Phenobarbital Concentrations Research Articles

Preliminary study of the association between the elimination parameters of phenytoin and phenobarbital.

Therapeutic drug monitoring is essential for both phenytoin and phenobarbital therapy given their narrow therapeutic indexes. Nevertheless, the measurement of either phenytoin or phenobarbital concentrations might not be available in some rural hospitals. Information assisting individualized phenytoin and phenobarbital combination therapy is important. This study's objective was to determine the relationship between the maximum rate of metabolism of phenytoin (Vmax) and phenobarbital clearance (CLPB), which can serve as a guide to individualized drug therapy. Data on phenytoin and phenobarbital concentrations of 19 epileptic patients concurrently receiving both drugs were obtained from medical records. Phenytoin and phenobarbital pharmacokinetic parameters were studied at steady-state conditions. The relationship between the elimination parameters of both drugs was determined using simple linear regression. A high correlation coefficient between Vmax and CLPB was found [r=0.744; p<0.001 for Vmax (mg/kg/day) vs. CLPB (L/kg/day)]. Such a relatively strong linear relationship between the elimination parameters of both drugs indicates that Vmax might be predicted from CLPB and vice versa. Regression equations were established for estimating Vmax from CLPB, and vice versa in patients treated with combination of phenytoin and phenobarbital. These proposed equations can be of use in aiding individualized drug therapy.

Serum Phenobarbital Concentrations and Timing of Blood Collection in Epileptic Dogs on Chronic Treatment

Serum Phenobarbital Concentrations and Timing of Blood Collection in Epileptic Dogs on Chronic Treatment

Standardized Treatment of Neonatal Status Epilepticus Improves Outcome.

We aimed to decrease practice variation in treatment of neonatal status epilepticus by implementing a standardized protocol. Our primary goal was to achieve 80% adherence to the algorithm within 12 months. Secondary outcome measures included serum phenobarbital concentrations, number of patients progressing from seizures to status epilepticus, and length of hospital stay. Data collection occurred for 6 months prior and 12 months following protocol implementation. Adherence of 80% within 12 months was partially achieved in patients diagnosed in our hospital; in pretreated patients, adherence was not achieved. Maximum phenobarbital concentrations were decreased (56.8 vs 41.0 µg/mL), fewer patients progressed from seizures to status epilepticus (46% vs 36%), and hospital length of stay decreased by 9.7 days in survivors. In conclusion, standardized, protocol-driven treatment of neonatal status epilepticus improves consistency and short-term outcome.

Levetiracetam in the management of feline audiogenic reflex seizures: a randomised, controlled, open-label study.

Objectives Currently, there are no published randomised, controlled veterinary trials evaluating the efficacy of antiepileptic medication in the treatment of myoclonic seizures. Myoclonic seizures are a hallmark of feline audiogenic seizures (FARS). Methods This prospective, randomised, open-label trial compared the efficacy and tolerability of levetiracetam (20-25 mg/kg q8h) with phenobarbital (3-5 mg/kg q12h) in cats with suspected FARS that experienced myoclonic seizures. Cats were included that had ⩾12 myoclonic seizure days during a prospective 12 week baseline period. This was followed by a 4 week titration phase (until a therapeutic serum concentration of phenobarbital was achieved) and a 12 week treatment phase. Results Fifty-seven cats completed the study: 28 in the levetiracetam group and 29 in the phenobarbital group. A reduction of ⩾50% in the number of myoclonic seizure days was seen in 100% of patients in the levetiracetam group and in 3% of patients in the phenobarbital group ( P <0.001) during the treatment period. Levetiracetam-treated cats had higher freedom from myoclonic seizures (50.0% vs 0%; P <0.001) during the treatment period. The most common adverse events were lethargy, inappetence and ataxia, with no difference in incidence between levetiracetam and phenobarbital. Adverse events were mild and transient with levetiracetam but persistent with phenobarbital. Conclusions and relevance These results suggest that levetiracetam is an effective and well tolerated treatment for cats with myoclonic seizures and is more effective than phenobarbital. Whether it will prevent the occurrence of generalised tonic-clonic seizures and other forebrain signs if used early in the course of FARS is not yet clear.

Pharmacokinetics of Phenobarbital in Microenema Via Macy Catheter Versus Suppository

ContextThe 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. ObjectivesTo 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. MethodsThis 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. ResultsMean 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). ConclusionThese 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.

Propafenone enhances the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model.

Antiarrhythmic and antiepileptic drugs share some mechanisms of actions. Therefore, possibility of interactions between these in epileptic patients with cardiac arrhythmias is quite considerable. Herein, we attempted to assess interactions between propafenone and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital. Effects of propafenone on seizures were determined in the electroconvulsive threshold test in mice. Interactions between propafenone and antiepileptic drugs were estimated in the model of maximal electroshock. Motor coordination was evaluated in the chimney test, while long-term memory in the passive-avoidance task. Brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. Propafenone up to 50mg/kg did not affect the electroconvulsive threshold, significantly enhancing this parameter at doses of 60-90mg/kg. Applied at its subthreshold doses, propafenone potentiated the antielectroshock action of all four tested classical antiepileptics: carbamazepine, valproate, phenytoin, and phenobarbital. Propafenone alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory in mice. Propafenone did not change brain concentration of phenytoin and phenobarbital; however, it significantly decreased brain levels of carbamazepine and increased those of valproate. Propafenone exhibits its own anticonvulsant effect and enhances the action of classical antiepileptic drugs against electrically induced convulsions in mice. Further investigations are required to determine the effect of propafenone on antiepileptic therapy in humans.

Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics.

Phenobarbital is an effective and safe anticonvulsant drug introduced in clinical use in 1904. Its mechanism of action is the synaptic inhibition through an action on GABAA. The loading dose of phenobarbital is 20 mg/kg intravenously and the maintenance dose is 3 to 4 mg/kg by mouth. The serum concentration of phenobarbital is up to 40 µg/ml. Nonresponders should receive additional doses of 5 to 10 mg/kg until seizures stop. Infants with refractory seizures may have a serum concentration of phenobarbital of 100 µg/ml. Phenobarbital is metabolized in the liver by CYP2C9 with minor metabolism by CYP2C19 and CYP2E1. A quarter of the dose of phenobarbital is excreted unchanged in the urine. In adults, the half-life of phenobarbital is 100 hours and in term and preterm infants is 103 and 141 hours, respectively. The half-life of phenobarbital decreases 4.6 hours per day and it is 67 hours in infants 4 week old.

The effects of cimetidine chronic treatment on conventional antiepileptic drugs in mice

The aim of this study was to evaluate the effects of 1-day, 7-day and 14-day administrations of cimetidine on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, phenytoin and phenobarbital) against maximal electroshock (MES)-induced convulsions in mice. Electroconvulsions were evoked in Albino Swiss mice by a current delivered via ear-clip electrodes. In addition, the effects of cimetidine, AEDs alone and their combinations were studied on performance and long-term memory tests. Pharmacokinetic changes in plasma and brain concentrations of AEDs after cimetidine administration were evaluated with immunofluorescence. Cimetidine (up to 100mg/kg) after 1-day administration did not affect the electroconvulsive threshold in animals. Moreover, in the 14-day treatment, cimetidine administered at a dose of 40mg/kg did not significantly change the electroconvulsive threshold in the MES-test, cimetidine administered 14-day (at 20mg/kg) significantly increased the anticonvulsant activity of carbamazepine, staying without effects after a 1-day and 7-day studies. In contrast, both the 7-day and 14-day administrations of cimetidine resulted in significant reductions of protective efficacy of the phenobarbital. Only valproate and phenytoin were not affected by cimetidine (20mg/kg) in all experimental period. Cimetidine administered 1-day, did not alter total brain concentrations and free plasma levels of all AEDs tested, whilst the 14-day study elevated carbamazepine plasma and brain concentration and reduced phenobarbital brain concentration. Cimetidine co-applied with AEDs did not impair performance of mice evaluated in the chimney test however, it worsened long-term memory in animals. Based on this preclinical study, a special caution is advised when treating epileptic patients with combinations of phenobarbital or carbamazepine with cimetidine.

Evaluation of postmortem drug concentrations in cerebrospinal fluid compared with blood and pericardial fluid

In forensic toxicology, body fluids are important materials not only as alternatives to blood but also for investigation of postmortem drug redistributions and pharmaco-/toxicokinetic analysis; however, there are limited data on postmortem drug distributions in cerebrospinal fluid (CSF). The present study reviewed toxicological data of autopsy cases (n=103), in which drugs were detected in CSF using gas chromatography/mass spectrometry (GC/MS), to investigate drug concentrations in CSF, compared with blood and pericardial fluid (PCF) concentrations. Oral/injected amphetamines (n=23) showed similar CSF and blood/PCF concentrations with partly lower CSF concentrations (about ×0.5–1.1). CSF concentrations of the venous anesthetic midazolam (n=7) were lower with poor correlations. Oral caffeine (n=15), acetaminophen (n=7), chlorpheniramine (n=6), dihydrocodeine (n=6), and phenobarbital (n=21) showed equivalent to lower CSF concentrations (about ×0.2–1.2), compared with blood and PCF concentrations; however, CSF phenobarbital concentrations were high in a fatal intoxication case. CSF concentrations of phenothiazine derivatives (n=29) were markedly lower (about ×0.1) than blood/PCF concentrations. The distribution of the local anesthetic lidocaine used in critical medical care (n=49) markedly varied by case. These findings suggest that CSF is useful in routine forensic toxicology as an alternative to blood as well as for investigating pharmaco-/toxicokinetics and postmortem redistributions.

Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model.

RationaleSeizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies.ObjectivesThe aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs)—carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA).MethodsAnticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects.ResultsIntraperitoneal injection of 75 mg kg−1 of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg−1 of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg−1 dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg−1) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT.ConclusionsEnhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients.

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314l/h. Based on the final model, co-therapy with usual VPA dose of 1000mg/day, resulted in PB CL/F average decrease of about 25%, while 2000mg/day leads to an average 50% decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

Effects of caste on the expression of genes associated with septic injury and xenobiotic exposure in the Formosan subterranean termite.

As social insects, termites live in densely populated colonies with specialized castes under conditions conducive to microbial growth and transmission. Furthermore, termites are exposed to xenobiotics in soil and their lignocellulose diet. Therefore, termites are valuable models for studying gene expression involved in response to septic injury, immunity and detoxification in relation to caste membership. In this study, workers and soldiers of the Formosan subterranean termite, Coptotermes formosanus, were challenged by bacterial injection or by no-choice feeding with a sublethal concentration (0.5%) of phenobarbital. Constitutive and induced expression of six putative immune response genes (two encoding for lectin-like proteins, one for a ficolin-precursor, one for the Down syndrome cell adhesion molecule, one for a chitin binding protein, and one for the gram-negative binding protein 2) and four putative detoxification genes (two encoding for cytochrome P450s, one for glutathione S-transferase, and one for the multi antimicrobial extrusion protein), were measured via quantitative real time polymerase chain reaction and compared within and among 1) colonies, 2) treatment types and 3) castes via ANOVA. Eight genes were inducible by septic injury, feeding with phenobarbital or both. Colony origin had no effect on inducibility or differential gene expression. However, treatment type showed significant effects on the expression of the eight inducible genes. Caste effects on expression levels were significant in five of the eight inducible genes with constitutive and induced expression of most target genes being higher in workers than in soldiers.

Developmental cardiotoxicity effects of four commonly used antiepileptic drugs in embryonic chick heart micromass culture and embryonic stem cell culture systems

Antiepileptic drugs (AEDs) are commonly used drugs in pregnant women with epilepsy. Prenatal exposure to AEDs increases the risk of major or minor congenital malformation during embryonic development. The precise mode of action and intracellular mechanisms of these AEDs during embryonic development remains unclear. To determine relative teratogenic risk of AEDs, four AED drugs including valproic acid (VPA), phenytoin (PHT), phenobarbital (PB), and trimethadione (TMD) were tested using two in vitro systems (the embryonic chick heart micromass (MM) culture and the in vitro differentiating mouse embryonic stem cells into cardiomyocytes culture systems). Cardiomyocyte cultures (the heart MM and ES cell-derived cardiomyocytes) were treated with or without different concentrations of PHT, PB, TMD (10–100μM), and VPA (100–2000μM). 5-Fluorouracil (5-FU) (1–10μM) and l-ascorbic acid (10–1000μM) were used as positive and negative controls. It was found that these four commonly used AEDs and 5-FU tested have the potential to inhibit embryonic heart cell differentiation (p<0.05) without inducing any cytotoxicity. VPA at higher concentrations (⩾800μM), and 5-FU at all doses proved to be cytotoxic in the differentiating ES cell culture system. The results demonstrated in this study suggest that the use of these four commonly prescribed AEDs during pregnancy may have an effect on embryonic heart development, and may be associated with congenital cardiovascular defects.

Reboxetine and its influence on the action of classical antiepileptic drugs in the mouse maximal electroshock model

BackgroundOur previous studies revealed that different classes of antidepressant drugs differently affect seizure phenomena. Continuing our research in this field, in the present study we wanted to investigate the influence of acute and chronic treatment with reboxetine, a selective norepinephrine reuptake inhibitor, on the anticonvulsant action of classical antiepileptic drugs. MethodsExperiments were conducted in the model of electroconvulsive threshold and maximal electroshock in mice. Motor coordination was evaluated in the chimney test and long term memory in the step-through passive avoidance task. Brain concentrations of antiepileptic drugs were detected by fluorescence polarization immunoassay. ResultsAcute treatment with reboxetine (8–16mg/kg) significantly raised the electroconvulsive threshold. In contrast, chronic reboxetine (2–16mg/kg) did not affect this parameter. Single administration of the antidepressant applied at its subthreshold doses enhanced the action of valproate, carbamazepine and phenobarbital. The antielectroshock effect of phenytoin was also potentiated by acute reboxetine, but only at doses increasing the threshold. Repeated administration of reboxetine (8–12mg/kg) enhanced the anticonvulsant action of carbamazepine, but not that of three remaining antiepileptic drugs. Neither acute nor chronic reboxetine changed the brain concentrations of valproate, carbamazepine, phenytoin or phenobarbital. Therefore, all revealed interactions seem to be pharmacodynamic. In terms of undesired effects, acute/chronic reboxetine and its combinations with classical antiepileptic drugs did not significantly impair motor performance or long-term memory in mice. ConclusionsAs far as the obtained data can be extrapolated into clinical conditions, it seems that reboxetine may be safely used in the treatment of depressive disorders in epileptic patients.

Evaluation of therapeutic phenobarbital concentrations and application of a classification system for seizures in cats: 30 cases (2004–2013)

To determine the percentage of cats with a phenobarbital (PB) concentration between 15 and 45 μg/mL that had a ≥ 50% reduction in the number of seizures and to investigate applicability of the 2011 International League Against Epilepsy (ILAE) classification system in cats. Retrospective case series. 30 cats with suspected or confirmed epilepsy. Medical records for 2004 to 2013 at 3 veterinary hospitals were searched. Information collected included signalment, duration of observation before treatment, frequency of seizures before PB administration, seizure phenotype, dose of PB, serum PB concentration, number of seizures after PB administration, duration of follow-up monitoring, and survival time. A modified 2011 ILAE classification system was applied to all cats. Seizure control was achieved in 28 of 30 (93%) cats with a serum PB concentration of 15 to 45 μg/mL. This comprised 10 of 11 cats with structural epilepsy, 14 of 15 cats with unknown epilepsy, and 4 of 4 cats with presumptive unknown epilepsy. Thirteen cats had no additional seizures after initiation of PB treatment. Seizure control was achieved in most cats with a serum PB concentration between 15 and 45 μg/mL, regardless of the cause of the seizures. A modified 2011 ILAE classification was applied to cats with seizures and enabled classification of cats without specific genetic testing and without identified structural or inflammatory disease. This classification system should be incorporated into veterinary neurology nomenclature to standardize communication between veterinarians and improve comparisons among species.

What is Needed for Optimal Therapeutic Drug Monitoring?

BioanalysisVol. 6, No. 2 EditorialWhat is needed for optimal therapeutic drug monitoring?William ClarkeWilliam ClarkeDepartment of Pathology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Sheikh Zayed Tower B-1020F, Baltimore, MD 21287, USA. Search for more papers by this authorEmail the corresponding author at wclarke@jhmi.eduPublished Online:14 Jan 2014https://doi.org/10.4155/bio.13.314AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: harmonizationlaboratory improvementpersonalized medicineproficiency testingquality assurance–QCtherapeutic drug monitoringReferences1 Pippenger CE, Gillen HW. Gas chromatographic analysis for anticonvulsant drugs in biologic fluids. Clin. Chem.15(7),582–590 (1969).Crossref, Medline, CAS, Google Scholar2 Feldman RG, Pippenger CE. The relation of anticonvulsant drug levels to complete seizure control. J. Clin. Pharmacol.16(1),51–59 (1976).Crossref, Medline, CAS, Google Scholar3 Kupferberg HJ. Quantitative estimation of diphenylhydantoin, primidone and phenobarbital in plasma by gas-liquid chromatography. Clin. Chim. Acta29(2),282–288 (1970).Crossref, Medline, CAS, Google Scholar4 Kupferberg HJ, Longacre-Shaw J. Mephobarbital and phenobarbital plasma concentrations in epileptic patients treated with mephobarbital. Ther. Drug Monit.1(1),117–122 (1979).Crossref, Medline, CAS, Google Scholar5 Levy G. What are narrow therapeutic index drugs? Clin. Pharmacol. Ther.63(5),501–505 (1998).Crossref, Medline, CAS, Google Scholar6 Oette M, Kroidl A, Gobels K et al. Predictors of short-term success of antiretroviral therapy in HIV infection. J. Antimicrob. Chemother.58(1),147–153 (2006).Crossref, Medline, CAS, Google Scholar7 Teng JF, Mabasa VH, Ensom, MH. The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors. Ther. Drug Monit.34(1),85–97 (2012).Crossref, Medline, CAS, Google Scholar8 Bach DM, Straseski JA, Clarke W. Therapeutic drug monitoring in cancer chemotherapy. Bioanalysis2(5),863–879 (2010).Link, CAS, Google Scholar9 Horowitz GL. Establishment and use of reference values. In: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics (5th Edition). Burtis CA, Ashwood ER, Bruns, DE (Eds). Elsevier Saunders, St. Louis, MO, USA, 95–118 (2012).Google ScholarFiguresReferencesRelatedDetails Vol. 6, No. 2 Follow us on social media for the latest updates Metrics Downloaded 184 times History Published online 14 January 2014 Published in print January 2014 Information© Future Science LtdKeywordsharmonizationlaboratory improvementpersonalized medicineproficiency testingquality assurance–QCtherapeutic drug monitoringFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

Can we safely administer the recommended dose of phenobarbital in very low birth weight infants?

We investigated whether the recommended phenobarbital loading dose of 15-20 mg/kg with maintenance of 3-4 mg/kg/day can safely be administered to very low birth weight preterm newborns with seizures. Twenty-four convulsive preterms of <1,500 g were enrolled in the study. Phenobarbital was administered intravenously with a loading dose of 15 mg/kg in approximately 10-15 min. After 24 h, the maintenance dose of 3 mg/kg/day was administered as a single injection. Blood samples were obtained 2, 24, 48, 72, and 96 h after the phenobarbital loading dose was administered, immediately before the next phenobarbital dose was injected. None of the cases had plasma phenobarbital concentrations above the therapeutic upper limit of 40 μg/mL on the 2nd hour; one case (4.7%), on the 24th; 11 cases (45.8%), on the 48th; 15 cases (62.5%), on the 72nd; and 17 cases (70.8%), on the 96th hour. A negative correlation was detected between the serum concentrations of phenobarbital and gestational age on the 72th (p, 0.036; r, -0.608) and 96th hour (p, 0.043; r, -0.769). We suggest that particular attention should be done while administering phenobarbital in preterms, as blood levels of phenobarbital are higher than the reference ranges that those are often reached with the recommended doses in these groups of babies.

A Child Exposed to Primidone Not Prescribed for Her

A 7.5-year-old girl who was treated with phenobarbital (PHB) for epilepsy was admitted with decreased levels of consciousness. She had been known to have high PHB levels of unknown cause, without symptoms. Her PHB levels were very high, as expected, but primidone levels were also detected although she and her parents denied history of primidone administration. We wished to rule out intentional unprescribed use of primidone. Our retrospective review showed 3 other children with high PHB concentrations where primidone was also detected when PHB levels were over 130 μmol/L. Complementary studies confirmed that high-dose PHB can convert to its prodrug primidone, which has not been reported previously.

Effect of acute and chronic tianeptine on the action of classical antiepileptics in the mouse maximal electroshock model

BackgroundThe aim of the study was to analyze the influence of acute and chronic treatment with tianeptine, an antidepressant selectively accelerating presynaptic serotonin reuptake, on the protective activity of classical antiepileptic drugs in the maximal electroshock test in mice. MethodsElectroconvulsions were produced by means of an alternating current (50Hz, 25mA, 0.2 s) delivered via ear-clip electrodes. Motor impairment and long-term memory deficits in animals were quantified in the chimney test and in the passive-avoidance task, respectively. Brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay. ResultsAcute and chronic treatment with tianeptine (25–50mg/kg) did not affect the electroconvulsive threshold. Furthermore, tianeptine applied in both acute and chronic protocols enhanced the anticonvulsant action of valproate and carbamazepine, but not that of phenytoin. Neither acute nor chronic tianeptine changed the brain concentrations of valproate, carbamazepine or phenytoin. On the other hand, both single and chronic administration of tianeptine diminished the brain concentration of phenobarbital. In spite of this pharmacokinetic interaction, the antidepressant enhanced the antielectroshock action of phenobarbital. In terms of adverse effects, acute/chronic tianeptine (50mg/kg) and its combinations with classic antiepileptic drugs did not impair motor performance or long-term memory in mice. ConclusionThe obtained results justify the conclusion that tianeptine may be beneficial in the treatment of depressive disorders in the course of epilepsy.

Effectiveness of Continuous Veno-Venous Hemofiltration and Intermittent Hemodialysis in the Treatment of Severe Acute Phenobarbital Poisoning

Background: Phenobarbital poisoning is common in Vietnam. The aim of this study was to compare the effectiveness of continuous veno-venous hemofiltration (CVVH) and hemodialysis (HD) on clinical outcomes in the treatment of severe acute phenobarbital poisoning. Methods: This was a retrospective observational historically controlled study. 42 patients with severe phenobarbital poisoning were enrolled. 21 patients were treated with HD and 21 with CVVH. Both groups received similar supportive therapies consisting of mechanical ventilation, forced alkaline diuresis and multiple-dose activated charcoal. Results: Following one course of treatment with HD (4 hours) or CVVH (~19.5 hours) the mean (SD) blood phenobarbital concentration (BPC) had decreased to 3.9 (2.5) and 3.2 (2.3) mg/dL respectively (P=0.232). Mean percentage decrease in BPC after HD and CVVH were 62.7 (12.4) and 61.5 (22.0) % respectively, showing no significant difference (P=0.782). Mean duration of coma and mechanical ventilation in CVVH group was 31.9 (26.6) and 39.7 (27.9) hours, significantly shorter than those in HD group with 66.1 (32.5) and 66.7 (32.2) hours (P=0.002; 0.001) respectively. Conclusion: One course of treatment with CVVH and HD decreased the BPC to a similar extent but this was not associated with similar clinical outcomes. Although, CVVH was not associated with rapid fall in blood phenobarbital level, it clearly had clinical advantages by shortening the duration of coma and mechanical ventilation and with lack of coma recurrence in severe phenobarbital poisoning.