terapéutico , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/efectos adversos , Tiempo de Internación/estadística & datos numéricos , Lesiones Traumáticas del Encéfalo/complicaciones , Delirio por Abstinencia Alcohólica/tratamiento farmacológico , AncianoRESUMEN
OBJECTIVE: Epilepsy is a chronic disease that requires long-term monitoring and treatment. It is suspected that there is a interaction between the use of anti-seizure medications and the risk of cardiovascular disease. The aim of the study is to investigate the association between the intake of phenobarbital, carbamazepine and valproic acid and their serum drug concentrations (SDC) with various cardiovascular risk parameters (homocysteine, folic acid, vitamin B12, total cholesterol (TC), triglycerides, high- and low-density lipoprotein (LDL)). METHODS: This is a cross-sectional study. Data (demographic characteristics and laboratory results) of patients treated for epilepsy in a tertiary care hospital between January 2020 and February 2022 were analyzed retrospectively (n = 2014). Kruskal Wallis, Mann-Whitney U, correlation analysis was used, p < 0.05 was considered statistically significant. RESULTS: The median age of patients was 15 years (IQR:8-31) and 48.3 % were women. The highest homocysteine level was found in patients receiving valproic acid, but it was not statistically significant. Patients receiving phenobarbital had the highest levels of folic acid and B12 and the lowest levels of total cholesterol and low-density lipoprotein cholesterol, which was statistically significant. In patients receiving carbamazepine, a moderately negative significant association was found between serum drug concentration and folic acid levels and a moderately positive significant association was found between TC and LDL levels. CONCLUSION: In our study, the majority of patients were children and adolescents. Regular monitoring of drug serum concentrations and metabolic parameters may be useful to select the safest drug in terms of cardiovascular disease risk. Randomized controlled trials on the long-term effects of anti-seizure treatment are needed.
Asunto(s)
Anticonvulsivantes , Carbamazepina , Enfermedades Cardiovasculares , Epilepsia , Ácido Valproico , Humanos , Femenino , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/sangre , Anticonvulsivantes/efectos adversos , Estudios Transversales , Masculino , Adulto , Epilepsia/tratamiento farmacológico , Epilepsia/sangre , Adolescente , Adulto Joven , Ácido Valproico/uso terapéutico , Ácido Valproico/efectos adversos , Ácido Valproico/sangre , Enfermedades Cardiovasculares/sangre , Niño , Carbamazepina/uso terapéutico , Carbamazepina/sangre , Carbamazepina/efectos adversos , Homocisteína/sangre , Fenobarbital/uso terapéutico , Fenobarbital/sangre , Estudios Retrospectivos , Vitamina B 12/sangre , Factores de Riesgo de Enfermedad Cardiaca , Ácido Fólico/sangreRESUMEN
BACKGROUND: Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these medicines is phenobarbital, which may cause side effects in long-term consumption. Alternative drugs can be used to reduce these side effects. This study seeks the comparison of the effects of phenobarbital & levetiracetam as adjuvant therapy in neonatal abstinence syndrome. METHODS: This randomized clinical trial was performed in one year from May 2021 until May 2022. The neonates who were born from mothers with substance use disorder and had neonatal abstinence syndrome in Afzalipoor Hospital of Kerman were studied. The treatment started with morphine initially and every four hours the infants were checked. The infants who were diagnosed with uncontrolled symptoms After obtaining informed consent from the parents were randomly divided into two groups and treated with secondary drugs, either phenobarbital or levetiracetam. RESULTS: Based on the obtained results, it was clear that there was no significant difference between the hospitalization time of the two infant groups under therapy (phenobarbital: 18.59 days versus Levetiracetam 18.24 days) (P-value = 0.512). Also, there was no significant difference between both groups in terms of the frequency of re-hospitalization during the first week after discharge, the occurrence of complications, and third treatment line prescription (P-value = 0.644). CONCLUSIONS: Based on the obtained results, like hospitalization duration time (P-value = 0.512) it seems that levetiracetam can be used to substitute phenobarbital in treating neonatal abstinence syndrome. TRIAL REGISTRATION: The current study has been registered in the Iran registry of clinical trials website (fa.irct.ir) on the date 25/2/2022 with registration no. IRCT20211218053444N2.
Asunto(s)
Síndrome de Abstinencia Neonatal , Extractos Vegetales , Trastornos Relacionados con Sustancias , Recién Nacido , Lactante , Femenino , Humanos , Síndrome de Abstinencia Neonatal/tratamiento farmacológico , Síndrome de Abstinencia Neonatal/diagnóstico , Levetiracetam/uso terapéutico , Unidades de Cuidado Intensivo Neonatal , Fenobarbital/uso terapéutico , HospitalizaciónRESUMEN
This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy (PWWE). Data collected from the medical records of 224 PWWE aged < 40 years with controlled or refractory seizures and 492 pregnant women without epilepsy (PWNE) control group from high-risk maternity hospitals in Alagoas between 2008 and 2021 were included in this study. The obstetric and neonatal outcomes observed in PWWE were pregnancy-related hypertension (PrH) (18.4%), oligohydramnios (10.3%), stillbirth (6.4%), vaginal bleeding (6%), preeclampsia (4.7%), and polyhydramnios (3%). There was a greater likelihood of PrH in PWWE with generalized tonic-clonic seizures (GTCS) and that of maternal intensive care unit (ICU) admissions in those with GTCS and status epilepticus, and phenytoin and lamotrigine use. PWWE with GTCS had a higher risk of stillbirth and premature delivery. PWWE with status epilepticus were treated with lamotrigine. Phenobarbital (PB) with diazepam were commonly used in GTCS and status epilepticus. Total 14% patients did not use ASM, while 50.2% used monotherapy and 35.8% used polytherapy. Total 60.9% of patients used PB and 25.2% used carbamazepine. This study described the association between the adverse obstetric and neonatal outcomes and severe seizure types in PWWE.
Asunto(s)
Epilepsia , Estado Epiléptico , Recién Nacido , Femenino , Humanos , Embarazo , Lamotrigina/uso terapéutico , Mujeres Embarazadas , Estudios Retrospectivos , Mortinato/epidemiología , Brasil/epidemiología , Anticonvulsivantes/efectos adversos , Convulsiones/tratamiento farmacológico , Convulsiones/epidemiología , Convulsiones/inducido químicamente , Epilepsia/tratamiento farmacológico , Fenobarbital/uso terapéutico , Estado Epiléptico/inducido químicamenteRESUMEN
ABSTRACT: The authors described tacrolimus dosing in a kidney transplant patient concurrently treated with phenobarbital, where measuring the tacrolimus area under the curve was necessary to achieve adequate drug exposure and improve kidney function.
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Área Bajo la Curva , Monitoreo de Drogas , Inmunosupresores , Trasplante de Riñón , Fenobarbital , Tacrolimus , Humanos , Interacciones Farmacológicas , Monitoreo de Drogas/métodos , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Inmunosupresores/sangre , Fenobarbital/uso terapéutico , Tacrolimus/farmacocinética , Tacrolimus/uso terapéutico , Tacrolimus/sangreRESUMEN
Drug hypersensitivity reactions (DHRs) manifested as vasculitis are rare. Antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), sulphonamides, diuretics, immunosupressants and anticonvulsants are the most common culprits for drug-induced leukocytoclastic vasculitis (LCV) but there is scarce information about barbiturates. We present a case of 53-year-old female with severe vasculitis after phenobarbital- and NSAIDs-containing medications use. The preliminary diagnosis of drug-induced vasculitis was made based on anamnestic and clinical data. Further examinations confirmed the diagnosis of LCV and excluded other more common causes of vasculitis. The causative significance of used medications was assessed by long-term observation of the patient after the reaction, including the drug challenge series and Naranjo's Adverse Drug Reaction Probability Scale. It was concluded that phenobarbital is the most probable culprit drug. The patient's data were included in the Armenian Registry of Patients with Severe DHRs. Since then, the patient has avoided only barbiturate-containing drugs and no reactions were noted. Thus, the case indicates that even with limited diagnostic capabilities, the final diagnosis of rare drug-induced LCV and even rarer culprit drug can be established by comparing the available data. Awareness about phenobarbital and proper recording of the case are important in the management and prevention of DHRs manifested as vasculitis.
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Fenobarbital , Vasculitis Leucocitoclástica Cutánea , Humanos , Femenino , Fenobarbital/efectos adversos , Persona de Mediana Edad , Vasculitis Leucocitoclástica Cutánea/inducido químicamente , Anticonvulsivantes/efectos adversos , Antiinflamatorios no Esteroideos/efectos adversos , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/diagnósticoRESUMEN
Exposure at conception to phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) has been associated with several different effects on the fetus, including hypoplasia of the distal phalanges, dysmorphic facial features, and structural abnormalities such as oral clefts and neural tube defects. One question is whether each of these antiepileptic drugs (AEDs) has the same effects or just similar effects. A systematic examination of the fingers of children exposed at conception to PHT, PB, or CBZ, as monotherapy, has been used to address this question. The findings in the examinations of the fingers of 115 AED-exposed children (40, PHT; 34, PB; 41, CBZ) and their parents were compared to the findings in 111 age- and sex-matched children and their parents. The evaluations used were both subjective assessments and objective measurements. Shortening and narrowing of the fifth fingernail and an increased frequency of arch patterns in the dermal ridges were more common in PHT-exposed children. A significant decrease in the length of the nail, but not width, occurred in the PB-exposed children. Stiffness of the interphalangeal joints was more common in the CBZ-exposed children. The findings in children exposed to PHT, PB, or CBZ, as monotherapy, showed that all three exposures in early pregnancy affected the fingers, but the effects were not the same. The most striking effects were present in PHT-exposed children.
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Anticonvulsivantes , Carbamazepina , Dedos , Fenobarbital , Fenitoína , Efectos Tardíos de la Exposición Prenatal , Humanos , Carbamazepina/efectos adversos , Fenitoína/efectos adversos , Femenino , Fenobarbital/efectos adversos , Embarazo , Dedos/anomalías , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Masculino , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Niño , Anomalías Inducidas por Medicamentos/patología , Preescolar , Uñas/efectos de los fármacos , Uñas/patología , LactanteRESUMEN
Understanding cytochrome P450 (CYP) enzymes in the canine intestine is vital for predicting drug metabolism and developing safer oral medications. This study evaluates canine colonoids as a model to assess the expression and induction of essential intestinal CYP enzymes.Canine colonoids were cultured in expansion medium (EM) with Wnt-3A and in differentiation medium (DM) without Wnt-3A. We assessed the mRNA expression of CYP2B11, CYP2C21, CYP3A12, and CYP3A98 using qPCR and examined the effects of rifampicin and phenobarbital as inducers.Our findings show that DM significantly increased the mRNA expression of CYP3A98 and CYP2B11, but not CYP3A12, compared to EM. CYP2C21, not typically expressed in the intestine, remained unexpressed in colonoids. Rifampicin induced CYP3A98, aligning with pregnane x receptor (PXR) regulation, while phenobarbital did not, suggesting no constitutive androstane receptor (CAR) involvement. CYP2B11 did not respond to either inducer, suggesting alternative regulatory pathways in canine colonoids.This study is a pioneering effort to establish conditions for studying P450 expression in canine colonoids, confirming significant CYP3A98 expression in the canine intestine. It demonstrated colonoids can induce CYP activity post drug treatments. Further research is needed to enhance species-specific drug metabolism understanding and validate this model for broader applications.
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Sistema Enzimático del Citocromo P-450 , Animales , Perros , Sistema Enzimático del Citocromo P-450/metabolismo , Rifampin/farmacología , Fenobarbital/farmacología , Intestinos/efectos de los fármacos , Organoides/metabolismo , Organoides/efectos de los fármacos , Mucosa Intestinal/metabolismo , Inductores de las Enzimas del Citocromo P-450/farmacologíaRESUMEN
Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10â¯121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.
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Anomalías Inducidas por Medicamentos , Anticonvulsivantes , Epilepsia , Complicaciones del Embarazo , Humanos , Femenino , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Adulto , Embarazo , Adulto Joven , Adolescente , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Anomalías Inducidas por Medicamentos/epidemiología , Anomalías Inducidas por Medicamentos/etiología , Persona de Mediana Edad , Estudios Longitudinales , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/epidemiología , Estudios Prospectivos , Ácido Valproico/efectos adversos , Ácido Valproico/uso terapéutico , Efectos Tardíos de la Exposición Prenatal/epidemiología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Fenitoína/efectos adversos , Fenitoína/uso terapéutico , Lamotrigina/efectos adversos , Lamotrigina/uso terapéutico , Carbamazepina/efectos adversos , Fenobarbital/efectos adversos , Fenobarbital/uso terapéutico , Estudios de Cohortes , Oxcarbazepina/efectos adversos , Oxcarbazepina/uso terapéutico , PrevalenciaRESUMEN
BACKGROUND: Many anti-seizure medications (ASMs) trigger neuronal cell death when administered during a confined period of early life in rodents. Prototypical ASMs used to treat early-life seizures such as phenobarbital induce this effect, whereas levetiracetam does not. However, most prior studies have examined the effect of ASMs in naïve animals, and the degree to which underlying brain injury interacts with these drugs to modify cell death is poorly studied. Moreover, the degree to which drug-induced neuronal cell death differs as a function of sex is unknown. METHODS: We treated postnatal day 7 Sprague Dawley rat pups with vehicle, phenobarbital (75 mg/kg) or levetiracetam (200 mg/kg). Separate groups of pups were pre-exposed to either normoxia or graded global hypoxia. Separate groups of males and females were used. Twenty-four hours after drug treatment, brains were collected and processed for markers of cell death. RESULTS: Consistent with prior studies, phenobarbital, but not levetiracetam, increased cell death in cortical regions, basal ganglia, hippocampus, septum, and lateral thalamus. Hypoxia did not modify basal levels of cell death. Females - collapsed across treatment and hypoxia status, displayed a small but significant increase in cell death as compared to males in the cingulate cortex, somatosensory cortex, and the CA1 and CA3 hippocampus; these effects were not modulated by hypoxia or drug treatment. CONCLUSION: We found that a history of graded global hypoxia does not alter the neurotoxic profile of phenobarbital. Levetiracetam, which does not induce cell death in normal developing animals, maintained a benign profile on the background of neonatal hypoxia. We found a sex-based difference, as female animals showed elevated levels of cell death across all treatment conditions. Together, these data address several long-standing gaps in our understanding of the neurotoxic profile of antiseizure medications during early postnatal development.
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Anticonvulsivantes , Fenobarbital , Masculino , Animales , Ratas , Femenino , Anticonvulsivantes/farmacología , Animales Recién Nacidos , Levetiracetam/farmacología , Ratas Sprague-Dawley , Fenobarbital/farmacología , Muerte Celular , Hipoxia/tratamiento farmacológicoRESUMEN
BACKGROUND: Phenobarbital has been used in the emergency department (ED) as both a primary and adjunctive medication for alcohol withdrawal, but previous studies evaluating its impact on patient outcomes are limited by heterogenous symptom severity. OBJECTIVES: We compared the clinical outcomes of ED patients with moderate alcohol withdrawal who received phenobarbital, with or without benzodiazepines, with patients who received benzodiazepine treatment alone. METHODS: This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of ED patients with moderate alcohol withdrawal between 2015 and 2020. Patient encounters were classified into two treatment categories based on medication treatment: phenobarbital alone or in combination with benzodiazepines vs. benzodiazepines alone. Chi-square test or Fisher's exact was used to analyze categorical variables and the Student's t-test for continuous data. RESULTS: Among the 287 encounters that met inclusion criteria, 100 received phenobarbital, compared with 187 that received benzodiazepines alone. Patients who received phenobarbital were provided significantly more lorazepam equivalents. There was a significant difference in the percentage of patient encounters that required admission to the hospital in the phenobarbital cohort compared with the benzodiazepine cohort (75% vs. 43.3%, p < 0.001). However, there was no difference in admission level of care to the floor (51.2% vs. 52.0%), stepdown (33.8% vs. 28%), or intensive care unit (15% vs. 20%), respectively. CONCLUSIONS: Patients who received phenobarbital for moderate alcohol withdrawal were more likely to be admitted to the hospital, but there was no difference in admission level of care when compared with patients who received benzodiazepines alone. Patients who received phenobarbital were provided greater lorazepam equivalents in the ED.
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Alcoholismo , Síndrome de Abstinencia a Sustancias , Humanos , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Estudios Retrospectivos , Lorazepam/farmacología , Lorazepam/uso terapéutico , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Servicio de Urgencia en HospitalRESUMEN
BACKGROUND: Drug-resistant epilepsy (DRE) is a refractory neurological disorder. There is ample evidence that suggest that γ-aminobutyric acid-a (GABAA) receptors could be one of the mechanisms responsible for the development of drug resistance in epilepsy. It is also known that the cAMP response element binding protein (CREB) plays a possible key role in the transcriptional regulation of GABAA. OBJECTIVE: This study explores the role of CREB in the development of DRE and the effect of CREB on GABA-related receptors in DRE. METHODS: The CREB expression was increased or decreased in the hippocampus of normal rats by lentiviral transfection, who then underwent the lithium-pilocarpine-induced epilepsy model. Phenobarbital (PB) sodium and carbamazepine (CBZ) were used to select a drug-resistant epileptic model. The expression levels of GABAA receptor α1, ß2, and γ2 subunits and CREB protein were measured in the rat hippocampus by western blot and fluorescent quantitative PCR. RESULTS: The frequency and duration of seizures increased in the overexpression group compared to that in the control group. In addition, the severity, frequency, and duration of seizures decreased in the group with decreased expression. The hippocampus analysis of the expression levels of the CREB protein and CREB mRNA yielded similar findings. Altering the CREB protein expression in the rat hippocampus could negatively regulate the expression and transcript levels of GABAA receptors α1, ß2, and γ2, suggesting that CREB may serve as a potential target for the development of treatment protocols and drugs for epilepsy. CONCLUSION: Our study shows that enhanced CREB expression promotes the development of DRE and negatively regulates GABAA receptor levels and that the inhibition of CREB expression may reduce the incidence of DRE.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Epilepsia Refractaria , Hipocampo , Ratas Sprague-Dawley , Receptores de GABA-A , Animales , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Masculino , Epilepsia Refractaria/metabolismo , Ratas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-A/biosíntesis , Pilocarpina/toxicidad , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Modelos Animales de Enfermedad , Fenobarbital/farmacologíaRESUMEN
OBJECTIVE: To evaluate factors associated with borderline/clinical range Child Behavior Checklist (CBCL) scores in opioid-exposed children. STUDY DESIGN: Retrospective study of 94 children with prenatal opioid exposure evaluated with the CBCL at age 2 years. RESULTS: Twenty-eight children (30%) had borderline/clinical findings on the CBCL, with 27% scoring borderline/clinical for Externalizing Problems. In the multivariable model, lower Bayley-III motor scores and discharge home with mother with safety plan were associated with borderline/clinical Externalizing Problems. Medication treatment for neonatal opioid withdrawal syndrome (NOWS) was associated with normal Externalizing Problems scores. Treatment with clonidine or phenobarbital was associated with scores in the normal range in all broadband CBCL measures. CONCLUSION: Specific factors are associated with behavioral and emotional challenges measured by borderline/clinical CBCL scores among opioid-exposed children.
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Trastornos de la Conducta Infantil , Síndrome de Abstinencia Neonatal , Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Embarazo , Estudios Retrospectivos , Preescolar , Masculino , Trastornos de la Conducta Infantil/inducido químicamente , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Recién Nacido , Fenobarbital/uso terapéutico , Fenobarbital/efectos adversos , Análisis MultivarianteRESUMEN
OBJECTIVES: Phenobarbital serves as an antiepileptic drug (AED) and finds application in the treatment of epilepsy either as monotherapy or adjunctive therapy. This drug exhibits various pharmacodynamic properties that account for its beneficial effects as well as potential side effects. Accurate measurement of its concentration is critical for optimizing AED therapy through appropriate dose adjustments. Therefore, our objective was to develop and validate a new reference measurement procedure (RMP) for the accurate quantification of phenobarbital levels in human serum and plasma. METHODS: A sample preparation protocol based on protein precipitation followed by a high dilution step was established in combination with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using a C8 column to separate target analytes from known and unknown interferences. Assay validation and determination of measurement uncertainty were performed based on current guidelines. Selectivity and Specificity were assessed using spiked serum and plasma samples; to investigate possible matrix effects (MEs) a post-column infusion experiment and a comparison of standard line slopes was performed. Precision and accuracy were determined within a multiday precision experiment. RESULTS: The RMP was shown to be highly selective and specific, with no evidence of matrix interferences. It can be used to quantify phenobarbital in the range of 1.92 to 72.0⯵g/mL. Intermediate precision was less than 3.2â¯%, and repeatability coefficient of variation (CV) ranged from 1.3 to 2.0â¯% across all concentration levels. The relative mean bias ranged from -3.0 to -0.7â¯% for native serum levels, and from -2.8 to 0.8â¯% for Li-heparin plasma levels. The measurement uncertainties (k=1) for single measurements and target value assignment were 1.9 to 3.3â¯% and 0.9 to 1.6â¯%, respectively. CONCLUSIONS: A novel LC-MS/MS-based candidate RMP for the quantification of phenobarbital in human serum and plasma is presented which can be used for the standardization of routine assays and the evaluation of clinically relevant samples.