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International Journal of Molecular... Mar 2022In cattle, phenobarbital (PB) upregulates target drug-metabolizing enzyme (DME) mRNA levels. However, few data about PB's post-transcriptional effects are actually...
In cattle, phenobarbital (PB) upregulates target drug-metabolizing enzyme (DME) mRNA levels. However, few data about PB's post-transcriptional effects are actually available. This work provides the first, and an almost complete, characterization of PB-dependent changes in DME catalytic activities in bovine liver using common probe substrates and confirmatory immunoblotting investigations. As expected, PB increased the total cytochrome P450 (CYP) content and the extent of metyrapone binding; moreover, an augmentation of protein amounts and related enzyme activities was observed for known PB targets such as CYP2B, 2C, and 3A, but also CYP2E1. However, contradictory results were obtained for CYP1A, while a decreased catalytic activity was observed for flavin-containing monooxygenases 1 and 3. The barbiturate had no effect on the chosen hydrolytic and conjugative DMEs. For the first time, we also measured the 26S proteasome activity, and the increase observed in PB-treated cattle would suggest this post-translational event might contribute to cattle DME regulation. Overall, this study increased the knowledge of cattle hepatic drug metabolism, and further confirmed the presence of species differences in DME expression and activity between cattle, humans, and rodents. This reinforced the need for an extensive characterization and understanding of comparative molecular mechanisms involved in expression, regulation, and function of DMEs.
Topics: Animals; Cattle; Cytochrome P-450 Enzyme System; Enzyme Induction; Liver; Microsomes, Liver; Phenobarbital; Xenobiotics
PubMed: 35408925
DOI: 10.3390/ijms23073564 -
Veterinary Medicine and Science May 2021Phenobarbital-responsive sialadenosis (PRS) can cause nausea and vomiting, and is rarely reported in dogs.
BACKGROUND
Phenobarbital-responsive sialadenosis (PRS) can cause nausea and vomiting, and is rarely reported in dogs.
OBJECTIVES
An 8-year-old neutered, male Pomeranian dog was presented to our teaching hospital with vomiting that began 2 years ago. The clinical signs repeatedly improved and deteriorated despite treatment.
METHODS
The only abnormality found on physical examination was salivary gland enlargement, and no specific findings were observed on blood analysis and imaging tests. The results of the fine needle aspirate cytology from the salivary glands revealed possible sialadenosis. Phenobarbital was prescribed, and the patient's symptoms resolved. However, upon discontinuing drug, the patient's clinical signs recurred and did not improve even after re-introduction of phenobarbital and the addition of other anticonvulsant drugs. An oesophageal stricture was observed on an oesophagram, and fibrosis was confirmed endoscopically. A balloon dilation was performed to expand the stenosis.
RESULTS
After the first procedure, the patient's clinical signs initially improved, but relapsed 2 weeks later. A total of three oesophageal dilation procedures were performed using a sequentially larger diameter balloon. After the third procedure, the patient's clinical signs were managed without recurrence. The cause of recurrent gastrointestinal signs following the initial successful treatment of phenobarbital-responsive sialadenosis was due to oesophageal stricture formation.
CONCLUSIONS
This case report demonstrates the successful management of PRS with subsequent oesophageal stricture formation in a dog.
Topics: Animals; Catheterization; Dog Diseases; Dogs; Esophageal Stenosis; Phenobarbital; Salivary Gland Diseases; Treatment Outcome
PubMed: 33410603
DOI: 10.1002/vms3.416 -
Seizure May 2022Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the... (Review)
Review
BACKGROUND
Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the potential adverse effects caused by exposure to antiseizure medications (ASMs).
OBJECTIVE
The objectives of this review were: to evaluate concentrations of ASMs in breastmilk of lactating WWE, qualitatively synthesize evidence that can be used to estimate theoretical doses as estimated daily intake (EDI) and relative infant dose (RID) of ASMs, and to evaluate potential risks to infants as a result of exposure to ASMs from breastmilk.
METHODS
This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42020223645. The databases: MEDLINE/PubMed, EMBASE, CINAHL/EBSCO, COCHRANE, SpringerLink, ScienceDirect, Summon, WHO International Clinical Trials Registry Platform, and SCOPUS were systematically searched. A qualitative synthesis was adopted in this study.
RESULTS
A total of 15 records were included in this systematic review. The included studies reported levels of 8 ASMs in the breastmilk of WWE. The highest RIDs of carbamazepine, lamotrigine, primidone, phenobarbital, gabapentin, valproic acid, ethosuximide, levetiracetam, and topiramate were 3.70%, 36.33%, 4.96%, 3.15%, 4.37%, 1.90%, 31.49%, 12.50%, and 12.18%, respectively. Breastfeeding might be limited or even discontinued when signs of excessive sedation/drowsiness and/or poor weight gain are evident on infants exposed to primidone and phenobarbital, ethosuximide/primidone, or ethosuximide/phenobarbital.
CONCLUSIONS
Concentrations of ASMs can be detected in breastmilk of WWE and plasma/serum of infants exposed via breastmilk. Healthcare providers and WWE might use the findings of this study to make informed decisions on the safety of breastfeeding while taking ASMs.
Topics: Anticonvulsants; Breast Feeding; Epilepsy; Ethosuximide; Female; Humans; Infant; Lactation; Milk, Human; Phenobarbital; Primidone
PubMed: 35427849
DOI: 10.1016/j.seizure.2022.03.017 -
Internal and Emergency Medicine Sep 2022Given the increase in benzodiazepine (BZD) and Z-drug (ZD) use disorder, this study described the use of phenobarbital (PHB) as detoxification in clinical practice. A... (Observational Study)
Observational Study
Given the increase in benzodiazepine (BZD) and Z-drug (ZD) use disorder, this study described the use of phenobarbital (PHB) as detoxification in clinical practice. A 15-year observational retrospective study was performed on medical records of BZD-ZD use disorder patients detoxified with PHB at the Toxicology Unit and Poison Centre, Careggi University Hospital, Florence (Italy). A multivariate logistic regression was used to estimate odd ratios (ORs) and related 95% confidence intervals (CI) of "treatment failure" considering demographic and pharmacological characteristics. "Hospitalisation length", "PHB discharge dose", and "BZD-ZD free status" at discharge were also calculated. During detoxification, out of 355 patients (57% of men), with a mean age of 42.92 years, only 20 (5.6%) treatment failures were recorded: 19 were discharged against medical advice or due to misbehaviour, and only one for PHB-related non-serious skin rash. Analysis showed a higher probability to be BZD-ZD free at discharge for subjects who reported to be employed (OR 2.29; CI 95% 1.00-5.24), for those who abused oral drops of BZD-ZD (OR 2.16, CI 1.30-3.59), and for those treated with trazodone (OR 2.86, CI 1.14-7.17) during hospital stay. A hospitalisation length of > 7 days was observed for patients with opioid maintenance therapy (OR 2.07, CI 1.20-3.58) for substance use disorder, and for those treated with more than 300 mg/day of PHB equivalents at hospital admission (OR 1.68, CI 1.03-2.72). Our results suggested that PHB can be considered a valuable detoxification option for different types of BZD and ZD use disorder patients.
Topics: Adult; Analgesics, Opioid; Benzodiazepines; Humans; Male; Phenobarbital; Retrospective Studies; Substance-Related Disorders
PubMed: 35412225
DOI: 10.1007/s11739-022-02976-0 -
Medicine Dec 2022previous studies have shown that phenobarbital (PB) is a effective and safe drug in the treatment of benign convulsions with mild gastroenteritis (CwG), but there is a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
previous studies have shown that phenobarbital (PB) is a effective and safe drug in the treatment of benign convulsions with mild gastroenteritis (CwG), but there is a lack of large sample prospective randomized controlled study of different doses. This study was a prospective randomized controlled study on the efficacy and safety of different doses of phenobarbital for CwG. There has been no similar study.
METHODS
One hundred twenty CwG cases were included in this study. All of them were hospitalized in the Department of Neurology of Jiangxi Provincial Children's Hospital from January 2019 to August 2021. They were randomly divided into 10 mg/kg single dose group (Group A, n = 60) and 5 mg/kg single dose group (Group B, n = 60). The criteria for judging the efficacy of PB in our study were there was no convulsion in the course of acute gastroenteritis within 2 weeks after using PB.
RESULTS
The effective rate was 93.33% in group A and 80.00% in group B. There was significant difference between the 2 groups (P < .05). Drowsiness was the most frequent adverse reaction. 14 cases in group A and 7 cases in group B had drowsiness. There was no significant difference between the 2 groups in the incidence of adverse events such as somnolence, ataxia, abnormal liver function, anemia, abnormal leukocyte, respiratory depression, cognitive impairment, rash, abnormal platelet and abnormal renal function (P > .05). All side reaction were transient.
CONCLUSION
it is suggested that PB 10 mg/kg intravenously should be used as soon as possible for CwG, which has high effectiveness and safety.
Topics: Child; Humans; Infant; Prospective Studies; Seizures; Gastroenteritis; Phenobarbital; Incidence
PubMed: 36550836
DOI: 10.1097/MD.0000000000031495 -
JAMA Pediatrics Apr 2018More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie,... (Comparative Study)
Comparative Study Observational Study
IMPORTANCE
More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown.
OBJECTIVE
To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy.
DESIGN, SETTING, AND PARTICIPANTS
The Early Life Epilepsy Study-a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers-enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age.
EXPOSURES
Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure.
MAIN OUTCOMES AND MEASURES
The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations.
RESULTS
Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]).
CONCLUSIONS AND RELEVANCE
Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.
Topics: Anticonvulsants; Cohort Studies; Drug Prescriptions; Epilepsy; Female; Humans; Infant; Levetiracetam; Male; Phenobarbital; United States
PubMed: 29435578
DOI: 10.1001/jamapediatrics.2017.5211 -
The Cochrane Database of Systematic... Jan 2007The aim of drug treatment for epilepsy is to prevent seizures without causing adverse effects. To achieve this, drug dosages need to be individualised. Measuring... (Review)
Review
BACKGROUND
The aim of drug treatment for epilepsy is to prevent seizures without causing adverse effects. To achieve this, drug dosages need to be individualised. Measuring antiepileptic drug levels in body fluids (therapeutic drug monitoring) is frequently used to optimise drug dosage for individual patients.
OBJECTIVES
To review the evidence regarding the effects of therapeutic drug monitoring upon outcomes in epilepsy.
SEARCH STRATEGY
We searched the Cochrane Epilepsy Group Specialised Register (September 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 4), MEDLINE (January 1966 to April 2005) and EMBASE (1974 to May 2005). No language restrictions were imposed. We checked the reference lists of retrieved articles for additional reports of relevant studies.
SELECTION CRITERIA
Randomised controlled trials comparing the outcomes of antiepileptic drug monotherapy guided by therapeutic drug monitoring with drug treatment without the aid of therapeutic drug monitoring.
DATA COLLECTION AND ANALYSIS
We based this review on published aggregate data. The main outcomes measured were the proportions of patients achieving a 12-month remission from seizures, reporting adverse effects, and being withdrawn from the treatment they had been randomised to receive.
MAIN RESULTS
Only one study met the inclusion criteria for the review. In this open study, 180 patients with newly-diagnosed, untreated epilepsy were randomised to treatment with the antiepileptic drug selected by their physician either with or without therapeutic drug serum level monitoring as an aid to dosage adjustments. The antiepileptic drugs used were carbamazepine, valproate, phenytoin, phenobarbital and primidone. A 12-month remission from seizures was achieved by 60% of the patients randomised to therapeutic drug monitoring (intervention group) and by 61% in the control group. A total of 56% in the intervention group and 58% in the control group were seizure free during the last 12 months of follow up. Adverse effects were reported by 48% in the intervention group and 47% of the control group patients. Of those randomised to therapeutic drug monitoring, 62% completed the two-year follow up compared with 67% of the control group.
AUTHORS' CONCLUSIONS
We found no clear evidence to support routine antiepileptic drug serum concentration measurement with the aim of reaching predefined target ranges for the optimisation of treatment of patients with newly-diagnosed epilepsy with antiepileptic drug monotherapy. However, this does not exclude the possible usefulness of therapeutic drug monitoring of specific antiepileptic drugs during polytherapy, in special situations or in selected patients, although evidence is lacking.
Topics: Anticonvulsants; Carbamazepine; Drug Monitoring; Epilepsy; Humans; Phenobarbital; Phenytoin; Primidone; Valproic Acid
PubMed: 17253477
DOI: 10.1002/14651858.CD002216.pub2 -
Xenobiotica; the Fate of Foreign... Nov 2012In humans and rodents, phenobarbital (PB) induces hepatic and extra-hepatic drug metabolizing enzymes (DMEs) through the activation of specific nuclear receptors (NRs)....
In humans and rodents, phenobarbital (PB) induces hepatic and extra-hepatic drug metabolizing enzymes (DMEs) through the activation of specific nuclear receptors (NRs). In contrast, few data about PB transcriptional effects in veterinary species are available. The constitutive expression and modulation of PB-responsive NR and DME genes, following an oral PB challenge, were investigated in cattle liver and extra-hepatic tissues (duodenum, kidney, lung, testis, adrenal and muscle). Likewise to humans and rodents, target genes were expressed to a lower extent compared to the liver with few exceptions. Phenobarbital significantly affected hepatic CYP2B22, 2C31, 2C87, 3A and UDP-glucuronosyltransferase 1A1-like, glutathione S-transferase A1-like and sulfotransferase 1A1-like (SULT1A1-like) mRNAs and apoprotein amounts; in extra-hepatic tissues, only duodenum showed a significant down-regulation of SULT1A1-like gene and apoprotein. Nuclear receptor mRNAs were never affected by PB. Presented data are the first evidence about the constitutive expression of foremost DME and NR genes in cattle extra-hepatic tissues, and the data obtained following a PB challenge are suggestive of species-differences in drug metabolism; altogether, these information are of value for the extrapolation of pharmacotoxicological data among species, the characterization of drug-drug interactions as well as the animal and consumer's risk caused by harmful residues formation.
Topics: Animals; Cattle; Hypnotics and Sedatives; Inactivation, Metabolic; Liver; Male; Phenobarbital; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear
PubMed: 22694178
DOI: 10.3109/00498254.2012.694493 -
Journal of the Formosan Medical... May 2012Neonatal seizures are common and often reflect a severe underlying neurologic dysfunction in neonates. Phenobarbital remains the mainstay of treatment of neonatal... (Review)
Review
Neonatal seizures are common and often reflect a severe underlying neurologic dysfunction in neonates. Phenobarbital remains the mainstay of treatment of neonatal seizures, however, but it is ineffective in many patients and has adverse profiles in cognition. Furthermore, gamma-aminobutyric acid is excitatory early in brain development; therefore, treatment of neonatal seizures with phenobarbital must be cautious. In this review, we highlight the substantial progress that has been made in animal studies, and translate these results to the treatment of seizures in human neonates.
Topics: Animals; Anticonvulsants; Brain; Humans; Infant, Newborn; Phenobarbital; Seizures; Translational Research, Biomedical
PubMed: 22656393
DOI: 10.1016/j.jfma.2011.12.007 -
Journal of Pain and Symptom Management Jun 2016The oral route is compromised for nearly all patients approaching death. When agitation, seizures, or other intractable symptoms occur, a quick, discreet, comfortable,... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
The oral route is compromised for nearly all patients approaching death. When agitation, seizures, or other intractable symptoms occur, a quick, discreet, comfortable, and effective alternate route for medication delivery that is easy to administer in the home setting is highly desirable.
OBJECTIVES
To characterize the early absorption profile, variability, and comfort of phenobarbital given in microenema suspensions delivered via the Macy Catheter(®) (MC) vs. the same dose given via suppository.
METHODS
This was a randomized, open-label, crossover study comparing the early absorption profile of equal doses of phenobarbital administered rectally in three treatment phases: phenobarbital suppository and two different microenemas with phenobarbital tablets crushed and suspended in 6 mL (MC-6) or 20 mL (MC-20) of tap water.
RESULTS
Mean plasma phenobarbital concentrations at 10 minutes were 12× higher for MC-20 and 8× higher for MC-6 compared to suppository. Concentrations achieved in 30 minutes via MC-20 took almost three hours to achieve with suppository. Mean AUC values were higher for MC-20 and MC-6 (82% and 46%, respectively) vs. suppository (P < 0.05). There was less variability in absorption for MC-20 and MC-6 (1.4- to 1.9-fold difference) compared to a 4.4-fold difference via suppository. MC administrations were reported as "not uncomfortable" compared to suppositories, which were reported as "mildly uncomfortable" (P < 0.05).
CONCLUSION
These results suggest phenobarbital oral tablets crushed and suspended in water and administered via the MC is superior to suppository in delivering the medication reliably and rapidly.
Topics: Administration, Rectal; Adult; Area Under Curve; Catheterization; Cross-Over Studies; Female; Hospice Care; Humans; Hypnotics and Sedatives; Male; Phenobarbital; Suppositories; Young Adult
PubMed: 27112311
DOI: 10.1016/j.jpainsymman.2015.12.339