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PloS One 2023Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous...
BACKGROUND
Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants.
MATERIALS AND METHODS
The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001.
RESULTS
After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs.
CONCLUSIONS
PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.
Topics: Animals; Male; Rats; Anticonvulsants; Diazepam; Pentylenetetrazole; Phenobarbital; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Seizures; Sildenafil Citrate; Tadalafil
PubMed: 38033148
DOI: 10.1371/journal.pone.0294754 -
The Cochrane Database of Systematic... May 2021Any 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...
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.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Anticonvulsants; Cognition; Depression; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Male; Phenobarbital; Randomized Controlled Trials as Topic; Secondary Prevention
PubMed: 33973646
DOI: 10.1002/14651858.CD011922.pub4 -
The Annals of Pharmacotherapy Jan 2024Phenobarbital may offer advantages over benzodiazepines for severe alcohol withdrawal syndrome (SAWS), but its impact on clinical outcomes has not been fully elucidated.
BACKGROUND
Phenobarbital may offer advantages over benzodiazepines for severe alcohol withdrawal syndrome (SAWS), but its impact on clinical outcomes has not been fully elucidated.
OBJECTIVE
The purpose of this study was to determine the clinical impact of phenobarbital versus benzodiazepines for SAWS.
METHODS
This retrospective cohort study compared phenobarbital to benzodiazepines for the management of SAWS for patients admitted to progressive or intensive care units (ICUs) between July 2018 and July 2022. Patients included had a history of delirium tremens (DT) or seizures, Clinical Institute Withdrawal Assessment of Alcohol-Revised (CIWA-Ar) >15, or Prediction of Alcohol Withdrawal Severity Scale (PAWSS) score ≥4. The primary outcome was hospital length of stay (LOS). Secondary outcomes included progressive or ICU LOS, incidence of adjunctive pharmacotherapy, and incidence/duration of mechanical ventilation.
RESULTS
The final analysis included 126 phenobarbital and 98 benzodiazepine encounters. Patients treated with phenobarbital had shorter median hospital LOS versus those treated with benzodiazepines (2.8 vs 4.7 days; < 0.0001); a finding corroborated by multivariable analysis. The phenobarbital group also had shorter median progressive/ICU LOS (0.7 vs 1.3 days; < 0.0001), and lower incidence of dexmedetomidine ( < 0.0001) and antipsychotic initiation ( < 0.0001). Fewer patients in the phenobarbital group compared to the benzodiazepine group received new mechanical ventilation ( = 0.045), but median duration was similar (1.2 vs 1.6 days; = 1.00).
CONCLUSION AND RELEVANCE
Scheduled phenobarbital was associated with decreased hospital LOS compared to benzodiazepines for SAWS. This was the first study to compare outcomes of fixed-dose, nonoverlapping phenobarbital to benzodiazepines in patients with clearly defined SAWS and details a readily implementable protocol.
PubMed: 38247044
DOI: 10.1177/10600280231221241 -
European Journal of Clinical... Oct 2022Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the... (Review)
Review
Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the event of short-term (5 days) nirmatrelvir/ritonavir co-exposure. Therefore, in this report, we identified drugs that require dose adjustment because of drug-drug interactions (DDIs) between nirmatrelvir/ritonavir and AEDs. We hereby used four databases (Micromedex Drug Interaction, Liverpool Drug Interaction Group for COVID-19 Therapies, Medscape Drug Interaction Checker, and Lexicomp Drug Interactions) and DDI-Predictor.In the light of applying the DDI-Predictor, for carbamazepine, clobazam, oxcarbazepine, eslicarbazepine, phenytoin, phenobarbital, pentobarbital, rufinamide, and valproate as CYP3A4 inducers, we recommend that a dose adjustment of short-term nirmatrelvir/ritonavir as a substrate (victim) drug would be more appropriate instead of these AEDs to avoid impending DDI-related threats in patients with epilepsy.
Topics: Anticonvulsants; Carbamazepine; Clobazam; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Humans; Oxcarbazepine; Pentobarbital; Phenobarbital; Phenytoin; Ritonavir; Valproic Acid; COVID-19 Drug Treatment
PubMed: 35930055
DOI: 10.1007/s00228-022-03370-7 -
Implementation of a Phenobarbital-based Pathway for Severe Alcohol Withdrawal: A Mixed-Method Study.Annals of the American Thoracic Society Oct 2021Several institutions have implemented phenobarbital-based pathways for the treatment of alcohol withdrawal syndrome (AWS). However, little is known about the care...
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. 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. 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. Four themes related to clinician acceptability and feasibility of the phenobarbital-based pathway emerged: ) designing a pathway that balanced standardization with clinical judgment promoted acceptability, ) pathway simplicity promoted feasibility, ) implementing pathway-driven care streamlined the workflow, and ) 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 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). 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.
Topics: Alcoholism; Humans; Length of Stay; Phenobarbital; Retrospective Studies; Substance Withdrawal Syndrome
PubMed: 33945771
DOI: 10.1513/AnnalsATS.202102-121OC -
Xenobiotica; the Fate of Foreign... Aug 2021To compare drug-drug interaction (DDI) between tacrolimus and different formulations of phenobarbital in paediatrics and adults.Physiologically based pharmacokinetics...
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 C 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.
Topics: Adult; Area Under Curve; Child; Drug Interactions; Humans; Immunosuppressive Agents; Models, Biological; Pediatrics; Pharmaceutical Preparations; Phenobarbital; Tacrolimus
PubMed: 34151692
DOI: 10.1080/00498254.2021.1943564 -
Expert Review of Neurotherapeutics Jul 2022Seizures are the main neurological emergency during the neonatal period and are mostly acute and focal. The prognosis mainly depends on the underlying etiology.... (Review)
Review
INTRODUCTION
Seizures are the main neurological emergency during the neonatal period and are mostly acute and focal. The prognosis mainly depends on the underlying etiology. Conventional multichannel video-electroencephalographic (cEEG) monitoring is the gold standard for diagnosis, but treatment remains a challenge.
AREAS COVERED
This review, based on PubMed search over the last 4 decades, focuses on the current treatment options for neonatal seizures based on cEEG monitoring. There is still no consensus on seizure therapy, owing to poor scientific evidence. Traditionally, the first-line treatments are phenobarbital and phenytoin, followed by midazolam and lidocaine, but their efficacy is limited. Therefore, current evidence strongly suggests the use of alternative antiseizure medications. Randomized controlled trials of new drugs are ongoing.
EXPERT OPINION
Therapy for neonatal seizures should be prompt and tailored, based on semeiology, mirror of the underlying cause, and cEEG features. Further research should focus on antiseizure medications that directly act on the etiopathogenetic mechanism responsible for seizures and are therefore more effective in seizure control.
Topics: Anticonvulsants; Electroencephalography; Epilepsy; Humans; Infant, Newborn; Infant, Newborn, Diseases; Phenobarbital; Seizures
PubMed: 35876114
DOI: 10.1080/14737175.2022.2105698 -
Neurochemical Research Feb 2021Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were...
Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were determined in the tonic-clonic seizure model and rotarod test in mice. The interaction profile of four classic antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) with TPL-16 was also determined in the tonic-clonic seizure model in mice. The protective effects of TPL-16 from tonic-clonic seizures (as ED values) and acute neurotoxic effects of TPL-16 (as TD values) were determined in 4 pretreatment times (15, 30, 60 and 120 min after its i.p. administration), in adult male albino Swiss mice. The interaction profile of TPL-16 with carbamazepine, phenobarbital, phenytoin and valproate in the tonic-clonic seizure model was determined with isobolographic analysis. Total concentrations of carbamazepine, phenobarbital, phenytoin and valproate were measured in the mouse brain homogenates. The candidate for novel antiepileptic drug (TPL-16) administered separately 15 min before experiments, has a beneficial profile with protective index (as ratio of TD and ED values) amounting to 5.58. The combination of TPL-16 with valproate produced synergistic interaction in the tonic-clonic seizure model in mice. The combinations of TPL-16 with carbamazepine, phenobarbital and phenytoin produced additive interaction in terms of protection from tonic-clonic seizures in mice. None of the total brain concentrations of classic AEDs were changed significantly after TPL-16 administration in mice. Synergistic interaction for TPL-16 with valproate and the additive interaction for TPL-16 with carbamazepine, phenobarbital and phenytoin in the tonic-clonic seizures in mice allows for recommending TPL-16 as the promising drug for further experimental and clinical testing.
Topics: Animals; Anticonvulsants; Carbamazepine; Drug Synergism; Male; Mice; Muscle Strength; Phenobarbital; Phenytoin; Rotarod Performance Test; Seizures; Thiones; Triazoles; Valproic Acid
PubMed: 33206316
DOI: 10.1007/s11064-020-03175-z -
Epilepsia Open Dec 2021Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate...
OBJECTIVE
Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist.
METHODS
We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset.
RESULTS
The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity.
SIGNIFICANCE
Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.
Topics: Animals; Anticonvulsants; Brain; Drug Therapy, Combination; Ketamine; Midazolam; Phenobarbital; Rats; Soman
PubMed: 34657398
DOI: 10.1002/epi4.12552 -
Pediatrics Mar 2021Despite the neonatal opioid withdrawal syndrome (NOWS) epidemic in the United States, evidence is limited for pharmacologic management when first-line opioid medications...
BACKGROUND AND OBJECTIVES
Despite the neonatal opioid withdrawal syndrome (NOWS) epidemic in the United States, evidence is limited for pharmacologic management when first-line opioid medications fail to control symptoms. The objective with this study was to evaluate outcomes of infants receiving secondary therapy with phenobarbital compared with clonidine, in combination with morphine, for the treatment of NOWS.
METHODS
We performed a retrospective cohort study of infants with NOWS from 30 hospitals. The primary outcome measures were the length of hospital stay, duration of opioid treatment, and peak morphine dose. Outcomes were compared by group by using analysis of variance and multivariable linear regression controlling for relevant confounders.
RESULTS
Of 563 infants with NOWS treated with morphine, 32% ( = 180) also received a secondary medication. Seventy-two received phenobarbital and 108 received clonidine. After adjustment for covariates, length of hospital stay was 10 days shorter, and, in some models, duration of morphine treatment was 7.5 days shorter in infants receiving phenobarbital compared with those receiving clonidine, with no difference in peak morphine dose. Infants were more likely to be discharged from the hospital on phenobarbital than clonidine (78% vs 29%, < .0001).
CONCLUSIONS
Among infants with NOWS receiving morphine and secondary therapy, those treated with phenobarbital had shorter length of hospital stay and shorter morphine treatment duration than clonidine-treated infants but were discharged from the hospital more often on secondary medication. Further investigation is warranted to determine if the benefits of shorter hospital stay and shorter duration of morphine therapy justify the possible neurodevelopmental consequences of phenobarbital use in infants with NOWS.
Topics: Analgesics; Analgesics, Opioid; Clonidine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Length of Stay; Linear Models; Male; Morphine; Neonatal Abstinence Syndrome; Phenobarbital; Retrospective Studies
PubMed: 33632932
DOI: 10.1542/peds.2020-017830