[BIS values were useful on the evaluation of consciousness recovery in acute Vegetamin-A poisoning: report of a case].

A 37-year-old man was admitted to our hospital with acute phenobarbital poisoning. On arrival, he was in deep coma with respiro-circulatory depressions. The serum concentration of the agent was elevated to 149.04 µg/mL which was consistent with a lethal concentration level. He underwent a gastric lavage, administration of activated charcoal, urinary alkalinazation and bowel irrigation. Respiro-circulatory status was recovered rapidly, while the serum concentration of phenobarbital did not decrease smoothly. Although the concentration of the agent decreased to 77.07 µg/mL that should be a comatose level, BIS values were gradually elevated, and then eventually the patient regained his consciousness. Because he was a chronic user of Vegetamin-A containing phenobarbital, the serum level might not have been correlated with symptoms. BIS values were highly reflective of the consciousness level, so it could be a useful indicator for predicting the consciousness levels of patients in deep coma with acute poisoning from hypnotic agents.

Pharmacological and neuroethological studies of three antiepileptic drugs in the Genetic Audiogenic Seizure Hamster (GASH:Sal).

Epilepsy modeling is essential for understanding the basic mechanisms of the epileptic process. The Genetic Audiogenic Seizure Hamster (GASH:Sal) exhibits generalized tonic-clonic seizures of genetic origin in response to sound stimulation and is currently being validated as a reliable model of epilepsy. Here, we performed a pharmacological and neuroethological study using well-known and widely used antiepileptic drugs (AEDs), including phenobarbital (PB), valproic acid (VPA), and levetiracetam (LEV). The intraperitoneal administration of PB (5-20mg/kg) and VPA (100-300mg/kg) produced a dose-dependent decrease in GASH:Sal audiogenic seizure severity scores. The administration of LEV (30-100mg/kg) did not produce a clear effect. Phenobarbital showed a short plasmatic life and had a high antiepileptic effect starting at 10mg/kg that was accompanied by ataxia. Valproic acid acted only at high concentrations and was the AED with the most ataxic effects. Levetiracetam at all doses also produced sedation and ataxia side effects. We conclude that the GASH:Sal is a reliable genetic model of epilepsy suitable to evaluate AEDs.

Interaction profile of Zizyphus jujuba with phenytoin, phenobarbitone, and carbamazepine in maximal electroshock-induced seizures in rats.

The antiepileptic effect of hydroalcoholic extract of Zizyphus jujuba (HEZJ) in experimental seizures was demonstrated earlier. The present study aimed to evaluate the pharmacokinetic and pharmacodynamic interactions of HEZJ with phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) in maximal electroshock (MES)-induced seizures in male Wistar rats. Maximal electroshock (70 mA, 9 ms pulse width, 0.2 s) was used to induce seizures. Blood samples were collected at two time points for estimation of serum PHT, PB, and CBZ levels using high-pressure liquid chromatography (HPLC). Co-administration of HEZJ with the sub-therapeutic doses of PHT, PB, and CBZ exhibited 66.7, 66.7, and 50.0% protection against tonic hind limb extension as compared to 33.3, 33.3, and 50% protection respectively, in the groups treated with PHT, PB, and CBZ alone in their sub-therapeutic doses. Co-administration of HEZJ with the sub-therapeutic doses of these antiepileptic drugs (AEDs) showed significant improvement in cognitive functions as compared to MES group as well as these AEDs alone. A significant increase in glutathione levels and decrease in malondialdehyde levels were observed with pretreatment of HEZJ with the sub-therapeutic doses of these AEDs. Co-administration of HEZJ with PHT, PB, and CBZ did not cause any significant changes in the serum concentrations of these AEDs. The results of the present study indicate that the co-administration of HEZJ with sub-therapeutic doses of PHT and PB potentiated the antiepileptic effect of PHT and PB in MES-induced seizures with no change found in the antiepileptic effect of CBZ.

Interactions between riluzole and conventional antiepileptic drugs -- a comparison of results obtained in the subthreshold method and isobolographic analysis.

The exact types of pharmacodynamic interactions between riluzole and conventional antiepileptic drugs were evaluated in two available ways, the subthreshold and isobolographic analysis. Maximal electroshock test in mice was used as an animal model for generalized tonic-clonic convulsions. In the first method, riluzole (1.25-2.5 mg/kg) significantly raised the electroconvulsive threshold in mice. The drug administered at its subprotective dose of 0.3125 mg/kg enhanced the antiseizure activity of carbamazepine and phenobarbital, while, when applied at the higher dose of 0.625 mg/kg, it potentiated also the action of valproate and diphenylhydantoin. Riluzole (0.625) alone and in combinations with antiepileptic drugs did not produced any motor or log-term memory deficit. Results obtained from isobolographic analysis determined pure additive interaction between riluzole and all used conventional antiepileptic drugs. Since riluzole did not change plasma concentrations of co-administered antiepileptics, pharmacokinetic interactions, at least in terms of their free plasma levels, do not seem probable. The results of the present study confirm significant antiseizure properties of riluzole in the model of generalized tonic-clonic epileptic attacks. Moreover, comparison of effects obtained from both methods evaluating drug interactions strongly indicates a crucial role of the isobolographic analysis in verification and supplementation data achieved from the subthreshold method.

Pretreatment with Ginkgo biloba extract weakens the hypnosis action of phenobarbital and its plasma concentration in rats.

In a previous study, we found that orally administered Ginkgo biloba extract (GBE) induced hepatic cytochrome P450 (CYP) in rats, especially the CYP2B type. This fact suggested that GBE influenced the availability and safety of drugs that were metabolized via CYP2B type enzymes. To confirm this possibility, in this study we examined the effect of feeding a 0.1, 0.5 and 1.0% GBE diet for 2 weeks on the pharmacokinetics and pharmacological action of phenobarbital, which is known to be metabolized by CYP2B in Wistar rats. The feeding of GBE markedly shortened the sleeping time in rats. Furthermore, the maximal phenobarbital plasma concentration (Cmax) and the 24-h area under the curve (AUC0-24) were decreased in rats fed GBE. These findings indicate that GBE reduces the therapeutic potency of phenobarbital via enhancement of cytochrome P450 expression, and raises the possibility that GBE and drug interactions may occur clinically.

[Can treatment associated with ticlopidine and nifedipine increase serum levels of phenobarbital?]. / ¿Puede el tratamiento asociado con ticlopidina y nifedipina aumentar los niveles séricos de fenobarbital?

INTRODUCTION: We report a case in which the association between ticlopidine, nifedipine and phenobarbital was linked with a higher than expected phenobarbital concentration in serum, which suggested a possible interaction between these drugs. CASE REPORT: A 67 year old male who received treatment with phenobarbital, digoxin, nifedipine, ticlopidine, paroxetine and clorazepate dipotassium. The first control of the level of phenobarbital in serum was performed without any symptoms or signs of toxicity or ineffectiveness. A phenobarbital concentration in serum of 21.4 mg/L was obtained, with a serum level/dosage ratio of 16.7. DISCUSSION: The serum level/dosage ratio of phenobarbital that was found in this case is almost twice as high as expected. In the absence of other factors that can explain this finding, we believe that two drugs (ticlopidine and nifedipine) may be involved in an interaction with phenobarbital. CONCLUSIONS: The high value of the serum level/dosage ratio that was found makes it advisable to monitor the concentrations of phenobarbital in serum in treatment associated with ticlopidine or nifedipine, especially when adjusting the dosage, beginning or ending treatment with these drugs.

Niguldipine impairs the protective activity of carbamazepine and phenobarbital in amygdala-kindled seizures in rats.

There is evidence that some calcium (Ca(2+)) channel inhibitors enhance the protective activity of antiepileptic drugs. Since clinical trials have not provided consistent data on this issue, the objective of this study was to evaluate the interaction of a dihydropyridine, niguldipine, with conventional antiepileptics in amygdala-kindled rats. Niguldipine (at 7.5 but not at 5 mg/kg) displayed a significant anticonvulsant effect, as regards seizure and afterdischarge durations in amygdala-kindled convulsions in rats, a model of complex partial seizures. No protective effect was observed when niguldipine (5 mg/kg) was combined with antiepileptics at subeffective doses, i.e. valproate (75 mg/kg), diphenylhydantoin (40 mg/kg), or clonazepam (0.003 mg/kg). Unexpectedly, the combined treatment of niguldipine (5 mg/kg) with carbamazepine (20 mg/kg) or phenobarbital (20 mg/kg) resulted in a proconvulsive action. BAY k-8644 (an L-type Ca(2+) channel activator) did not modify the protective activity of niguldipine (7.5 mg/kg) or the opposite action of this dihydropyridine (5 mg/kg) in combinations with carbamazepine or phenobarbital. A pharmacokinetic interaction is not probable since niguldipine did not affect the free plasma levels of the antiepileptics. These data indicate that the opposite actions of niguldipine alone or combined with carbamazepine (or phenobarbital) were not associated with Ca(2+) channel blockade. The present results may argue against the use of niguldipine as an adjuvant antiepileptic or for cardiovascular reasons in patients with complex partial seizures.

Oral high-dose phenobarbital therapy for early infantile epileptic encephalopathy.

We report oral high-dose phenobarbital therapy for a patient with early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome). At 1 month of age, many series of tonic spasms, with raising limbs and crying lasting for a few minutes, developed and increased up to approximately 300 times per day. Initially intravenous midazolam (0.5 mg/kg/hour) slightly decreased the seizures, although oral vitamin B6, valproic acid, clonazepam, and zonisamide had little effect. Oral high-dose phenobarbital therapy was begun at a dosage of 15 mg/kg/day, and the seizures markedly decreased to 5-10 times per day and the epileptic discharges on electroencephalogram greatly decreased. Serum phenobarbital levels ranged between 60 and 100 mg/dL. High-dose phenobarbital therapy should be considered for the treatment of early infantile epileptic encephalopathy with suppression bursts.

Characterization of the pharmacodynamics of several antiepileptic drugs in a direct cortical stimulation model of anticonvulsant effect in the rat.

In this investigation a newly developed direct cortical stimulation technique was evaluated for measurement of anticonvulsant efficacy in rats. The kinetics of drug action for carbamazepine, phenytoin, valproate, phenobarbital, ethosuximide and oxazepam were studied in conjunction with their pharmacokinetics. Motor cortex stimulation with a ramp-shaped pulse train allowed successive determination of a threshold for localized seizure activity (TLS) and for generalized seizure activity (TGS). For each drug the time course of effect was followed in individual animals. Differential effects on the pharmacodynamic parameters were seen. Phenytoin and carbamazepine clearly elevated the TGS. However, phenytoin did not affect TLS and carbamazepine only marginally. Valproate increased both TLS and TGS to the same extent. Phenobarbital and oxazepam elevated both thresholds, but the effect on TGS was more pronounced. Ethosuximide had little effect on both thresholds. Comparison with other animal models suggested that elevation of TLS reflects an effect on seizure initiation, whereas elevation of TGS above TLS reflects an effect on seizure propagation. All drugs exhibited a nonlinear relationship between plasma concentration and anticonvulsant efficacy, without ceiling of anticonvulsant intensity at the highest concentrations. The effective concentration range of most compounds coincided with the "therapeutic" range in humans. The direct cortical stimulation technique is useful for preclinical monitoring of anticonvulsant efficacy with most antiepileptic drugs because it allows detection of both qualitative and quantitative differences. In addition the model is particularly useful for time course studies.

Clinical evaluation of five therapeutic drugs using dry film multilayer technology on the OPUS immunoassay system.

Five therapeutic drug assays, carbamazepine, phenobarbital, phenytoin, theophylline, and valproic acid, were evaluated using an automated random access system for performing thin dry film multilayer competitive immunoassays, the OPUS analyzer. All reagents for the therapeutic drug assays are contained in a coated multilayer film chip encased within a plastic bar-coded test module and require no external or supplementary reagents. A serum or plasma sample is applied to the test module by the instrument and the fluorescence intensity from the module is measured after 6 minutes. We found the OPUS assays acceptable for clinical use. Within-run coefficient of variations were 2.3-6.7%, between-run, 2.9-7.6%. These methods correlated well with the Abbott TDx, having correlation coefficients of 0.92-0.97. Because of the instrument design and the stability of the reagents, weekly calibration is not needed and samples can be run immediately upon receipt in a random access fashion or can be batched together.

Balance and cognitive impairment in two epileptic patients before and after vagal nerve stimulation.

Balance and cognition were assessed in two patients with uncontrolled complex partial seizures. The patients were on anticonvulsant medications and were treated with left vagal stimulation. Balance and cognition were assessed before and after vagal stimulation, and the results were compared with age matched controls and older patients with Parkinson's disease. Severe impairments of function were found in the epileptic patients, and such negative effects of medication make vagal stimulation a potentially practical alternative treatment for uncontrolled epilepsy.

Comparative experimental study of antiepileptics--regional specificity of antiepileptic action of carbamazepine, phenobarbital and valproate sodium.

The antiepileptic action of carbamazepine (CBZ), phenobarbital (PB), and valproate sodium (VPA) was examined in 109 adult male rabbits during steady state serum levels produced on the basis of the pharmacokinetics of each drug. The duration and discharge pattern of electrically induced focal and secondarily generalized after-discharges (ADs) in the motor, visual cortices and hippocampus were compared before and after administration of doses of each drug. A CBZ level of 3-30 micrograms/ml shortened the duration of both neocortical and hippocampal ADs. CBZ at levels above 5 micrograms/ml suppressed the spread in the secondarily generalized ADs originating from the neocortical areas, but not that originating from the hippocampus. PB levels of 10-80 micrograms/ml shortened the duration of both neocortical ADs, especially motor ADs, whereas they had little or no effect on the hippocampal ADs. VPA showed inhibitory effects on both the neocortical and hippocampal AD durations only at high levels of 400-1,100 micrograms/ml. However, the inhibitory effects were more marked on the latter than the former, and further, the effects were enhanced as time elapsed. These results suggest that the action of each drug on focal seizures is region-specific.

The use of a pharmacological indicator to investigate compliance in patients with a poor response to antirheumatic therapy.

Twenty-six patients with rheumatoid arthritis which was poorly controlled despite high dose D-penicillamine were studied. Compliance was assessed by standard methods (return tablet count and interview). In addition low-dose phenobarbitone was included in the penicillamine formulation as a pharmacological indicator of compliance. Using these techniques incomplete compliance was apparent in 11 patients (42%). All such patients were identified by the pharmacological marker. Only one admitted poor compliance at interview and only six returned more than a few tablets too many. The reason for the high incidence of poor compliance in this selected group is not apparent but it may represent a significant cause of failure with D-penicillamine therapy. The use of low-dose phenobarbitone may have wider applications in the investigation of patients with other conditions who fail to respond adequately to treatment.

A new experimental model for drug studies: effects of phenobarbital and phenytoin on photosensitivity in the lateral geniculate-kindled cat.

Photosensitivity was acquired as a result of kindling in the lateral geniculate body (GL), and the GL-kindled cat pretreated with DL-allylglycine showed a stable level of photosensitivity. To test the usefulness as a model for the evaluation of anticonvulsant drugs, the effects of phenobarbital (PB) and phenytoin (PHT) on photosensitivity were studied in the GL-kindled cat under DL-allylglycine. PB (5 and 10 mg/kg intravenously, i.v.) completely suppressed photically induced seizures in most subjects at plasma concentrations of 7-16 micrograms/ml, and this anticonvulsant action persisted for at least 4 h after the injection. PHT (15 mg/kg, i.v.) at plasma concentrations of 9-15 micrograms/ml produced toxic signs, e.g., pupil dilatation, hypersalivation, and tachypnea. At this dose, PHT was inactive against photically induced myoclonus but prevented the elicitation of a generalized tonic-clonic convulsion. From these results showing that the effects of anticonvulsant drugs on photically induced seizures can be assessed in relation to plasma concentration and acute neurologic toxicity, we suggest that the GL-kindled cat is a potentially useful animal model of epilepsy for testing the efficacy of anticonvulsant drugs.

The course of hyperbilirubinemia in the very low birth weight infant treated with phenobarbital.

We examined the effect of early phenobarbital therapy on the course of jaundice in 57 infants with birth weight below 1,500 g. The study group of 28 infants was treated with a phenobarbital loading dose of 20 mg/kg at 4.2 (3.6) [mean (SD)] hours of age, followed by a maintenance dose of 5 mg/kg/day for one week; 29 infants served as controls. Seventeen study and 19 control infants suffered from periventricular-intraventricular hemorrhage (IVH). The two groups had comparable risk factors that can potentially affect the course of hyperbilirubinemia. Peak serum bilirubin concentration was 7.9 (1.8) mg/dl in the treated group and 8.6 (2.2) mg/dl in the control group. Three infants in the treated group and seven infants in the control group had peak serum bilirubin concentration above 10 mg/dl. These differences in the peak serum bilirubin concentration or in the number of infants with peak serum bilirubin concentrations above 10 mg/dl are not statistically significant. However, treated infants achieved peak serum bilirubin concentration earlier (mean age 90 hours as compared to 138 hours in control infants), and required phototherapy for a shorter duration of time (5.5 days in the treated group as compared to 7.5 days in the control group). While these differences in the two groups with regard to age of peak serum bilirubin concentration and duration of phototherapy are statistically significant, they do not seem to be clinically important. Thus, in our group of very low birth infants phenobarbital failed to show any clinically important effects on the course of jaundice when used in conjunction with phototherapy.

Progabide for refractory partial epilepsy: a controlled add-on trial.

Progabide, an experimental GABA-ergic antiepileptic drug, was given in a placebo-controlled double-blind cross-over trial to 19 adult patients with chronic partial epilepsy refractory to previous high-dose antiepileptic drug therapy. A mean daily dose of 32 mg/kg (range, 16 to 63) of progabide did not significantly change the seizure frequency. In patients with a therapeutic response, progabide led to an increase in the plasma concentration of phenytoin and phenobarbital. Comedication with carbamazepine was associated with a poor response to progabide. Side effects were mild except for a several-fold increase of SGOT and SGPT, which required withdrawal of progabide in one patient. Progabide does not seem to be the drug urgently needed for failures of previous high-dose drug therapy.

Serum folate concentrations during pregnancy in women with epilepsy: relation to antiepileptic drug concentrations, number of seizures, and fetal outcome.

Serum folate concentrations, blood counts, and antiepileptic drug concentrations were measured during 133 pregnancies of 125 women with epilepsy. There was an inverse correlation between serum folate concentrations and concentrations of phenytoin and phenobarbitone. The number of epileptic seizures during pregnancy showed no association with serum folate concentrations. No cases of maternal tissue folate deficiency or fetal damage attributable to low maternal serum folate were observed. Maternal serum folate concentrations for infants with structural birth defects, "fetal hydantoin syndrome," or perinatal death were similar to those for healthy babies. A low dose (100 to 1000 micrograms daily) of folate supplement appeared sufficient for pregnant women with epilepsy despite the antifolic action of antiepileptic medication. Monitoring folate concentrations in pregnant women with high serum concentrations of phenytoin or phenobarbitone is recommended.