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PubMed1992

A case of phenobarbital exacerbation of a preexisting maladaptive behavior partially suppressed by chlorpromazine and misinterpreted as chlorpromazine efficacy.

An adult female with developmental disability was prescribed chlorpromazine for the target behaviors of aggression and self-injurious behavior (SIB), and she was prescribed phenobarbital for seizures. Upon a chlorpromazine minimal effective dose reduction, target behaviors increased and dosage was returned to prior levels with the conclusion that chlorpromazine was controlling the target behaviors. Upon subsequent reduction and discontinuation of phenobarbital, however, chlorpromazine was able to be reduced with no increase in target behaviors. Ten years of behavioral data are presented to support the hypothesis that phenobarbital was exacerbating maladaptive behaviors. Given tardive dyskinesia (TD), clinicians and interdisciplinary teams should remain alert to the following client profile: (1) prescribed phenobarbital (or primidone), (2) prescribed neuroleptics, especially at high dosages, to control maladaptive behaviors, (3) failure of neuroleptic gradual minimal effective dose attempts, and (4) possible presence of behavioral procedures, especially intrusive procedures, to control maladaptive behaviors. This profile should trigger a "red flag" as to the possibility of phenobarbital behavioral side effects or exacerbation of preexisting maladaptive behaviors.

Adult↗
PubMed1987

Lamotrigine: single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy.

Twenty-three residential patients on chronic antiepileptic drugs (AEDs) were entered into an open study of 4 weeks duration. Baseline variables and seizure frequency were determined in the first week. All patients received a single dose of lamotrigine in the second week to determine single-dose pharmacokinetic parameters. Twenty patients then received daily or twice daily lamotrigine for a week. Post-treatment seizure frequency was observed for a further week. Patients taking liver enzyme inducing antiepileptic drugs showed a mean lamotrigine plasma elimination half-life (T1/2) of 14 h (+/- 7) (T1/2 of normal volunteers = 24 h) and those taking sodium valproate and an inducing AED showed a mean lamotrigine T1/2 of 30 h (+/- 10). The plasma concentrations of co-administered sodium valproate, phenytoin, carbamazepine, phenobarbitone and primidone were not altered by 1 week lamotrigine dosing. There was a significant reduction in complex partial seizures in the treatment week compared with baseline. Some patients showed a marked increase in seizure frequency on stopping lamotrigine. There was an increase in reports of drowsiness during lamotrigine administration, but there were no clinically significant changes in any safety measure.

Adolescent↗
PubMedDate not supplied

The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices.

Calculation of protective or therapeutic indices is widely used in primary and secondary screening for drugs with selective anticonvulsant activity. The protective index is the median minimal 'neurotoxic' dose, TD50, divided by median effective dose, ED50. TD50s are usually determined by tests, such as the rotarod test or the chimney test, for quantification of 'minimal neurological deficit', such as motor impairment, while median effective doses are commonly determined in the maximal electroshock seizure (MES) test or the s.c. pentylenetetrazol (PTZ) seizure test in mice or rats. For antiepileptic drug development, it has been proposed previously that only compounds with an estimated protective index of at least 5 should proceed to further evaluation. However, various technical, biological and pharmacological factors can influence anticonvulsant or 'neurotoxic' potencies and thereby protective indices. In order to reevaluate the value of protective indexes in the prediction of drugs with selective anticonvulsant action, protective indices were determined for various clinically used antiepileptic drugs in standardized seizure tests, i.e. MES and s.c. PTZ tests in mice and rats, as well as in seizure threshold tests. For most drugs, similar TD50s were determined in the rotarod and chimney test. When protective indices were calculated for the different seizure models, only few drugs reached an index of 5 (some not even reaching an index of 2) in the traditional MES or s.c. PTZ tests in mice and rats. In contrast, using anticonvulsant doses determined by seizure threshold tests, the 5 primary drugs against generalized tonic-clonic seizures, i.e., carbamazepine, phenytoin, phenobarbital, primidone and valproate, had indices of more than 5 in the MES threshold model, while drugs with efficacy against absence and myoclonic seizures, i.e., valproate, ethosuximide and the benzodiazepines, had protective indices of at least 5 in the i.v. PTZ seizure threshold model. The data substantiate that valuable information can be obtained by estimation of protective indices. However, in order to minimize the possibility that an interesting new anticonvulsant compound is overlooked during primary or secondary screening, a protective index of 2 should be considered sufficient in case of traditional MES or s.c. PTZ models with fixed seizure stimulus. Alternatively, seizure threshold models could be used for calculation of protective indices in order to avoid underestimation of anticonvulsant selectivity of test compounds.

Animals↗
PubMed1995

Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-inducing antiepilepsy drugs.

The effect of hepatic enzyme-inducing antiepilepsy drugs (AEDs) on the clinical pharmacokinetics of tiagabine, a new AED, was studied in the steady-state condition. Patients with epilepsy entered this two-day study on a previously stable regimen of one to three enzyme-inducing drugs (phenytoin, phenobarbital, carbamazepine, and/or primidone) and tiagabine.HCl (24, 40, 56, or 80 mg daily). Patients were confined on both days, and serial blood samples were collected. Plasma tiagabine concentrations were determined by high-performance liquid chromatography; pharmacokinetic parameters were calculated using noncompartmental methods. Tiagabine pharmacokinetics were linear at all doses, as substantiated by the lack of significant differences among groups for dose-adjusted Cmax, Cmin, and AUC0-6. Some diurnal variation occurred, as evidenced by a statistically significant time effect for dose-adjusted AUC0-6. The effect was small, however, and possibly not clinically relevant. The harmonic mean half-lives of 3.8 to 4.9 h were remarkably constant across dosages and shorter than those of historical control subjects not taking enzyme-inducing AEDs suggesting that epilepsy patients not taking enzyme-inducing AEDs may require lower tiagabine.HCl doses to achieve the plasma levels observed in patients taking these drugs.

Adolescent↗
PubMed2006

A novel high sensitivity HPLC assay for topiramate, using 4-chloro-7-nitrobenzofurazan as pre-column fluorescence derivatizing agent.

A new, sensitive and simple high-performance liquid chromatographic method for analysis of topiramate, an antiepileptic agent, using 4-chloro-7-nitrobenzofurazan as pre-column derivatization agent is described. Following liquid-liquid extraction of topiramate and an internal standard (amlodipine) from human serum, derivatization of the drugs was performed by the labeling agent in the presence of dichloromethane, methanol, acetonitrile and borate buffer (0.05 M; pH 10.6). A mixture of sodium phosphate buffer (0.05 M; pH 2.4): methanol (35:65 v/v) was eluted as mobile phase and chromatographic separation was achieved using a Shimpack CLC-C18 (150 x 4.6 mm) column. In this method the limit of quantification of 0.01 microg/mL was obtained and the procedure was validated over the concentration range of 0.01 to 12.8 microg/mL. No interferences were found from commonly co-administrated antiepileptic drugs including phenytoin, phenobarbital carbamazepine, lamotrigine, zonisamide, primidone, gabapentin, vigabatrin, and ethosuximide. The analysis performance was carried-out in terms of specificity, sensitivity, linearity, precision, accuracy and stability and the method was shown to be accurate, with intra-day and inter-day accuracy from -3.4 to 10% and precise, with intra-day and inter-day precision from 1.1 to 18%.

Anticonvulsants↗
PubMed2005

Supercritical fluid chromatography/tandem mass spectrometric method for analysis of pharmaceutical compounds in metabolic stability samples.

Packed-column supercritical fluid chromatography (pSFC) coupled to an atmospheric pressure chemical ionization (APCI) source and a tandem mass spectrometer (MS/MS) for rapid and simultaneous determination of clozapine, ondansetron, tolbutamide and primidone in in vitro samples was developed in support of metabolic stability experiments. The effects of the eluent flow-rate and composition as well as the nebulizer temperatures on the ionization efficiency of the analytes in positive ion mode under normal phase pSFC conditions were studied. The metabolic stability of the test drug components through microsomal incubation by the proposed pSFC-APCI/MS/MS approaches requiring approximately 1 min per samples were evaluated with respect to specificity, durability and accuracy. These metabolic stability results obtained by pSFC-MS/MS methods are in a good agreement with those obtained by fast high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method.

Animals↗
PubMed2006

Rapid and simultaneous determination of sulfamethoxazole and trimethoprim in human plasma by high-performance liquid chromatography.

A simple and reproducible high-performance liquid chromatographic method was developed for simultaneous determination of sulfamethoxazole (SMX) and trimethoprim (TMP) in human plasma. The method entailed injection of the samples after deproteination with perchloric acid and subsequent neutralizing. Primidone was used as internal standard. Chromatography was performed on a C(18) column (250 mm x 4.6 mm, 5 microm) under isocratic elution with 50 mM aqueous sodium dihydrogen phosphate-acetonitrile-triethylamine (100:25:0.5, v/v), pH 5.9. Detection was made at 240 nm and analyses were run at a flow-rate of 1.5 ml/min at a temperature of 35 degrees C. The recovery was 83.4, 88.5 and 98.2% for TMP, SMX and internal standard, respectively. The precision of the method was 2.6-9.8% over the concentration range of 0.125-2 microg/ml for TMP and 0.39-50 microg/ml for SMX. The limit of quantification (LOQ) in plasma was 0.125 and 0.39 microg/ml for TMP and SMX, respectively. The method was used for a bioequivalence study.

Anti-Infective Agents↗
PubMed2006

Novel anticonvulsant drugs.

Principles of complex mechanisms of action of anticonvulsants including latest reports concerning new antiepileptic drugs (AED) are considered. Different aspects of new anticonvulsant drugs (2nd generation) from preclinical and clinical testing, pharmacokinetics, and mono or combination therapy in children and adults are summarized. In the following condensed synopsis pharmacological and clinical characteristics of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB) and tiagabine (TGB) as well as topiramate (TPM) and zonisamide (ZNS) are discussed. In addition to the mechanisms of action, pharmacokinetics, interactions, indications and dosages as well as side effects are considered. Important data concerning the effect and tolerability of anticonvulsant drugs can be obtained from controlled studies. In comparison to drugs of the first generation (phenobarbital [PB], primidon [PRD], phenytoin [PHT], carbamazepine [CBZ] and valproic acid [VPA]) the potential for interactions and side effects due to enzyme induction or inhibition is reduced by most of the anticonvulsant drugs of the second generation. New anticonvulsant drugs increase the spectrum of treatment and represent further steps with regard to the optimization of an individual therapy of the epilepsies.

Amines↗
PubMed2006

Anticonvulsant activity and tolerance of ELB138 in dogs with epilepsy: a clinical pilot study.

A new antiepileptic and anxiolytic drug, ELB138, was evaluated in a clinical pilot study in dogs with newly diagnosed or chronic idiopathic epilepsy. The purpose was to verify clinically the anticonvulsant effectiveness of this substance, which had already been demonstrated experimentally. Data from 29 dogs treated with ELB138 were compared with results obtained retrospectively from 82 dogs treated with conventional antiepileptic medication. The reduction in seizure frequency using ELB138 in dogs with newly diagnosed idiopathic epilepsy was comparable to the reduction in dogs treated either with phenobarbital or primidone. In dogs with chronic epilepsy and add-on therapy with either ELB138 or potassium bromide, such supplementation reduced the seizure frequency and the duration and severity of seizures. The most obvious difference between ELB138 treatment and conventional medications became clear in the evaluation of side effects, which in those dogs treated with ELB138 were rare, and consisted mostly of transient polyphagia. This pilot study confirmed that ELB138 has a potent anticonvulsant effect in dogs with idiopathic epilepsy. These results will form the basis for a multicentre, blinded study.

Animals↗
PubMed2004

Epilepsy and bone health in adults.

Adults taking antiepileptic drugs (AEDs) have an augmented risk for osteopenia and osteoporosis because of abnormalities of bone metabolism associated with AEDs. The increased fracture rates that have been described among patients with epilepsy may be related both to seizures and to AEDs. The hepatic enzyme-inducing AEDs phenytoin, phenobarbital, and primidone have the clearest association with decreased bone mineral density (BMD). Carbamazepine, also an enzyme-inducing drug, and valproate, an enzyme inhibitor, may also adversely affect bone, but further study is needed. Little information is available about specific effects of newer AEDs on bone. Physicians are insufficiently aware of the association between AEDs and bone disease; a survey found that fewer than one-third of neurologists routinely evaluated AED-treated patients for bone disease, and fewer than 10% prescribed prophylactic calcium and vitamin D. Physicians should counsel patients taking AEDs about good bone health practices, and evaluation of bone health by measuring BMD is warranted after 5 years of AED treatment or before treatment in postmenopausal women.

Adult↗
PubMed2000

Biotin and biocytin uptake into cultured primary calf brain microvessel endothelial cells of the blood-brain barrier.

The uptake of biotin and the closely related biocytin was characterized in primary cultures of calf brain microvessel endothelial (CBME) cells. Biotin uptake was found to be Na(+)-gradient dependent and independent of changes in the membrane potential. Concentration dependence revealed a single saturation mechanism with a K(m) of 47 microM and a V(max) of 101 pmol/min/mg. Inhibition studies demonstrated dependence on metabolic energy and the necessity for a free carboxyl group for transport activity. The anticonvulsants primidone and carbamazepine had no inhibitory effect. Biotin uptake into CBME cells is a secondary active, electroneutral, saturable and specific process. Biocytin which accumulates in biotinidase deficiency, a human congenital disorder, did not inhibit biotin uptake and was not transported into these cells. The presence of human serum with normal biotinidase activity significantly reduced biotin uptake by about 50%. Further, added biocytin was hydrolyzed to biotin, which accumulated intracellularly but to a lesser extent than added free biotin. Biotin uptake after addition of plasma of biotinidase-deficient patients was not different from that in the presence of normal serum. These results indicate that the absence of biotinidase activity in serum does not reduce blood-brain barrier transport of biotin.

Amidohydrolases↗
PubMed1977

Solvent suppression of the decomposition of phenobarbital during on-column methylation with trimethylanilinium hydroxide.

Gas-liquid chromatographic (GLC) analysis of phenobarbital by on-column methylation with trimethylanilinium hydroxide gives rise to a major decomposition product, N-methyl-2-phenylbutyramide, in addition to the methylated barbiturate, N,N'-dimethylphenobarbital. This reaction occurs nearly exclusively in the solution phase in the injection port of the gas chromatography. A mechanism for the decomposition reaction consistent with the available information is presented. This decomposition is shown to be inhibited by certain solvents and this effect forms the basis of a new analytical technique for the simultaneous GLC analysis of phenobarbital, primidone, and diphenylhydantoin.

Aniline Compounds↗
PubMed1999

Metabolism of carbamazepine by CYP3A6: a model for in vitro drug interactions studies.

Carbamazepine (CBZ) is widely used in the treatment of epilepsy. The drug is principally metabolized by CYPs to 10, 11-epoxy carbamazepine (CBZ-E) but this metabolite more toxic than the parent drug, does possess anticonvulsant properties. In humans, CYP3A4, CYP2C8 and CYP1A2 have been shown to be implicated in CBZ biotransformation. Our purpose was to establish an experimental model to determine the interaction of CBZ with other antiepileptic drugs. We first identified the CYP isoforms that metabolized CBZ in rabbit. We used liver microsomes from rabbit treated with various compounds known to induce principally some CYPs subfamilies. Having tested all the compounds we demonstrated that only the animals treated with CYP3A inducers were able to metabolize CBZ strongly. The CBZ biotransformation was inhibited by anti CYP3A antibodies. All the CYP3A subfamily substrates specifically decrease CBZ-E formation. In our experiment we did not observe any inhibition with CYP2C substrate. These data provide evidence that in rabbit the CYP3A subfamily is primarily involved in CBZ metabolism. Using this model we investigated the interaction of CBZ with phenobarbital, phenytoin, ethosuccimide, primidone, progabide, vigabatrin and lamotrigine.

Animals↗
PubMed1983

Experimental chronic epilepsy in rats: a screening method for antiepileptic drugs.

Rats were rendered epileptic by subpial injection of an FeCl3 solution. Epileptiform discharges, recorded by chronically implanted extradural electrodes, were evident within 48 h of surgery and persisted for more than 6 months. It is demonstrated that this model is useful for studying new antiepileptic agents since a series of clinically effective drugs (diazepam, clonazepam, Na phenobarbital, primidone, carbamezepine, ethosuximide, diphenylhydantoin, Na valproate, GABOB) show an activity which is does-dependent and within a range satisfactorily related to human dosages.

Animals↗
PubMed2002

[Primary orthostatic tremor].

INTRODUCTION: Tremor is frequent in neurologic practice but primary orthostatic tremor was first described in 1984. Its prevalence accounts for around 4% for tremors explored in neurophysiology; in contrast, essential and parkinsonian tremors represent respectively 28 and 22% of these cases. EXEGESIS: Orthostatic tremor is characterized by its appearance while standing. Walking, sitting, and lying down are unaffected. Clinical examination is normal except for unsteadiness disappearing when walking. Surface electromyography in the standing position is necessary for the diagnosis and shows a regular rapid tremor (frequency around 14 to 18 Hz). Its pathophysiology is unknown. CONCLUSION: Clonazepam is the first-line treatment for orthostatic tremor. In cases of resistance or side effects of this drug orthostatic tremor may be improved by primidone or, as in our case, gabapentin.

Female↗
PubMed1999

Treatment of epilepsy in the elderly.

Management of epilepsy in the elderly involves many challenges, including the presence of concomitant diseases, polypharmacy and changes in body physiology. Age-related changes in pharmacokinetics and pharmacodynamics have to be taken into account in order to avoid potentially severe adverse drug reactions in elderly people. The present study reviews the most commonly used antiepileptic drugs (AEDs) in the elderly. Because some AEDs may induce the metabolism of other agents and reduce the effectiveness of several drugs, the physicians have to carefully evaluate concomitant drugs being administered. Moreover, the main problems appear to be when beginning therapy, the first choice drug, the appropriate dosage and pharmacologic compliance. Elderly patients must be screened for hepatic and renal functions before beginning a treatment with an AED, carefully interviewed to reduce complaints for drug side-effects which may negatively influence compliance and monitored for total and free blood levels. Besides the 'classic' AEDs, such as phenytoin, phenobarbital, carbamazepine, valproic acid, primidone and benzodiazepines, the review shows the possible advantages of new AEDs, such as felbamate, gabapentin, lamotrigine, oxcarbazepine and gamma-vinyl-GABA, which may be used in the elderly too for their good tolerability. A careful control of drug assumption is requested in the elderly, especially when it is difficult to achieve seizure control.

Adult↗
PubMed1998

Familial cortical tremor with epilepsy: an under-recognized familial tremor.

The authors report three Japanese families presenting with cortical tremor and epilepsy. The patients showed either tremulous finger movements or seizures as the initial symptoms between 19 and 30 years of the age without progression. Postural tremor resembled essential tremor and responded to the anticonvulsants such as clonazepam, primidone and sodium valproate. Seizures were infrequent. These patients seem to have the same disorder as what the authors have described as 'familial cortical tremor with epilepsy'. Familial cortical tremor must be more common than previously thought and should be taken into consideration in the patients with 'familial essential tremor' who do not respond well to beta-blockers.

Adult↗
PubMed2002

Occurrence, fate, and removal of pharmaceutical residues in the aquatic environment: a review of recent research data.

The occurrence and fate of pharmaceutically active compounds (PhACs) in the aquatic environment has been recognized as one of the emerging issues in environmental chemistry. In some investigations carried out in Austria, Brazil, Canada, Croatia, England, Germany, Greece, Italy, Spain, Switzerland, The Netherlands, and the U.S., more than 80 compounds, pharmaceuticals and several drug metabolites, have been detected in the aquatic environment. Several PhACs from various prescription classes have been found at concentrations up to the microg/l-level in sewage influent and effluent samples and also in several surface waters located downstream from municipal sewage treatment plants (STPs). The studies show that some PhACs originating from human therapy are not eliminated completely in the municipal STPs and are, thus, discharged as contaminants into the receiving waters. Under recharge conditions, polar PhACs such as clofibric acid, carbamazepine, primidone or iodinated contrast agents can leach through the subsoil and have also been detected in several groundwater samples in Germany. Positive findings of PhACs have, however, also been reported in groundwater contaminated by landfill leachates or manufacturing residues. To date, only in a few cases PhACs have also been detected at trace-levels in drinking water samples.

Animals↗