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Biomedical subjects

B F Bourgeois

Publications and source records attributed to B F Bourgeois.

At least 37 records · Page 2Linked to original sources
PubMed1995

Important pharmacokinetic properties of antiepileptic drugs.

The choice of an antiepileptic drug (AED) is guided primarily by efficacy and safety criteria. However, the pharmacokinetic properties of an AED determine its ease of use, i.e., its ability to predictably produce and maintain optimal plasma concentrations. Desirable and clinically important pharmacokinetic properties of an AED include complete or constant bioavailability, slow enteral absorption or availability of a sustained-release formulation, availability of a parenteral formulation for acute treatment, rapid penetration into the brain, a single-compartment volume of distribution, low and nonsaturable protein binding, and linear elimination kinetics, with an elimination half-life of about 24 h. The absence of autoinduction of enzymatic biotransformation, active metabolites, and pharmacokinetic drug interactions is also important. In clinical practice, the most undesirable pharmacokinetic properties are lack of a parenteral formulation, short elimination half-life, nonlinear elimination kinetics, autoinduction of enzymatic biotransformation, and interaction with other drugs. No AED is presently marketed or under development that meets all of the desirable criteria. Some of the newer AEDs, although not "ideal" agents, have pharmacokinetic profiles that are not shared by their predecessors, including elimination exclusively by the kidney, absence of drug interactions, and dose-related bioavailability.

Acetates↗
PubMed1994

Pharmacodynamic interactions between phenytoin and valproate: individual and combined antiepileptic and neurotoxic actions in mice.

Although the current trend is to use monotherapy in the treatment of epilepsy, combination therapy is still employed in patients who have failed to respond to monotherapy. There is little clinical or experimental documentation of evidence against or in favor of anticonvulsant combination therapy. In this context, anticonvulsant and neurotoxic pharmacodynamic interactions between phenytoin (PHT) and valproate (VPA) were assessed in an experimental model in mice. All results were expressed in terms of brain drug concentrations for eliminating any pharmacokinetic interaction from the analysis. Both the median neurotoxic and the median anticonvulsant brain concentrations were determined for each drug used alone and for the combination. The interaction for the combination of PHT and VPA was shown to be supraadditive for the anticonvulsant activity, indicating an antiepileptic potentiation, whereas neurotoxicity was simply additive. These results suggest a potential benefit in terms of overall efficacy versus toxicity for the combination of PHT and VPA, as compared with PHT or VPA used alone.

Animals↗
PubMed1994

Pharmacologic intervention and treatment of childhood seizure disorders: relative efficacy and safety of antiepileptic drugs.

Four antiepileptic drugs (AEDs) represent > 90% of all AEDs prescribed in the United States. The efficacies of the available AEDs are surprisingly similar and far from complete, and none is entirely safe. Thus, the incidence of side effects is often the determining factor in the choice of AED. Clinical decisions about which AED to select should be made on the basis of the combination of efficacy and toxicity, expressed as a protective or therapeutic index (TI). Efficacy seldom comes without some degree of toxicity, whereas toxicity can occur in the absence of any efficacy. As the dose of the AED increases, efficacy can reach a plateau but toxicity does not. Complete seizure control should not be the final goal of epilepsy treatment; optimal AED therapy is equal to the highest possible TI, not necessarily to maximal seizure control. Each AED has a different TI, and each has a different TI in every patient. This is confounded further when combinations of AED are prescribed.

Animals↗
PubMed1994

Felbamate in the treatment of partial-onset seizures.

Felbamate (FBM, Felbatol/Taloxa) has been the object of several trials that are innovative and unique. First, FBM is the first antiepileptic drug (AED) to have been submitted to a controlled efficacy study in patients with the Lennox-Gastaut syndrome (LGS) before being submitted for regulatory approval. Second, FBM was tested in patients discontinued from other AEDs for presurgical monitoring. Third, FBM was the first experimental AED to have been tested in controlled monotherapy trials. Overall, these studies succeeded in demonstrating that FBM is relatively safe and effective against both partial-onset seizures and the generalized seizures occurring in the LGS. The results of some of these studies could not always be expressed by using the more familiar concept of percent seizure reduction because, for ethical reasons, the efficacy variable had to be defined in terms of time to the nth seizure or in terms of escape criteria. This may make it more difficult to evaluate just how effective FBM is in comparison with other AEDs. Another reason why the efficacy of FBM cannot yet be fully assessed is that in all the studies the FBM dosage was limited to a maximum of 3,600 mg/day or 45 mg/kg/day. At this dosage, FBM produced no toxicity in the majority of patients, and its full therapeutic toxicity in the majority of patients, and its full therapeutic effect may have to be re-evaluated in the future at higher dosages.

Adult↗
PubMed1994

Pharmacology and therapeutic aspects of antiepileptic drugs in pediatrics.

In the past year, several new antiepileptic drugs have emerged that have potential benefits for children with epilepsy. The spectrum of adverse effects is the principal feature that differentiates among the older drugs used to treat partial and related seizures, including simple partial, complex partial, and partial secondarily generalized seizures. Based on studies in adults with refractory seizures, the new or investigational compounds felbamate, gabapentin, lamotrigine, and vigabatrin should be active against these types of seizures in children, but none of them have been subjected to pediatric randomized controlled trials, and no studies have been done that compare new and old drugs in this category. Thus, the new drugs hold promise in children with these types of seizures, but their role relative to old drugs has not been elucidated. Several of the new drugs are active against myoclonic and generalized tonic-clonic seizures, but thus far, none have been proven to possess antiabsence activity in children. Open-label investigations suggest that lamotrigine may be helpful in Lennox-Gastaut syndrome, and vigabatrin in infantile spasms. Only felbamate has been evaluated in a randomized controlled study in children, in which it has proven beneficial against astatic and generalized tonic-clonic seizures in children with Lennox-Gastaut syndrome. Whereas investigations of these and other novel drugs are ongoing, this is an active and exciting period in pediatric antiepileptic drug development.

Adult↗
PubMed1993

Clinical aspects of epilepsy including diagnosis, management, pharmacotherapy, and surgery.

This review emphasizes clinical manifestations, recognition of specific epileptic syndromes, use of antiepileptic drugs, and surgical evaluation and outcome. Juvenile myoclonic epilepsy is increasingly recognized but still underdiagnosed. Good evidence exists for a relationship between Landau-Kleffner syndrome (acquired epileptic aphasia) and electrical status epilepticus during sleep, which reflects the course of the aphasia. In focal onset seizures, the type of aura may be as valuable for determining the lobe of seizure onset as electroencephalographic and neuroimaging techniques. In temporal lobe seizures, postictal language assessment was used to determine the side of origin, and hippocampal and temporal volumetry using magnetic resonance imaging proved reliable indicators of the side of involvement. Valproate sodium and carbamazepine were equally effective for secondarily generalized tonic-clonic seizures, but carbamazepine was superior to valproate for complex partial seizures. One study suggests that in children, increased daytime sleep tendency persists 4 to 5 months after discontinuation of antiepileptic drugs and that neither drugs nor seizure activity are necessarily involved. Many recent publications were devoted to surgical treatment. The main issues reviewed concern patient selection and correlation between preoperative parameters and outcome after surgery.

Anticonvulsants↗
PubMed1989

The rational use of antiepileptic drugs in children.

The general rules of antiepileptic drug therapy in children with epilepsy have been reviewed. The first step should always consist of making every effort to document the diagnosis of epilepsy and to determine the exact type of seizure. The choice of the appropriate antiepileptic drug is dictated entirely by the seizure type. Once the drug of choice has been selected, it should be given alone. If the first drug remains ineffective against the seizures at the highest tolerated dose, a second drug should be tried alone. Drug combinations may be justified in patients with resistant disease or in patients with multiple seizure types. Because of their relatively high metabolic rate, children require high dosages of antiepileptic drugs in relation to their body weight. Determining blood levels of antiepileptic drugs is particularly important in children, but it should be kept in mind that the therapeutic range is a relative concept and that it should not be applied blindly.

Anticonvulsants↗
PubMed1988

Pharmacologic interactions between valproate and other drugs.

Valproate is often administered with other antiepileptic drugs, a practice that can lead to clinically significant pharmacologic interactions. Concomitant administration of such enzyme-inducing antiepileptic drugs as carbamazepine, phenobarbital, primidone, or phenytoin will markedly accelerate the metabolic conversion of valproate, particularly in children. In response to the effects of enzyme induction, valproate dosage may need to be doubled to maintain therapeutic serum levels. Valproate does not appear to induce enzymatic drug metabolism, but rather acts as a metabolic inhibitor. Because of this inhibition, phenobarbital dosage must often be reduced after valproate is added to the therapeutic regimen. Valproate also may markedly increase concentrations of the active epoxide metabolite of carbamazepine. The interaction between phenytoin and valproate results primarily from displacement from plasma proteins. The resulting increase in the free fraction of phenytoin alters the relationship between total phenytoin concentration and the drug's pharmacologic effect. Thus, clinical evidence of toxicity may be present at concentrations usually considered to be in the therapeutic range.

Anticonvulsants↗
PubMed1988

Anticonvulsant potency and neurotoxicity of valproate alone and in combination with carbamazepine or phenobarbital.

Although single drug therapy of epilepsy has been increasingly advocated, patients whose epilepsy is not controlled by monotherapy are commonly treated with more than one antiepileptic drug. In order to investigate the experimental background for antiepileptic drug combinations, the effect of the pharmacodynamic interactions between valproate and carbamazepine and between valproate and phenobarbital on the efficacy/toxicity ratio was studied in mice. All results were expressed in terms of drug concentrations in the brain in order to exclude possible pharmacokinetic interactions from the analysis. Purely additive interactions were found for the anticonvulsant effect when valproate was combined with carbamazepine as well as with phenobarbital. With regard to the neurotoxic effect, however, the interaction was additive between valproate and phenobarbital but infra-additive for valproate and carbamazepine. Thus, in this model, the combination of valproate and phenobarbital has no advantage over each drug alone, but the combination of valproate with carbamazepine has a better efficacy versus toxicity ratio than either valproate alone or carbamazepine alone. Based on these and previous results, there can be experimental evidence in favor of combining certain antiepileptic drugs, but each combination needs to be studied separately.

Animals↗
PubMed1988

Problems of combination drug therapy in children.

Despite the current trend toward monotherapy, polytherapy in children with epilepsy is still common. A drug combination is advantageous only if it achieves a higher efficacy:toxicity ratio (therapeutic index) or if its antiepileptic spectrum is wider. Studies of brain concentrations of antiepileptic drugs have so far shown that a higher efficacy:toxicity ratio is not achieved by most combinations. Problems are associated with drug combinations. First, numerous pharmacokinetic interactions are documented. These interactions, which can be associated with significant changes in blood levels at a given dose, make frequent measurements and dosage readjustments necessary. They can also alter the concentration of active metabolites or the free fraction of a drug. Second, toxicity can be assumed to be at least partially cumulative, since reduction in polytherapy has been shown to be associated with a reduction in side effects. Third, the therapeutic range appears to depend on whether a drug is taken alone or in combination, so that polytherapy confuses the interpretation of serum drug measurements. Fourth, the presence of more than one drug will add to the difficulty in evaluating the efficacy or side effects of any single drug. Finally, a pharmacodynamic interaction between valproate and several other antiepileptics, particularly the barbiturates, can lead to a stuporous state. Transition from polytherapy to monotherapy is much more difficult to achieve than the opposite.

Anticonvulsants↗
PubMed1988

Combination of valproate and ethosuximide: antiepileptic and neurotoxic interaction.

The combination of ethosuximide and valproate has been advocated, particularly in patients with atypical and myoclonic absences. This drug combination has been assessed experimentally in mice by studying the effect of the pharmacodynamic interactions between the two drugs on the efficacy vs. toxicity ratio. All results were expressed in terms of brain concentrations. A purely additive anticonvulsant interaction was found. However, due to a less than additive neurotoxic interaction, the combination had a better efficacy vs. toxicity score than either drug alone. These results, although not representative for all drug combinations, provide evidence that the dissociation between the anticonvulsant and the neurotoxic interaction of two antiepileptic drugs can result in a better protective index for certain combinations of antiepileptic drugs.

Animals↗
PubMed1987

Bioavailability of sodium valproate suppositories during repeated administration at steady state in epileptic children.

Oral administration of antiepileptic drugs can temporarily be impossible under certain conditions, such as altered states of consciousness, spike-wave stupour, gastro-intestinal disturbances with nausea and vomiting, prior to or during surgery or certain diagnostic procedures, and because of drug refusal in patients with mental retardation or psychiatric problems. Although rectal administration of sodium valproate (NaVPA) has been shown to be a possible alternative route, little is known about the bioavailability and local effects during repeated administration of NaVPA suppositories. These aspects were investigated in 13 epileptic children and adolescents on chronic NaVPA therapy. Eight patients were treated with the oral solution (Group A; mean age 10.6 years) and five patients with enteric coated tablets (Group B, mean age 16.4 years). In every patient five serum levels of VPA over a 24 h period were measured under steady-state conditions. Thereafter, suppositories were administered for 2-7 days and serum levels were again determined (identical dosing and sampling times). Bioavailability of NaVPA was calculated on the basis of the area under the concentration vs. time curve over 24 h. The average bioavailability for suppositories compared with the oral form was 112.4% in Group A and 99.5% in Group B. Fluctuations of serum VPA levels were very similar with suppositories and oral solution, and more pronounced than with the enteric coated tablets. Stool frequency was not increased by repeated administration of suppositories, except for a three-fold increase in one patient. There was no objective or subjective evidence of local irritation from the suppositories. In conclusion, NaVPA suppositories have the same bioavailability under steady-state conditions as oral preparations and they are well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Antiepileptic drug combinations and experimental background: the case of phenobarbital and phenytoin.

In view of the trend towards single drug therapy of epilepsy, the experimental background for thr combination of phenobarbital (PB) and phenytoin (PHT) was reassessed. Since potentiation of the anticonvulsant activity is in itself neither sufficient nor necessary to demonstrate the superiority of a drug combination, protection against maximal electroshock seizures as well as neurotoxicity were determined in mice. This allowed one to separate the neurotoxic from the anticonvulsant interaction and to base the analysis on changes in the therapeutic index (TI). Pharmacokinetic interactions were excluded from the analysis by expressing all results in terms of brain concentrations. The anticonvulsant interaction between PB and PHT was found to be additive, whereas the neurotoxic interaction was antagonistic. These results provide experimental documentation of one of the theories behind antiepileptic drug combinations. However, because PB had a markedly lower TI than PHT in this model, the TI of the drug combination was lower than the TI of PHT. Thus, the antagonism with regard to neurotoxicity was not sufficient to raise the TI of the combination above the TI of PHT.

Animals↗
PubMed1985

Michaelis-Menten kinetics and the steady-state serum phenytoin/hydroxyphenytoin ratio.

The effect of nonlinear kinetics on the steady-state ratio of serum phenytoin (PHT) to total 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) was studied in epileptic patients. In each patient, the ratio increased in a nonlinear fashion in relation to both the PHT dose and the PHT serum level. Patients with longer apparent PHT half-lives (t50%) had a higher PHT/p-HPPH ratio. The t50% was either measured directly and found to correlate well with the patient's calculated Michaelis-Menten parameters (Vmax and Km), or was calculated from Vmax and Km values. A close linear correlation was found between the steady-state PHT/p-HPPH ratio and t50% values, interindividually and intraindividually, i.e., as the t50% increased with increasing PHT concentration in a given patient, the PHT/p-HPPH ratio increased in the same proportion. This indicates a good correlation between the overall Michaelis-Menten kinetics of PHT elimination and the PHT/p-HPPH ratio. A close linear correlation between a wide range of PHT doses and steady-state serum total p-HPPH levels was found, suggesting that when the PHT dose is lower than Vmax, the fraction of PHT undergoing parahydroxylation is constant. It is concluded that if, in a given patient, the p-HPPH level corresponds to the value expected from the PHT dose, it can be assumed that compliance and bioavailability are adequate and that the dose does not exceed Vmax. In that case, the PHT/p-HPPH ratio will provide a good estimate of the t50% of PHT at that particular PHT level.

Adolescent↗
PubMed1984

Carbamazepine-10,11-diol steady-state serum levels and renal excretion during carbamazepine therapy in adults and children.

Steady-state levels of carbamazepine (CBZ), CBZ-10,11-epoxide (CBZ-E), and 10,11-dihydro-10,11-trans-dihydroxy-CBZ (CBZ-diol) were monitored in 53 adults and 16 children, and 24-h urinary excretion of CBZ-E and CBZ-diol was measured in 25 adults and 8 children. The CBZ dose correlated significantly with the serum level of the metabolites but not with the CBZ level. The variability of the CBZ dose/level ratio was related to comedication. Similarly, comedication altered the serum CBZ-diol/CBZ ratio and, to a lesser extent, the CBZ-E/CBZ as well as the CBZ-diol/CBZ-E ratios. Fluctuations of the CBZ-diol levels during the day were less than half as high as CBZ fluctuations. Children had a higher CBZ dose/level ratio and a relatively lower serum CBZ-diol/CBZ ratio, possibly because they also had a higher renal clearance for CBZ-diol. The fraction of the CBZ dose excreted as urinary CBZ-diol was equal in adults and children (35.2 and 36.2%, respectively). The results of this study suggest that the steady-state serum CBZ-diol/CBZ ratio is a sensitive indicator of enzymatic induction and that it can be useful in determining if unexpected CBZ levels can be attributed to the rate of enzymatic conversion of CBZ.

Adult↗
PubMed1984

Individual and combined antiepileptic and neurotoxic activity of carbamazepine and carbamazepine-10,11-epoxide in mice.

Anticonvulsant effect and neurological toxicity were investigated in mice for carbamazepine (CBZ) and its main metabolites, carbamazepine-10,11-epoxide (CBZ-E) and 10,11-dihydro-10,11-trans-dihydroxy-CBZ. The compounds were first tested separately and the results were expressed in terms of brain concentrations. Brain penetration was very poor for 10,11-dihydro-10,11-trans-dihydroxy-CBZ, which had neither anticonvulsant nor neurotoxic activity. Against maximal electroshock, CBZ was slightly more potent than CBZ-E and both were ineffective against pentylenetetrazole and bicuculline. CBZ and CBZ-E displayed similar neurotoxicity. Combined administration of CBZ and CBZ-E revealed a slightly synergistic interaction with regard to both anticonvulsant and neurotoxic action, the therapeutic index of the mixture being similar to that of CBZ. These results suggest that antiepileptic activity and neurological toxicity of CBZ are proportional to the sum of the concentrations of CBZ and its metabolite CBZ-E. Furthermore, variable levels of CBZ-E in relation to CBZ do not affect the overall therapeutic index. Finally, the results do not indicate that CBZ-E alone has any advantage over CBZ with regard to neurotoxic side-effects and therapeutic index.

Animals↗