-
CNS & Neurological Disorders Drug... 2023Drug design is one of the critical aspects of the drug development process. The present review focused on different heterocyclic molecules having anticonvulsant activity... (Review)
Review
Drug design is one of the critical aspects of the drug development process. The present review focused on different heterocyclic molecules having anticonvulsant activity with structural diversity and common pharmacophoric features. For the first time (1995), Dimmock and his team introduced specific arrangements of three important pharmacophores for anticonvulsant activity. These pharmacophores include two hydrophobic binding sites and one hydrogen binding site. After a few years (2012), Pandeya modified Dimmock's concept by adding one more pharmacophoric feature as an electron donor in the previously suggested pharmacophoric arrangement of the anticonvulsant. As a result, numerous scientists designed anticonvulsant drugs based on Dimmock's and Pandeya's concept. In addition, marketed anticonvulsant preparation containing Riluzole, Phenobarbital, Progabide, Ralitoline, etc., also holds the suggested pharmacophores by Dimmock and Pandeya's pharmacophoric concept. This review mainly focuses on the compilation of reported scientific literature in the last decade on the pharmacophoric features of different heterocyclic anticonvulsants, which will help develop new anticonvulsants.
Topics: Humans; Anticonvulsants; Seizures; Pharmacophore; Electroshock; Phenobarbital
PubMed: 35366788
DOI: 10.2174/1871527321666220401115529 -
European Journal of Internal Medicine Jun 2023Phenobarbital (PB) has been acknowledged among clinicians as a potential alternative to benzodiazepines (BZD) to decrease the need for hospital length of stay and...
BACKGROUND
Phenobarbital (PB) has been acknowledged among clinicians as a potential alternative to benzodiazepines (BZD) to decrease the need for hospital length of stay and complications associated with alcohol withdrawal syndrome (AWS). However, the level of evidence, including appropriate dosing, is unclear. We aim to summarize the evidence regarding PB used in AWS and provide future agendas for research.
METHODS
Following the PRISMA guidelines, we searched MEDLINE, EMBASE, ClinicalTrials.gov, and WHO ICTRP for all peer-reviewed articles and clinical trials using keywords including"alcohol withdrawal", "delirium tremens", "phenobarbital," and "barbiturate" from their inception to September 18, 2022.
RESULTS
We included 20 articles, nine in the emergency department (ED) and 11 in the general floors or intensive care units (ICUs). Studies performed in the ED included two RCTs, although both suffered from a considerably small sample size. Six studies done in the general floors or ICUs compared PB and BZD monotherapy, while four compared the utility of adjunct PB in addition to BZD compared with BZD monotherapy and one was a database study without specific dosing information. Overall, there was considerable heterogeneity in PB dosing, measured outcomes, and AWS severity measurement scales.
CONCLUSION
This systematic review summarizes the current evidence related to PB use in AWS. While considerable heterogeneity exists among studies available, PB as monotherapy without BZD may be a safe and effective alternative in AWS treatment. Future prospective studies or trials should focus on the standardization of PB dosing and outcomes.
Topics: Humans; Substance Withdrawal Syndrome; Alcoholism; Alcohol Withdrawal Delirium; Prospective Studies; Retrospective Studies; Phenobarbital; Benzodiazepines
PubMed: 36935249
DOI: 10.1016/j.ejim.2023.03.006 -
Drug Metabolism and Disposition: the... Feb 2023Phenobarbital (PB) is a commonly prescribed anti-epileptic drug that can also benefit newborns from hyperbilirubinemia. Being the first drug demonstrating hepatic... (Review)
Review
Phenobarbital (PB) is a commonly prescribed anti-epileptic drug that can also benefit newborns from hyperbilirubinemia. Being the first drug demonstrating hepatic induction of cytochrome P450 (CYP), PB has since been broadly used as a model compound to study xenobiotic-induced drug metabolism and clearance. Mechanistically, PB-mediated CYP induction is linked to a number of nuclear receptors, such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and estrogen receptor , with CAR being the predominant regulator. Unlike prototypical agonistic ligands, PB-mediated activation of CAR does not involve direct binding with the receptor. Instead, dephosphorylation of threonine 38 in the DNA-binding domain of CAR was delineated as a key signaling event underlying PB-mediated indirect activation of CAR. Further studies revealed that such phosphorylation sites appear to be highly conserved among most human nuclear receptors. Interestingly, while PB is a pan-CAR activator in both animals and humans, PB activates human but not mouse PXR. The species-specific role of PB in gene regulation is a key determinant of its implication in xenobiotic metabolism, drug-drug interactions, energy homeostasis, and cell proliferation. In this review, we summarize the recent progress in our understanding of PB-provoked transactivation of nuclear receptors with a focus on CAR and PXR. SIGNIFICANCE STATEMENT: Extensive studies using PB as a research tool have significantly advanced our understanding of the molecular basis underlying nuclear receptor-mediated drug metabolism, drug-drug interactions, energy homeostasis, and cell proliferation. In particular, CAR has been established as a cell signaling-regulated nuclear receptor in addition to ligand-dependent functionality. This mini-review highlights the mechanisms by which PB transactivates CAR and PXR.
Topics: Infant, Newborn; Animals; Humans; Receptors, Steroid; Xenobiotics; Receptors, Cytoplasmic and Nuclear; Liver; Phenobarbital; Cytochrome P-450 Enzyme System
PubMed: 36351837
DOI: 10.1124/dmd.122.000859 -
Epilepsy Research Sep 2023Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We aimed to evaluate the long-term effects of intravenous phenobarbital on adult patients with GCSE.
METHODS
This randomized clinical trial with a 12-month follow-up was performed in Xuanwu Hospital, Capital Medical University (Beijing, China) between February 2011 and December 2021. After the failure of intravenous diazepam treatment, adult patients with GCSE were randomized to receive either intravenous phenobarbital or valproate. Neurological outcome within 12-month was dichotomized as good (modified Rankin scale, mRS 0-2) or poor (mRS 3-6). Cognitive function was measured by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) were tested for mood disorders.
RESULTS
We consecutively recruited 166 patients with GCSE. After excluding individuals with termination after intravenous diazepam (n = 61), and with other exclusion criteria (n = 7), 98 patients were included and 88.0% (66/75) of survivors achieved seizure freedom at 12-month. Forty-five patients (45.92%) had good outcomes at 3-month and 57 patients (58.16%) had good outcomes at 12-month. And 46.67% (35/75) of survivors showed mRS improvement at 12-month (phenobarbital group, n = 17 vs. valproate group, n = 18, P = 0.321). Despite there was no significant difference with respect to good outcomes at 3-month (54.0% vs. 37.5%, P = 0.101), the rate of good outcomes in phenobarbital group was higher than valproate group at 12-month (68.0% vs. 47.92%, P = 0.044). A total of 43 patients successfully participated cognitive and emotional tests. Mild cognitive impairment was found in 7.14% of phenobarbital group and 50.0% in valproate group (P = 0.026). In addition, there were no significant differences with respect to anxiety (36.36% vs. 38.10%) and depression (31.82% vs. 47.62%) between the phenobarbital and valproate groups.
CONCLUSIONS
Combined with long term conventional therapy, intravenous phenobarbital group had more good outcomes than intravenous valproate group in Chinese adult patients with GCSE up to 12-month follow-up. This finding may prompt the option of intravenous phenobarbital especially in patients with limited access to new antiseizure drugs.
Topics: Humans; Adult; Valproic Acid; Anticonvulsants; Follow-Up Studies; Treatment Outcome; Status Epilepticus; Phenobarbital; Diazepam
PubMed: 37467704
DOI: 10.1016/j.eplepsyres.2023.107187 -
Neuropediatrics Oct 2023Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE)....
BACKGROUND
Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE). This systematic review aims to identify the best reported therapy for these patients, relating to phenotype, neurodevelopmental outcome, and an eventual correlation between phenotype and genotype.
METHODS
We searched on PubMed using the search terms "" AND "therapy" and "" AND "treatment"; we found 304 articles. Of these, 29 met our criteria. We collected the data from 194 patients. All 29 articles were retrospective studies.
RESULTS
In all, 104 patients were classified as DEE and 90 as BFNS. After treatment began, 95% of BFNS patients became seizure free, whereas the seizures stopped only in 73% of those with DEE. Phenobarbital and sodium channel blockers were the most used treatment in BFNS. Most of the DEE patients (95%) needed polytherapy for seizure control and even that did not prevent subsequent developmental impairment (77%).Missense mutations were discovered in 96% of DEE patients; these were less common in BFNS (50%), followed by large deletion (16%), truncation (16%), splice donor site (10%), and frameshift (7%).
CONCLUSION
Phenobarbital or carbamazepine appears to be the most effective antiseizure medication for children with a "benign" variant. On the contrary, polytherapy is often needed for DEE patients, even if it does not seem to improve neurological outcomes. In DEE patients, most mutations were located in S4 and S6 helix, which could serve as a potential target for the development of more specific treatment in the future.
Topics: Child; Infant, Newborn; Humans; Retrospective Studies; KCNQ2 Potassium Channel; Epilepsy, Benign Neonatal; Mutation; Seizures; Phenotype; Genotype; Phenobarbital
PubMed: 36948217
DOI: 10.1055/a-2060-4576 -
Epilepsy & Behavior : E&B Apr 2023Phenobarbital (PB) is one of the oldest Antiseizure Medicines (ASMs), which is in clinical use since 1912. Its value in the treatment of Status epilepticus is currently... (Review)
Review
Phenobarbital (PB) is one of the oldest Antiseizure Medicines (ASMs), which is in clinical use since 1912. Its value in the treatment of Status epilepticus is currently discussed controversially. Phenobarbital has fallen out of favor in many countries across Europe because of reports of hypotension, arrhythmias, and hypopnea. Phenobarbital has a strong antiseizure effect with remarkably little sedation. It exerts its clinical effects, through the increase of GABE-ergic inhibition and decrease of glutamatergic excitation by inhibition of AMPA receptors. Despite good preclinical evidence, there are remarkably few randomized controlled studies on humans in SE, which suggest, that it is at least as good as lorazepam in first-line treatment in early SE, and significantly better than valproic acid in benzodiazepine-resistant SE. Data from randomized trials and large non-randomized prospective and retrospective studies suggest, that Phenobarbital is well tolerated even if used in very high dose protocols. Thus, despite its decline in its popularity at least in Europe and North America, it should be considered a highly cost-effective treatment for early and established SE, not only in resource-limited settings. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.
Topics: Humans; Anticonvulsants; Retrospective Studies; Prospective Studies; Status Epilepticus; Phenobarbital
PubMed: 36807987
DOI: 10.1016/j.yebeh.2023.109104 -
Epilepsy & Behavior : E&B Jun 2022New-onset movement disorders have been frequently reported in association with the use of antiseizure medications (ASMs). The frequency of specific motor manifestations... (Review)
Review
New-onset movement disorders have been frequently reported in association with the use of antiseizure medications (ASMs). The frequency of specific motor manifestations and the spectrum of their semiology for various ASMs have not been well characterized. We carried out a systematic review of literature and conducted a search on CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and Scopus from inception to April 2021. We compiled the data for all currently available ASMs using the conventional terminology of movement disorders. Among 5123 manuscripts identified by the search, 437 met the inclusion criteria. The largest number of reports of abnormal movements were in association with phenobarbital, valproic acid, lacosamide, and perampanel, and predominantly included tremor and ataxia. The majority of attempted interventions for all agents were discontinuation of the offending drug or dose reduction which led to the resolution of symptoms in most patients. Familiarity with the movement disorder phenomenology previously encountered in relation with specific ASMs facilitates early recognition of adverse effects and timely institution of targeted interventions.
Topics: Anticonvulsants; Humans; Lacosamide; Movement Disorders; Phenobarbital; Valproic Acid
PubMed: 35483204
DOI: 10.1016/j.yebeh.2022.108693 -
The American Journal of Emergency... Apr 2022While there is ample data supporting the use of barbiturates and benzodiazepines (BZDs) for the treatment of alcohol withdrawal, there is a paucity of information on...
BACKGROUND
While there is ample data supporting the use of barbiturates and benzodiazepines (BZDs) for the treatment of alcohol withdrawal, there is a paucity of information on treating recurrent withdrawal among high healthcare utilizing patients. The purpose of this study was to assess the efficacy and safety of phenobarbital (PB), with or without adjuvant BZDs, for treatment of acute alcohol withdrawal in the emergency department (ED) in patients with high rates of recurrent withdrawal.
METHODS
This non-matched, self-controlled, retrospective cohort study evaluated patients seen in the ED of an urban trauma center and safety-net teaching hospital between July 1st, 2018, and July 31st, 2019. Patients treated for alcohol withdrawal were included if they had at least one visit where they received intravenous PB with or without BZDs, then during a separate encounter received BZD only. Each encounter was then assigned to a treatment group based on administration of PB only, BZD only, or the combination of PB and BZD. The primary outcomes were admission to hospital or discharge and return to the ED for any reason within 48 h of disposition.
RESULTS
A total of 137 unique patients were included, with 642 encounters composed of 245 PB only, 293 BZD only, and 104 combination visitations. No significant difference was found between the PB, BZD, or combination treatment groups for rates of admission (36.7%, 38.9%, and 46.1% respectively) or for return within 48 h (17.1%, 15.0%, and 13.5%). There was a significantly longer ED length of stay for the combination group (8.6 h) compared to either the PB or BZD only groups (6.4 and 7.0 h, respectively, p < 0.05) but not between the monotherapy groups. There were significantly higher rates of ICU admission and hypotension when PB and BZDs were used together (8.6% and 15.4%) versus either agent alone (PB 2.9% and 5.7%, BZD 3.8% and 4.5%, p < 0.05).
CONCLUSION
Among patients with multiple visits presenting with alcohol withdrawal, treatment with PB, BZDs, or both did not result in significantly different rates of admission or readmission within 48 h. Receiving a combination of PB and BZDs was associated with significantly longer ED length of stay, more ICU care, and increased incidence of hypotension as compared to either PB or a BZD alone.
Topics: Alcoholism; Benzodiazepines; Humans; Hypotension; Phenobarbital; Retrospective Studies; Substance Withdrawal Syndrome
PubMed: 35219012
DOI: 10.1016/j.ajem.2022.02.020 -
Journal of Feline Medicine and Surgery Sep 2023Phenobarbital (PB) q12h is the most common treatment recommendation for cats with recurrent epileptic seizures. Medicating cats may be challenging and result in...
OBJECTIVES
Phenobarbital (PB) q12h is the most common treatment recommendation for cats with recurrent epileptic seizures. Medicating cats may be challenging and result in decreased quality of life for both cat and owner. The aim of this retrospective study was to evaluate treatment with oral PB q24h in cats with presumptive idiopathic epilepsy.
METHODS
Nine cats with presumptive idiopathic epilepsy, receiving oral PB q24h, were included in a retrospective descriptive study.
RESULTS
Seizure remission was achieved in 88% (8/9) of the cats and good seizure control in 12% (1/9) of the cats, treated with a mean dose of oral PB of 2.6 mg/kg q24h (range 1.4-3.8 mg/kg). No cats required an increase of their PB frequency at any time during a mean follow-up period of 3.5 years (range 1.1-8.0 years). No cats displayed side effects or issues with compliance at the last recorded follow-up.
CONCLUSIONS AND RELEVANCE
Once-a-day administration of PB for feline epilepsy was safe and resulted in satisfactory seizure control for the nine cats included in this study. The results of this study justify exploring this topic further in larger prospective studies.
Topics: Cats; Animals; Retrospective Studies; Prospective Studies; Quality of Life; Epilepsy; Seizures; Phenobarbital; Cat Diseases
PubMed: 37747329
DOI: 10.1177/1098612X231196806 -
Addiction (Abingdon, England) Jul 2023Phenobarbital interacts with the mortality-reducing opioid agonist therapies buprenorphine and methadone, risking delayed opioid withdrawal and relapse when administered...
Phenobarbital interacts with the mortality-reducing opioid agonist therapies buprenorphine and methadone, risking delayed opioid withdrawal and relapse when administered concurrently. With increased adoption of phenobarbital into alcohol withdrawal protocols there should be safeguards in place to—in most cases—avoid phenobarbital for patients with a concurrent opioid use disorder.
Topics: Humans; Analgesics, Opioid; Substance Withdrawal Syndrome; Alcoholism; Opioid Epidemic; Buprenorphine; Methadone; Phenobarbital; Opioid-Related Disorders; Opiate Substitution Treatment
PubMed: 36967706
DOI: 10.1111/add.16194