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1.
Cells ; 10(12)2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34943889

RESUMO

Phenobarbital (PB), a widely used antiepileptic drug, is known to upregulate the expression of numerous drug-metabolizing enzymes and transporters in the liver primarily via activation of the constitutive androstane receptor (CAR, NR1I3). The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays an important role in intracellular citrate homeostasis that is associated with a number of metabolic syndromes and neurological disorders. Here, we show that PB markedly elevates the expression of SLC13A5 through a pregnane X receptor (PXR)-dependent but CAR-independent signaling pathway. In human primary hepatocytes, the mRNA and protein expression of SLC13A5 was robustly induced by PB treatment, while genetic knockdown or pharmacological inhibition of PXR significantly attenuated this induction. Utilizing genetically modified HepaRG cells, we found that PB induces SLC13A5 expression in both wild type and CAR-knockout HepaRG cells, whereas such induction was fully abolished in the PXR-knockout HepaRG cells. Mechanistically, we identified and functionally characterized three enhancer modules located upstream from the transcription start site or introns of the SLC13A5 gene that are associated with the regulation of PXR-mediated SLC13A5 induction. Moreover, metformin, a deactivator of PXR, dramatically suppressed PB-mediated induction of hepatic SLC13A5 as well as its activation of the SLC13A5 luciferase reporter activity via PXR. Collectively, these data reveal PB as a potent inducer of SLC13A5 through the activation of PXR but not CAR in human primary hepatocytes.


Assuntos
/metabolismo , Hepatócitos/metabolismo , Fenobarbital/farmacologia , Receptor de Pregnano X/metabolismo , Simportadores/genética , Sequência de Bases , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Íntrons/genética , Metformina/farmacologia , Modelos Biológicos , Receptor de Pregnano X/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Elementos de Resposta/genética , Simportadores/metabolismo
2.
Am J Vet Res ; 83(1): 86-94, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34727050

RESUMO

OBJECTIVE: To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs. ANIMALS: 9 healthy, purpose bred Beagles. PROCEDURES: A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study. RESULTS: Although there were variations in CBD PK variables in dogs receiving CBD alone or in conjunction with PB, significance differences in CBD PK variables were not found. No significant difference was observed in PB PK variables of dogs receiving PB alone or with CBD. During chronic CBD administration, mild gastrointestinal signs were observed in 5 dogs. At daily CBD doses of 10 to 20 mg/kg/d, hypoxia was observed in 5 dogs and increased serum alkaline phosphatase (ALP) activities (range, 301 to 978 U/L) was observed in 4 dogs. A significant increase in ALP activity was observed with chronic administration of CBD during phase 1 between day 0 and day 14. CONCLUSIONS AND CLINICAL RELEVANCE: No significant PK interactions were found between CBD and PB. Dose escalation of CBD or adjustment of PB in dogs is not recommended on the basis of findings of this study.


Assuntos
Canabidiol , Preparações Farmacêuticas , Animais , Cães , Interações Medicamentosas , Fenobarbital , Estudos Prospectivos
3.
Medicine (Baltimore) ; 100(36): e27172, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516512

RESUMO

ABSTRACT: The aim of this study was to explore the compliance of epilepsy patients in the Phenobarbital Epilepsy Management Project in a rural area of China and its influencing factors, so as to provide the basis for further strategies.A retrospective study researching on the compliance of epilepsy patients in the Phenobarbital Epilepsy Management Project of Rural China was conducted. The Nan County, Hunan Province as a typical rural China was selected as the study site. We collected the compliance and other relative factors from 2017 to 2019 though the Phenobarbital Epilepsy Management Project data system.The good compliance patients in the Phenobarbital Epilepsy Management Project in a rural area of China were 98.99% (393/397); only 4 cases had poor compliance. The factors affecting the compliance of epilepsy patients were "adverse reactions of digestive tract symptoms," "how the patient felt physically, mentally, or working and learning ability during this period," and "the ratio of the attack to the previous one."The rate of good compliance among the epilepsy patients in the Phenobarbital Epilepsy Management Project in a rural area of China was high. More attention to education, patients' psychology, and the curative effect of family members may improve the compliance of patients with epilepsy further.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Cooperação do Paciente/estatística & dados numéricos , Fenobarbital/uso terapêutico , Adolescente , Adulto , Anticonvulsivantes/administração & dosagem , Criança , Pré-Escolar , China , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenobarbital/administração & dosagem , Estudos Retrospectivos , População Rural , Adulto Jovem
4.
J Pharmacol Toxicol Methods ; 112: 107107, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34363961

RESUMO

Administration of a compound can induce drug-metabolizing enzymes (DMEs) in the liver. DME induction can affect various parameters in toxicology studies. Therefore, evaluation of DME induction is important for interpreting test compound-induced biological responses. Several methods such as measurement of hepatic microsomal DME activity using substrates, electron microscopy, or immunohistochemistry have been used; however, these methods are limited in throughput and specificity or are not quantitative. Liquid chromatography mass spectrometry (LC/MS)-based protein analysis can detect and quantify multiple proteins simultaneously per assay. Studies have shown that formalin-fixed paraffin-embedded (FFPE) samples, which are routinely collected in toxicology studies, can be used for LC/MS-based protein analysis. To validate the utility of LC/MS using FFPE samples for quantitative evaluation of DME induction, we treated rats with a DME inducer, phenobarbital, and compared the protein expression levels of 13 phase-I and 11 phase-II DMEs between FFPE and fresh frozen hepatic samples using LC/MS. A good correlation between data from FFPE and frozen samples was obtained after analysis. In FFPE and frozen samples, the expression of 6 phase-I and 8 phase-II DMEs showed a similar significant increase and a prominent rise in Cyp2b2 and Cyp3a1 levels. In addition, LC/MS data were consistent with the measurement of microsomal DME activities. These results suggest that LC/MS-based protein expression analysis using FFPE samples is as effective as that using frozen samples for detecting DME induction.


Assuntos
Preparações Farmacêuticas , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida , Formaldeído/toxicidade , Fígado , Inclusão em Parafina , Fenobarbital/toxicidade , Ratos , Fixação de Tecidos
5.
J Vet Intern Med ; 35(4): 1826-1833, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34223667

RESUMO

BACKGROUND: In dogs, antiepileptic drugs (AED) cause lethargy but quantitative data regarding the effects of AED on activity levels are not available, and little is known about how AEDs affect sleep quality. OBJECTIVE: To quantitatively compare activity levels and nocturnal activity in dogs previously diagnosed with idiopathic epilepsy (IE) receiving AEDs compared to age- and breed-matched control dogs. ANIMALS: Sixty-two dogs with IE and 310 control dogs. METHODS: This is a 3-month prospective parallel observational study. An activity monitoring device for dogs was used to measure daily activity levels and sleep scores in all dogs. RESULTS: Dogs with IE treated with AEDs had an 18% average lower baseline activity level compared to control dogs (P = .005; point estimate = 0.82, 95% confidence interval [CI], 0.75-0.90). The combination of phenobarbital and potassium bromide (KBr) was associated with an average 28% decrease in activity in dogs with IE compared to control dogs (P = .03; point estimate = 0.72; CI, 0.62-0.82). Mean sleep scores were not significantly different in dogs with IE receiving AEDs compared to control dogs (P = .43). However, higher dosages of KBr were associated with lower sleep scores (P = .01). CONCLUSIONS: Dogs with IE receiving AEDs have lower activity levels, but no difference in sleep scores, compared to controls. The combination of phenobarbital and KBr had the largest decrease in activity between groups. Higher doses of KBr may affect nocturnal activity in epileptic dogs.


Assuntos
Doenças do Cão , Epilepsia , Animais , Anticonvulsivantes/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Epilepsia/tratamento farmacológico , Epilepsia/veterinária , Fenobarbital/uso terapêutico , Estudos Prospectivos
6.
Cochrane Database Syst Rev ; 7: CD002059, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34231914

RESUMO

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using an opioid for treatment of NAS due to withdrawal from opioids in newborn infants. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via Cochrane Register of Studies Web and MEDLINE via Ovid. We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for eligible trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi- and cluster-RCTs which enrolled infants born to mothers with opioid dependence and who were experiencing NAS requiring treatment with an opioid. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 16 trials (1110 infants) with NAS secondary to maternal opioid use in pregnancy. Seven studies at low risk of bias were included in sensitivity analysis. Opioid versus no treatment / usual care: a single trial (80 infants) of morphine and supportive care versus supportive care alone reported no difference in treatment failure (risk ratio (RR) 1.29, 95% confidence interval (CI) 0.41 to 4.07; very low certainty evidence). No infant had a seizure. The trial did not report mortality, neurodevelopmental disability and adverse events. Morphine increased days hospitalisation (mean difference (MD) 15.00, 95% CI 8.86 to 21.14; very low certainty evidence) and treatment (MD 12.50, 95% CI 7.52 to 17.48; very low certainty evidence), but decreased days to regain birthweight (MD -2.80, 95% CI -5.33 to -0.27) and duration (minutes) of supportive care each day (MD -197.20, 95% CI -274.15 to -120.25). Morphine versus methadone: there was no difference in treatment failure (RR 1.59, 95% CI 0.95 to 2.67; 2 studies, 147 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study reported no difference in days hospitalisation (MD 1.40, 95% CI -3.08 to 5.88; 116 infants; low certainty evidence), whereas data from two studies found an increase in days treatment (MD 2.71, 95% CI 0.22 to 5.21; 147 infants; low certainty) for infants treated with morphine. A single study reported no difference in breastfeeding, adverse events, or out of home placement. Morphine versus sublingual buprenorphine: there was no difference in treatment failure (RR 0.79, 95% CI 0.36 to 1.74; 3 studies, 113 infants; very low certainty evidence). Neonatal or infant mortality and neurodevelopmental disability were not reported. There was moderate certainty evidence of an increase in days hospitalisation (MD 11.45, 95% CI 5.89 to 17.01; 3 studies, 113 infants), and days treatment (MD 12.79, 95% CI 7.57 to 18.00; 3 studies, 112 infants) for infants treated with morphine. A single adverse event (seizure) was reported in infants exposed to buprenorphine. Morphine versus diluted tincture of opium (DTO): a single study (33 infants) reported no difference in days hospitalisation, days treatment or weight gain (low certainty evidence). Opioid versus clonidine: a single study (31 infants) reported no infant with treatment failure in either group. This study did not report seizures, neonatal or infant mortality and neurodevelopmental disability. There was low certainty evidence for no difference in days hospitalisation or days treatment. This study did not report adverse events. Opioid versus diazepam: there was a reduction in treatment failure from use of an opioid (RR 0.43, 95% CI 0.23 to 0.80; 2 studies, 86 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study of 34 infants comparing methadone versus diazepam reported no difference in days hospitalisation or days treatment (very low certainty evidence). Adverse events were not reported. Opioid versus phenobarbital: there was a reduction in treatment failure from use of an opioid (RR 0.51, 95% CI 0.35 to 0.74; 6 studies, 458 infants; moderate certainty evidence). Subgroup analysis found a reduction in treatment failure in trials titrating morphine to ≧ 0.5 mg/kg/day (RR 0.21, 95% CI 0.10 to 0.45; 3 studies, 230 infants), whereas a single study using morphine < 0.5 mg/kg/day reported no difference compared to use of phenobarbital (subgroup difference P = 0.05). Neonatal or infant mortality and neurodevelopmental disability were not reported. A single study (111 infants) of paregoric versus phenobarbital reported seven infants with seizures in the phenobarbital group, whereas no seizures were reported in two studies (170 infants) comparing morphine to phenobarbital. There was no difference in days hospitalisation or days treatment. A single study (96 infants) reported no adverse events in either group. Opioid versus chlorpromazine: there was a reduction in treatment failure from use of morphine versus chlorpromazine (RR 0.08, 95% CI 0.01 to 0.62; 1 study, 90 infants; moderate certainty evidence). No seizures were reported in either group. There was low certainty evidence for no difference in days treatment. This trial reported no adverse events in either group. None of the included studies reported time to control of NAS. Data for duration and severity of NAS were limited, and we were unable to use these data in quantitative synthesis. AUTHORS' CONCLUSIONS: Compared to supportive care alone, the addition of an opioid may increase duration of hospitalisation and treatment, but may reduce days to regain birthweight and the duration of supportive care each day. Use of an opioid may reduce treatment failure compared to phenobarbital, diazepam or chlorpromazine. Use of an opioid may have little or no effect on duration of hospitalisation or treatment compared to use of phenobarbital, diazepam or chlorpromazine. The type of opioid used may have little or no effect on the treatment failure rate. Use of buprenorphine probably reduces duration of hospitalisation and treatment compared to morphine, but there are no data for time to control NAS with buprenorphine, and insufficient evidence to determine safety. There is insufficient evidence to determine the effectiveness and safety of clonidine.


Assuntos
Entorpecentes/uso terapêutico , Síndrome de Abstinência Neonatal/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Buprenorfina/uso terapêutico , Clorpromazina/uso terapêutico , Clonidina/uso terapêutico , Diazepam/uso terapêutico , Humanos , Hipnóticos e Sedativos/uso terapêutico , Recém-Nascido , Metadona/uso terapêutico , Morfina/uso terapêutico , Ópio/uso terapêutico , Fenobarbital/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Crit Rev Toxicol ; 51(5): 373-394, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34264181

RESUMO

Many nongenotoxic chemicals have been shown to produce liver tumors in mice and/or rats by a mode of action (MOA) involving activation of the constitutive androstane receptor (CAR). Studies with phenobarbital (PB) and other compounds have identified the key events for this MOA: CAR activation; increased hepatocellular proliferation; altered foci formation; and ultimately the development of adenomas/carcinomas. In terms of human relevance, the pivotal species difference is that CAR activators are mitogenic agents in mouse and rat hepatocytes, but they do not stimulate increased hepatocellular proliferation in humans. This conclusion is supported by substantial in vitro studies with cultured rodent and human hepatocytes and also by in vivo studies with chimeric mice with human hepatocytes. Examination of the literature reveals many similarities in the hepatic effects and species differences between activators of rodent CAR and the peroxisome proliferator-activated receptor alpha (PPARα), with PPARα activators also not being mitogenic agents in human hepatocytes. Overall, a critical analysis of the available data demonstrates that the established MOA for rodent liver tumor formation by PB and other CAR activators is qualitatively not plausible for humans. This conclusion is supported by data from several human epidemiology studies.


Assuntos
Neoplasias Hepáticas , Animais , Hepatócitos , Humanos , Fígado , Camundongos , Fenobarbital/toxicidade , Ratos , Receptores Citoplasmáticos e Nucleares/genética , Roedores
8.
J Pain Palliat Care Pharmacother ; 35(3): 167-174, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34264774

RESUMO

End of life (EoL) and refractory symptom management is a growing clinical topic and there is minimal literature to support effective treatment strategies, especially in individuals with a substance use disorder or opioids and/or benzodiazepine tolerance. We report the successful use of phenobarbital for proportionate EoL sedation in a 57-year-old man with opioid use disorder (heroin) and metastatic urothelial carcinoma presenting to an acute care hospital with intractable back pain related to bone metastases. During his hospitalization, his daily opioid requirement exceeded 1 gram of morphine equivalent daily dose (MEDD) with suboptimal pain control. The patient's clinical course was complicated by active heroin withdrawal, psychosocial suffering, and disease progression. Despite use of high-dose opioids and benzodiazepines, pain and anxiety were poorly controlled. After an acute medical decompensation, a goals of care discussion was held with his family and a determination with informed consent was made to change patient status to do not attempt resuscitation and proportionate sedation with phenobarbital was initiated to target refractory pain and agitation. Phenobarbital was continued for approximately 15 hours before patient peacefully died. Findings from this case report demonstrate the successful use of phenobarbital in opioid use disorder and benzodiazepine tolerance with intractable pain.


Assuntos
Carcinoma de Células de Transição , Dor Intratável , Neoplasias da Bexiga Urinária , Analgésicos Opioides , Morte , Humanos , Masculino , Pessoa de Meia-Idade , Dor Intratável/tratamento farmacológico , Dor Intratável/etiologia , Fenobarbital
9.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281174

RESUMO

Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia.


Assuntos
Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/terapia , Convulsões/terapia , Animais , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Humanos , Hipotermia Induzida/métodos , Hipotermia Induzida/tendências , Fenobarbital/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/fisiopatologia
10.
Am J Med ; 134(10): 1295-1299, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34181907

RESUMO

PURPOSE: The concomitant use of direct oral anticoagulants (DOAC) and strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels. METHODS: We retrospectively identified hospitalized patients simultaneously receiving a DOAC and carbamazepine, phenobarbital, phenytoin, or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady state were included. DOAC peak or trough levels were compared with on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified. RESULTS: We included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch). CONCLUSION: Our data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug-drug interaction.


Assuntos
Anticoagulantes/administração & dosagem , Indutores das Enzimas do Citocromo P-450/administração & dosagem , Administração Oral , Idoso , Carbamazepina/administração & dosagem , Interações Medicamentosas , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Fenobarbital/administração & dosagem , Fenitoína/administração & dosagem , Estudos Retrospectivos , Rifampina/administração & dosagem
11.
Xenobiotica ; 51(8): 877-884, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34151692

RESUMO

To compare drug-drug interaction (DDI) between tacrolimus and different formulations of phenobarbital in paediatrics and adults.Physiologically based pharmacokinetics (PBPK) models were used to evaluate DDI between phenobarbital (oral (p.o.) and intravenous (i.v.) formulations) and tacrolimus in paediatrics and adults. All dosing regimens were maintained for 7 days.Compared to i.v. phenobarbital, p.o. phenobarbital could decrease pharmacokinetic (PK) parameters of tacrolimus much more in both paediatrics and adults. On day 7, the results showed that the ratio of Cmax for tacrolimus in the presence and absence of phenobarbital were 0.13 (p.o.) and 0.48 (i.v.), respectively, in paediatrics, while 0.54 (p.o.) and 0.73 (i.v.) in adults, respectively. The ratios of the area under the concentration-time curve (AUC) were 0.06 (p.o.) and 0.18 (i.v.) in paediatrics, while 0.46 (p.o.) and 0.53 (i.v.) in adults, respectively. PK parameters of tacrolimus decreased more significantly in paediatrics compared to adults.In paediatric, phenobarbital had a greater impact on PK of tacrolimus than that in adults. P.o. phenobarbital reduced PK parameters of tacrolimus even more than i.v. administration. In clinical practice, the concentration monitoring and dosage adjustment of tacrolimus should be emphasised when co-administrated with phenobarbital, especially in paediatric or in p.o. formulation.Key pointsThe results indicated that p.o. and i.v. phenobarbital both had a significant DDI with tacrolimus in paediatrics and adults.Phenobarbital had a greater impact on the PK of tacrolimus over time in paediatrics.P.o. administration of phenobarbital can reduce the PK parameters of tacrolimus more.


Assuntos
Pediatria , Preparações Farmacêuticas , Adulto , Área Sob a Curva , Criança , Interações Medicamentosas , Humanos , Imunossupressores , Modelos Biológicos , Fenobarbital , Tacrolimo
12.
Epilepsia ; 62(7): 1677-1688, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34080183

RESUMO

OBJECTIVE: The kainic acid (KA)-induced status epilepticus (SE) model in rats is a well-defined model of epileptogenesis. This model closely recapitulates many of the clinical and pathological characteristics of human temporal lobe epilepsy (TLE) that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (traumatic brain injury, SE event, viral infection, etc.). Moreover, this model is suitable for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. The burden of human TLE is highly variable, similar to the post-KA SE rat model. In this regard, this model may have broad translational relevance. This report thus details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post-KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the burden of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS or lead to a reduced frequency/severity of SRS. METHODS: Rats were administered either everolimus (2-3 mg/kg po) beginning 1, 2, or 24 h after SE onset, or phenobarbital (60 mg/kg ip) beginning 1 h after SE onset. All treatments were administered once/day for 5-7 days. Rats in all studies (n = 12/treatment dose/study) were then monitored intermittently by video-electroencephalography (2 weeks on, 2 weeks off, 2 weeks on epochs) to determine latency to onset of SRS and disease burden. RESULTS: Although no adverse side effects were observed in our studies, no treatment significantly modified disease or prevented the presentation of SRS by 6 weeks after SE onset. SIGNIFICANCE: Neither phenobarbital nor everolimus administered at several time points after SE onset prevented the development of SRS. Nonetheless, we demonstrate a practical and moderate-throughput screen for potential antiepileptogenic agents in a rat model of TLE.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia do Lobo Temporal/prevenção & controle , Everolimo/uso terapêutico , Fenobarbital/uso terapêutico , Animais , Anticonvulsivantes/efeitos adversos , Peso Corporal , Convulsivantes , Efeitos Psicossociais da Doença , Modelos Animais de Doenças , Composição de Medicamentos , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Eletroencefalografia , Epilepsia do Lobo Temporal/induzido quimicamente , Everolimo/efeitos adversos , Ensaios de Triagem em Larga Escala , Ácido Caínico , Masculino , Fenobarbital/efeitos adversos , Ratos , Ratos Sprague-Dawley , Convulsões/prevenção & controle
13.
Ann Am Thorac Soc ; 18(10): 1708-1716, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33945771

RESUMO

Rationale: Several institutions have implemented phenobarbital-based pathways for the treatment of alcohol withdrawal syndrome (AWS). However, little is known about the care processes, effectiveness, and safety of phenobarbital-based pathways for intensive care unit (ICU) patients. Objectives: To examine clinician acceptability and feasibility and patient outcomes after the implementation of a phenobarbital-based pathway for medical ICU (MICU) patients with severe AWS. Methods: We conducted a mixed-method study of a quality-improvement intervention designed to improve the workflow without deleterious effects on outcomes. We used semistructured, qualitative interviews and surveys of clinicians to assess the acceptability and feasibility of the phenobarbital-based pathway and a previous benzodiazepine-based pathway. We used a noninferiority interrupted-time-series analysis to compare mechanical ventilation rates before and after implementation among MICU patients within an urban safety-net hospital who were admitted with severe alcohol withdrawal. We explored several secondary outcomes, including physical restraint use and hospital length of stay. Results: Four themes related to clinician acceptability and feasibility of the phenobarbital-based pathway emerged: 1) designing a pathway that balanced standardization with clinical judgment promoted acceptability, 2) pathway simplicity promoted feasibility, 3) implementing pathway-driven care streamlined the workflow, and 4) ad hoc implementation strategies facilitated new pathway uptake. Two hundred thirty-three and 252 patients were initiated on the benzodiazepine- and phenobarbital-based pathways, respectively. The rate of mechanical ventilation decreased from 17.1% to 12.9% after implementation of the phenobarbital-based pathway, and an adjusted mean difference of -4.9% (95% upper confidence interval [CI]: 0.7%) corresponding to relative change in the 95% upper limit of 4%, which was below the a priori noninferiority margin, was shown. After implementation, use of physical restraints decreased from 51.6% to 32.4% (mean difference, -18.0%; 95% CI: -26.4% to -9.7%), and the hospital length of stay was shorter (8.6-6.8 d; mean difference, -1.8 d; 95% CI: -3.4 to -0.2 d). Conclusions: Clinicians believed that the phenobarbital-based pathway was more efficient and simpler to use, and patient mechanical ventilation rates were noninferior compared with the previous benzodiazepine-based pathway for the treatment of severe AWS.


Assuntos
Alcoolismo , Síndrome de Abstinência a Substâncias , Humanos , Tempo de Internação , Fenobarbital , Estudos Retrospectivos
14.
Epilepsia ; 62(6): 1460-1471, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33955541

RESUMO

OBJECTIVES: Bumetanide was suggested as an adjunct to phenobarbital for suppression of neonatal seizures. This suggestion was based on the idea that bumetanide, by reducing intraneuronal chloride accumulation through inhibition of the Na-K-2Cl cotransporter NKCC1, may attenuate or abolish depolarizing γ-aminobutyric acid (GABA) responses caused by birth asphyxia. However, a first proof-of-concept clinical trial failed. This could have had several reasons, including bumetanide's poor brain penetration, the wide cellular NKCC1 expression pattern in the brain, and problems with the general concept of NKCC1's role in neonatal seizures. We recently replicated the clinical failure of bumetanide to potentiate phenobarbital's effect in a novel rat model of birth asphyxia. In this study, a clinically relevant dose (0.3 mg/kg) of bumetanide was used that does not lead to NKCC1-inhibitory brain levels. The aim of the present experiments was to examine whether a much higher dose (10 mg/kg) of bumetanide is capable of potentiating phenobarbital in this rat model. Furthermore, the effects of the two lipophilic bumetanide derivatives, the ester prodrug N,N-dimethylaminoethylester of bumetanide (DIMAEB) and the benzylamine derivative bumepamine, were examined at equimolar doses. METHODS: Intermittent asphyxia was induced for 30 min by exposing male and female P11 rat pups to three 7 + 3 min cycles of 9% and 5% O2 at constant 20% CO2 . All control pups exhibited neonatal seizures after the asphyxia. RESULTS: Even at 10 mg/kg, bumetanide did not potentiate the effect of a submaximal dose (15 mg/kg) of phenobarbital on seizure incidence, whereas a significant suppression of neonatal seizures was determined for combinations of phenobarbital with DIMAEB or, more effectively, bumepamine, which, however, does not inhibit NKCC1. Of interest, the bumepamine/phenobarbital combination prevented the neurodegenerative consequences of asphyxia and seizures in the hippocampus. SIGNIFICANCE: Both bumepamine and DIMAEB are promising tools that may help to develop more effective lead compounds for clinical trials.


Assuntos
Anticonvulsivantes/farmacologia , Asfixia Neonatal/complicações , Asfixia Neonatal/tratamento farmacológico , Benzilaminas/uso terapêutico , Bumetanida/uso terapêutico , Hipocampo/patologia , Degeneração Neural/patologia , Fenobarbital/farmacologia , Convulsões/tratamento farmacológico , Convulsões/etiologia , Animais , Animais Recém-Nascidos , Anticonvulsivantes/farmacocinética , Benzilaminas/farmacocinética , Encéfalo/metabolismo , Bumetanida/análogos & derivados , Bumetanida/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Masculino , Fenobarbital/farmacocinética , Gravidez , Ratos , Membro 2 da Família 12 de Carreador de Soluto/biossíntese
15.
Nat Chem Biol ; 17(8): 888-895, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33941924

RESUMO

The uniquely hollow structure of microtubules (MTs) confers characteristic mechanical and biological properties. Although most regulatory processes take place at the outer surface, molecular events inside MTs, such as α-tubulin acetylation, also play a critical role. However, how regulatory proteins reach the site of action remains obscure. To assess luminal accessibility, we first identified luminally positioned residues of ß-tubulin that can be fused to a protein of interest. We then developed a chemically inducible technique with which cytosolic proteins can be rapidly trapped at the lumen of intact MTs in cells. A luminal trapping assay revealed that soluble proteins of moderate size can enter the lumen via diffusion through openings at the MT ends and sides. Additionally, proteins forming a complex with tubulins can be incorporated to the lumen through the plus ends. Our approach may not only illuminate this understudied territory, but may also help understand its roles in MT-mediated functions.


Assuntos
Microtúbulos/metabolismo , Fenobarbital/metabolismo , Tubulina (Proteína)/metabolismo , Células Cultivadas , Humanos , Microtúbulos/química , Fenobarbital/química , Solubilidade , Tubulina (Proteína)/química
16.
Cochrane Database Syst Rev ; 5: CD011922, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33973646

RESUMO

BACKGROUND: Any type of seizure can be observed in Alzheimer's disease. Antiepileptic drugs seem to prevent the recurrence of epileptic seizures in most people with Alzheimer's disease. There are pharmacological and non-pharmacological treatments for epilepsy in people with Alzheimer's disease, however there are no current systematic reviews to evaluate the efficacy and tolerability of these treatments. This review aims to investigate these different modalities. This is an updated version of the Cochrane Review previously published in 2018. OBJECTIVES: To assess the efficacy and tolerability of pharmacological or non-pharmacological interventions for the treatment of epilepsy in people with Alzheimer's disease (including sporadic Alzheimer's disease and dominantly inherited Alzheimer's disease). SEARCH METHODS: For the latest update, on 3 August 2020 we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 31 July 2020). CRS Web includes randomized or quasi-randomized controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups, including Cochrane Epilepsy. In an effort to identify further published, unpublished and ongoing trials, we searched ongoing trials registers, reference lists and relevant conference proceedings; we also contacted trial authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials investigating treatment for epilepsy in people with Alzheimer's disease, with the primary outcomes of proportion of participants with seizure freedom and proportion of participants experiencing adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to there being limited available data. MAIN RESULTS: We included one randomized controlled trial (RCT) on pharmacological interventions; the trial included 95 participants. No studies were found for non-pharmacological interventions. Concerning the proportion of participants with seizure freedom, no significant differences were found for the comparisons of levetiracetam versus lamotrigine (RR) 1.20, 95% CI 0.53 to 2.71; 67 participants; very low-certainty evidence), levetiracetam versus phenobarbital (RR 1.01, 95% CI 0.47 to 2.19; 66 participants; very low-certainty evidence), or lamotrigine versus phenobarbital (RR 0.84, 95% CI 0.35 to 2.02; 57 participants; very low-certainty evidence). It seemed that levetiracetam could improve cognition and lamotrigine could relieve depression, while phenobarbital and lamotrigine could worsen cognition, and levetiracetam and phenobarbital could worsen mood. The risk of bias relating to allocation, blinding and selective reporting was unclear. We judged the certainty of the evidence for all outcomes to be very low. AUTHORS' CONCLUSIONS: This review does not provide sufficient evidence to support levetiracetam, phenobarbital or lamotrigine for the treatment of epilepsy in people with Alzheimer's disease. Regarding efficacy and tolerability, no significant differences were found between levetiracetam, phenobarbital and lamotrigine. Large RCTs with a double-blind, parallel-group design are required to determine the efficacy and tolerability of treatment for epilepsy in people with Alzheimer's disease.


Assuntos
Doença de Alzheimer/complicações , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Lamotrigina/uso terapêutico , Levetiracetam/uso terapêutico , Fenobarbital/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/administração & dosagem , Cognição/efeitos dos fármacos , Depressão/complicações , Depressão/tratamento farmacológico , Feminino , Humanos , Lamotrigina/administração & dosagem , Levetiracetam/administração & dosagem , Masculino , Fenobarbital/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária
17.
Cochrane Database Syst Rev ; 5: CD002053, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34002380

RESUMO

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using a sedative versus control (placebo, usual treatment or non-pharmacological treatment) for NAS due to withdrawal from opioids and determine which type of sedative is most effective and safe for NAS due to withdrawal from opioids. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included trials enrolling infants with NAS born to mothers with an opioid dependence with more than 80% follow-up and using randomised, quasi-randomised and cluster-randomised allocation to sedative or control. DATA COLLECTION AND ANALYSIS: Three review authors assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 10 trials (581 infants) with NAS secondary to maternal opioid use in pregnancy. There were multiple comparisons of different sedatives and regimens. There were limited data available for use in sensitivity analysis of studies at low risk of bias. Phenobarbital versus supportive care: one study reported there may be little or no difference in treatment failure with phenobarbital and supportive care versus supportive care alone (risk ratio (RR) 2.73, 95% confidence interval (CI) 0.94 to 7.94; 62 participants; very low-certainty evidence). No infant had a clinical seizure. The study did not report mortality, neurodevelopmental disability and adverse events. There may be an increase in days' hospitalisation and treatment from use of phenobarbital (hospitalisation: mean difference (MD) 20.80, 95% CI 13.64 to 27.96; treatment: MD 17.90, 95% CI 11.98 to 23.82; both 62 participants; very low-certainty evidence). Phenobarbital versus diazepam: there may be a reduction in treatment failure with phenobarbital versus diazepam (RR 0.39, 95% CI 0.24 to 0.62; 139 participants; 2 studies; low-certainty evidence). The studies did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be little or no difference in days' hospitalisation and treatment (hospitalisation: MD 3.89, 95% CI -1.20 to 8.98; 32 participants; treatment: MD 4.30, 95% CI -0.73 to 9.33; 31 participants; both low-certainty evidence). Phenobarbital versus chlorpromazine: there may be a reduction in treatment failure with phenobarbital versus chlorpromazine (RR 0.55, 95% CI 0.33 to 0.92; 138 participants; 2 studies; very low-certainty evidence), and no infant had a seizure. The studies did not report mortality and neurodevelopmental disability. One study reported there may be little or no difference in days' hospitalisation (MD 7.00, 95% CI -3.51 to 17.51; 87 participants; low-certainty evidence) and 0/100 infants had an adverse event. Phenobarbital and opioid versus opioid alone: one study reported no infants with treatment failure and no clinical seizures in either group (low-certainty evidence). The study did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be a reduction in days' hospitalisation for infants treated with phenobarbital and opioid (MD -43.50, 95% CI -59.18 to -27.82; 20 participants; low-certainty evidence). Clonidine and opioid versus opioid alone: one study reported there may be little or no difference in treatment failure with clonidine and dilute tincture of opium (DTO) versus DTO alone (RR 0.09, 95% CI 0.01 to 1.59; 80 participants; very low-certainty evidence). All five infants with treatment failure were in the DTO group. There may be little or no difference in seizures (RR 0.14, 95% CI 0.01 to 2.68; 80 participants; very low-certainty evidence). All three infants with seizures were in the DTO group. There may be little or no difference in mortality after discharge (RR 7.00, 95% CI 0.37 to 131.28; 80 participants; very low-certainty evidence). All three deaths were in the clonidine and DTO group. The study did not report neurodevelopmental disability. There may be little or no difference in days' treatment (MD -4.00, 95% CI -8.33 to 0.33; 80 participants; very low-certainty evidence). One adverse event occurred in the clonidine and DTO group. There may be little or no difference in rebound NAS after stopping treatment, although all seven cases were in the clonidine and DTO group. Clonidine and opioid versus phenobarbital and opioid: there may be little or no difference in treatment failure (RR 2.27, 95% CI 0.98 to 5.25; 2 studies, 93 participants; very low-certainty evidence). One study reported one infant in the clonidine and morphine group had a seizure, and there were no infant mortalities. The studies did not report neurodevelopmental disability. There may be an increase in days' hospitalisation and days' treatment with clonidine and opioid versus phenobarbital and opioid(hospitalisation: MD 7.13, 95% CI 6.38 to 7.88; treatment: MD 7.57, 95% CI 3.97 to 11.17; both 2 studies, 91 participants; low-certainty evidence). There may be little or no difference in adverse events (RR 1.55, 95% CI 0.44 to 5.40; 2 studies, 93 participants; very low-certainty evidence). However, there was oversedation only in the phenobarbital and morphine group; and hypotension, rebound hypertension and rebound NAS only in the clonidine and morphine group. AUTHORS' CONCLUSIONS: There is very low-certainty evidence that phenobarbital increases duration of hospitalisation and treatment, but reduces days to regain birthweight and duration of supportive care each day compared to supportive care alone. There is low-certainty evidence that phenobarbital reduces treatment failure compared to diazepam and very low-certainty evidence that  phenobarbital reduces treatment failure compared to chlorpromazine. There is low-certainty evidence of an increase in days' hospitalisation and days' treatment with clonidine and opioid compared to phenobarbital and opioid. There are insufficient data to determine the safety and incidence of adverse events for infants treated with combinations of opioids and sedatives including phenobarbital and clonidine.


Assuntos
Hipnóticos e Sedativos/uso terapêutico , Síndrome de Abstinência Neonatal/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Viés , Clorpromazina/uso terapêutico , Clonidina/uso terapêutico , Diazepam/uso terapêutico , Humanos , Recém-Nascido , Entorpecentes/uso terapêutico , Fenobarbital/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
19.
Ther Deliv ; 12(6): 461-475, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34013779

RESUMO

Background: Recently, intranasal administration has been suggested as a potential direct route to transport pharmaceuticals into the brain through the olfactory and trigeminal nerves, bypassing the blood-brain barrier. Materials & methods: The nasal hydrogels were prepared by a cold method using pluronic F-12 and chitosan. Results: All the selected formulations were gelled at 30°C. The gelation time varied from 5 to 10 min. The mucoadhesive strength was adequate to provide prolonged mucosal adhesion. The formulations exhibited good drug content after stability period of 3 months. The permeability studies revealed a high permeation of the drug through the surgically removed nasal tissue. Conclusion: The results suggest that the obtained hydrogels might be suitable candidates for the nasal delivery of phenobarbital sodium.


Assuntos
Hidrogéis , Fenobarbital , Administração Intranasal , Sistemas de Liberação de Medicamentos , Géis , Mucosa Nasal , Temperatura
20.
Seizure ; 89: 93-98, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34034063

RESUMO

OBJECT: To provide information on the characteristics of elderly epilepsy patients in rural Northeast China. METHOD: Consecutive patients (aged >60) who were diagnosed with convulsive epilepsy in seven counties in Jilin Province, Northeast China, between January 2010 and December 2019 were included in the program and were divided into the EOE (early-onset epilepsy) group and the LOE (late-onset epilepsy) group. The patients were followed up once a month, and demographics and clinical data were recorded. RESULT: There were 471 patients enrolled in this study, with 329 patients classified into the EOE group and 142 patients recruited into the LOE group. At baseline, the EOE group was younger than the LOE group (t=-9.007, p < 0.001). The most common etiologies for the EOE and LOE groups were post-trauma (4.0%, n=13) and stroke (9.2%, n=13). Elderly epilepsy patients had a good response to PB monotherapy, and no significant difference was found between the two groups (p > 0.05). EOE patients complained of more serious adverse events (p < 0.05), and drowsiness (52%) and ataxia (28%) were the most common adverse events reported by the EOE and LOE groups, respectively; however, more LOE patients were prone to withdrawal due to side effects (p = 0.036). A total of 63 patients withdrew from the study, and nonadherence was the commonest cause for withdrawal (56% in EOE and 50% in LOE). In the entire follow-up period, 112 patients (63 in the EOE group and 49 in the LOE group) died; the most common causes of death were stroke (n=44, 39%) and heart disease (n=36, 32%). The LOE group had a shorter survival time than the EOE group (χ2=42.216, p < 0.001). The LOE group (HR=3.47, 95% CI: 2.36-5.09) and higher seizure frequency (HR=1.72, 95% CI: 1.17-2.52) were the risk factors for death. CONCLUSION: Elderly epilepsy patients had a good response to PB monotherapy. EOE patients complained of more serious adverse events, but more LOE patients were prone to withdrawal due to side effects. Nonadherence was the commonest cause of drug withdrawal, and it reflects the limited education regarding the impact of seizures and the differences in priorities of rural communities. EOE patients survive longer than LOE patients.


Assuntos
Epilepsias Parciais , Epilepsia Generalizada , Epilepsia , Idoso , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , China/epidemiologia , Epilepsias Parciais/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Epilepsia Generalizada/tratamento farmacológico , Humanos , Fenobarbital/uso terapêutico , Projetos de Pesquisa , População Rural
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