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PubMed1983

Carbamazepine 10, 11 epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants.

Steady state carbamazepine (CBZ) plasma concentrations were similar in 15 epileptics receiving monotherapy and in 24 patients taking CBZ in combination with one other anticonvulsant. The ratio of CBZ 10, 11-epoxide (CBZ-E) to the parent drug was significantly higher (P less than 0.01) in those patients taking concomitant phenytoin (n = 9), phenobarbitone or primidone (n = 9), and valproic acid (n = 6) than in the patients receiving CBZ alone. In the monotherapy group, there was a significant correlation between CBZ-E/CBZ ratio and the concentration of the parent drug (P less than 0.05). If CBZ-E has equipotent anticonvulsant properties to CBZ in man as is the case in animal models, routine CBZ-E concentrations may provide further refinement in the therapeutic drug monitoring of CBZ.

Anticonvulsants↗
PubMed2006

Clinically relevant drug interactions with antiepileptic drugs.

Some patients with difficult-to-treat epilepsy benefit from combination therapy with two or more antiepileptic drugs (AEDs). Additionally, virtually all epilepsy patients will receive, at some time in their lives, other medications for the management of associated conditions. In these situations, clinically important drug interactions may occur. Carbamazepine, phenytoin, phenobarbital and primidone induce many cytochrome P450 (CYP) and glucuronyl transferase (GT) enzymes, and can reduce drastically the serum concentration of associated drugs which are substrates of the same enzymes. Examples of agents whose serum levels are decreased markedly by enzyme-inducing AEDs, include lamotrigine, tiagabine, several steroidal drugs, cyclosporin A, oral anticoagulants and many cardiovascular, antineoplastic and psychotropic drugs. Valproic acid is not enzyme inducer, but it may cause clinically relevant drug interactions by inhibiting the metabolism of selected substrates, most notably phenobarbital and lamotrigine. Compared with older generation agents, most of the recently developed AEDs are less likely to induce or inhibit the activity of CYP or GT enzymes. However, they may be a target for metabolically mediated drug interactions, and oxcarbazepine, lamotrigine, felbamate and, at high dosages, topiramate may stimulate the metabolism of oral contraceptive steroids. Levetiracetam, gabapentin and pregabalin have not been reported to cause or be a target for clinically relevant pharmacokinetic drug interactions. Pharmacodynamic interactions involving AEDs have not been well characterized, but their understanding is important for a more rational approach to combination therapy. In particular, neurotoxic effects appear to be more likely with coprescription of AEDs sharing the same primary mechanism of action.

Absorption↗
PubMed2006

Establishing a baseline for the monitoring of medicines availability for children in the UK: 1998-2002.

AIM: To determine changes in the availability, in terms of licensing and formulations, of medicines for children in the UK between 1998 and 2002. METHODS: Using the Association of British Pharmaceutical Industry (ABPI) Compendium of Data Sheets and Summaries of Product Characteristics (SPC) 1998 and the Medicines Compendium 2002, licensed medicines available in the UK in the calendar years 1998 and 2002 were examined. RESULTS: In 1998, 61% of chemical entities/fixed-dose combinations were licensed in some form for children compared with 64% in 2002. Of the chemical entities/fixed-dose combinations with oral formulations, 250 (33%) in 1998 had an oral formulation suitable for use by children and in 2002 there were 284 (34%). Of the 129 new chemical entities registered in the UK between 1998 and 2002, only 30 (23%) were licensed for under the age of 12 years and 19 (15%) for the neonatal age group. A total of 480 medicines licensed for children were withdrawn from marketing but only cisapride and primidone had no generic or therapeutic alternatives. CONCLUSION: Although there was improvement in the availability of medicines for children in the UK over the 5-year period (1998-2002), considerable inequities still existed between children and adults.

Child↗
PubMed1983

Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro.

Some pharmacological properties of the GABAA receptor complex in the rat cuneate nucleus slice have been assessed from depolarization responses to the gamma-aminobutyric acid (GABA) analogue muscimol and antagonism of the responses by bicuculline and picrotoxin. Responses to muscimol were potentiated by the following drugs, in descending order of potency with regard to the concentrations required in the Krebs medium: (+/-)-5-(1,3-dimethylbutyl)-5-ethylbarbituric acid [+/-)-DMBB) = (+/-)-quinalbarbitone = (+/-)-pentobarbitone greater than (+/-)-methyl-phenobarbitone = (-)-methylphenobarbitone greater than butobarbitone = chlormethiazole greater than phenobarbitone greater than barbitone = (+)-methylphenobarbitone. Primidone and phenylethylmalonamide were inactive. Calculation of the concentrations likely to be present in membrane lipids for equal potentiations of muscimol revealed little difference between quinalbarbitone, pentobarbitone, phenobarbitone and barbitone. The effect of picrotoxin as a muscimol antagonist was selectively reduced only by DMBB, chlormethiazole, phenobarbitone and (-)-methylphenobarbitone in concentrations that caused only a modest potentiation of muscimol. It is suggested that a specific site of action in the GABAA receptor complex is involved in the reduction of picrotoxin effect and that this may be relevant to the anticonvulsant properties of chlormethiazole, phenobarbitone and (-)-methylphenobarbitone. The potentiation of muscimol by chlormethiazole and the barbiturates in general involves a distinctly different site that is less selective and this may underlie the hypnotic properties of these drugs.

Animals↗
PubMedDate not supplied

Drug-induced hypersensitivity syndrome in a premature infant.

Fever, skin reactions, and limb edema because of drug-induced hypersensitivity have been reported in children because of various drugs, mainly aromatic antiepileptic drugs such as phenytoin, phenobarbital, carbamazepin, and primidone. The skin reactions differ in severity and range from mild maculopapular erythema to exfoliative dermatitis. They have been described in older children but have not been reported in newborn infants. We report a premature newborn infant who developed fever, skin reactions, and edema because of phenytoin while receiving anticonvulsant therapy.

Anti-Allergic Agents↗
PubMed1978

Effects of antiepileptics on both behavioral and electrographic seizure patterns induced by maximal electroshock in rats.

Effects of antiepileptics on both behavioral (TE) and electrographic seizure patterns induced by maximal electroshock were studied simultaneously in the same animal. The results obtained are as follows. All the antiepileptics used in this study depressed the TE seizure. Imipramine, biperiden, and lidocaine also depressed TE seizure, although they are not classified as antiepileptics. Phenobarbital, primidone, trimethadione, carbamazepine, ethosuximide, diazepam, clozapine, and imipramine had a depressant effect on electrographic seizures. However, phenytoin, ethotoin, phenacemide, and acetazolamide did not influence the electrographic seizure, in spite of having a strong effect on TE seizure. The present procedure, i.e., that of simultaneous observation of both behavioral and electrographic seizure patterns induced by maximal electroshock in the same animal, provides information which cannot be obtained from either behavior or EEG observation alone.

Animals↗
PubMed1982

Comparison of phenytoin and phenobarbital effects on far-field auditory and somatosensory evoked potential interpeak latencies.

Far-field somatosensory and auditory evoked potential (EP) interpeak latencies were measured in normal controls, epileptics not receiving medications, and epileptics receiving phenytoin, phenobarbital, or both. Phenytoin, but no phenobarbital, was associated with a prolongation of EP interpeak latencies at serum level concentrations over 20 micrograms/ml. Neither carbamazepine nor primidone in smaller series were associated with prolongation of EP interpeak latencies.

Epilepsy↗
PubMed1983

Potentiation of the antiepileptic activity of phenobarbital by nicotinamide.

Nicotinamide is a ligand of the benzodiazepine receptor and has been reported to have anticonvulsant activity. In addition, our previous clinical experience has raised the possibility that it may also potentiate the action of barbiturates. Therefore, we have examined the anticonvulsant activity and neurotoxicity of nicotinamide alone and in combination with phenobarbital in mice. Nicotinamide had its maximal anticonvulsant effect 15 min and its maximal sedative effect 45 min after intraperitoneal injection. At 15 min, the median effective dose was 586.5 mg/kg against bicuculline and 2,019 mg/kg against pentylenetetrazol. Nicotinamide was ineffective against maximal electroshock. It had a sedative effect, with a median toxic dose of 874.8 mg/kg by the Rotorod Toxicity Test at 45 min. At doses that were ineffective by themselves (0.01 effective dose) nicotinamide potentiated the anticonvulsant activity of phenobarbital against bicuculline and pentylenetetrazol, but the toxicity was not potentiated and therefore the therapeutic index of phenobarbital was improved by nicotinamide. These results suggest that nicotinamide may be useful as a therapeutic adjunct for the treatment of epilepsy with phenobarbital or primidone.

Animals↗
PubMed1984

Interaction of anticonvulsant drugs with adenosine receptors in the central nervous system.

The anticonvulsant carbamazepine inhibits binding of 1 nM [3H]N6-cyclohexyladenosine to rat cerebral and cerebellar A1 adenosine receptors with an IC50 value of about 50 microM. This concentration is well within that expected for therapeutic regimens. Other anticonvulsants such as phenobarbital, phenytoin, primidone, valproate sodium, and ethosuximide had little or no effect on binding, while theophylline and caffeine caused marked inhibition. Carbamazepine had no marked effect on cyclic AMP levels in guinea pig cerebral cortical or hippocampal slices, but was a weak inhibitor (IC50 about 200 microM) of 2-chloroadenosine-elicited accumulations of cyclic AMP via an A2 adenosine receptor in cortical slices. Carbamazepine is thus a somewhat selective ligand for A1 adenosine receptors in brain. The nature of its activity at those receptors is unclear, but its lack of central stimulant effects contrasts to the stimulant properties of A1 adenosine receptor antagonist such as caffeine and theophylline.

Adenosine↗
PubMed1984

Kinetics of penetration of common antiepileptic drugs into cerebrospinal fluid.

The rate of entry of common antiepileptic drugs and some active metabolites into cerebrospinal fluid (CSF) was studied in anesthetized dogs from which blood and CSF samples were withdrawn at short intervals. Diazepam, its active metabolites desmethyldiazepam and oxazepam, clonazepam, and ethosuximide entered the CSF very rapidly with mean half-times to equilibrium between 3 and 7 min. Valproic acid, phenytoin, phenobarbital, and carbamazepine went in more slowly, but mean penetration half-times were still only 12-18 min. Primidone, its metabolite phenylethylmalondiamide , and the active metabolite of carbamazepine, i.e., carbamazepine-10,11-epoxide, passed into CSF considerably slower, with half-times of 40-50 min. In order to evaluate to what extent physicochemical properties determine the penetration rates of antiepileptic drugs into the CSF, three factors were examined: the degree of ionization of the respective drugs at physiologic pH, the plasma protein binding, and the lipid-solubility, measured by organic solvent/buffer distribution ratios. Ionization was not considered as a rate-limiting factor, because all compounds except valproic acid were highly non-ionized at pH 7.4. No correlation was found between penetration rates and plasma protein binding, but at equilibrium, the ratio between CSF and total plasma concentrations was almost equal to the free fraction of drug in plasma. A significant correlation was found between penetration rate and the benzene/buffer distribution ratio of antiepileptic drugs, which indicates that the lipid-solubility, rather than the protein binding or the degree of ionization, plays the major role in determining the differences in rate of entry of these drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Nutritional influence on serum ammonia in young patients receiving sodium valproate.

Hyperammonemia is a common side effect of valproic acid (VPA) therapy. This study was designed to investigate a potential nutritional influence on serum ammonia levels during VPA therapy. In 10 VPA-treated young patients (5 receiving monotherapy, 5 receiving VPA-primidone polytherapy), venous serum ammonia, triglycerides, and cholesterol were measured on 3 consecutive days as follows: (a) after a 13-h overnight fast; (b) 2 h after an oral fat load with butter (1.2 g fat/kg body weight); and (c) 2 h after an oral protein load with fresh cheese (1 g protein/kg body weight). Ten young adults served as controls. After protein load VPA patients had significantly higher serum ammonia levels than controls (mean: 194 vs. 75 micrograms/dl in controls; p less than 0.006). Ammonia values were higher after protein load than after fat load or after fasting (p less than 0.0001). Patients receiving polytherapy had higher ammonia levels than patients receiving monotherapy (not significant). There was no correlation to the height of serum VPA levels. Clinical symptoms attributable to hyperammonemia (vomiting, apathy) were found in only one patient, and her serum ammonia was as high as 426 micrograms/dl. Triglycerides and cholesterol did not show any VPA-induced differences. We assume that VPA alters the short-term regulation of ureasynthesis. We recommend the avoidance of high protein intake in patients receiving VPA therapy, especially in young patients receiving polytherapy or comedication, or in risk situations like serious infections.

Adult↗
PubMed1987

Clinically significant carbamazepine drug interactions: an overview.

Knowledge of the principles of drug action and distribution contributes to an understanding of the occurrence of drug interactions. The pharmacologic action of most drugs is postulated to occur by the formation of a drug-receptor complex at the site of action that is capable of altering the physiologic response of the target system. The therapeutic response observed depends on the sum of the numerous factors that can affect the disposition pattern of a drug. In an individual, the response to a given drug dose remains relatively constant, but in a large population, a fixed dose can produce a range of plasma concentrations and therefore varied clinical responses. For most drugs, there is a linear relationship between the total dose and the plasma concentration achieved at steady state. Saturation, or zero-order, kinetics accounts for nonlinear increases in drug concentration with dosage increase. Drug-drug interactions with carbamazepine include several types. (1) Autoinduction of carbamazepine metabolism increases the carbamazepine clearance rate, decreases the half-life, and decreases serum concentrations; the clinician must reevaluate a patient's serum levels at 4 to 6 weeks after initiation of therapy. (2) Carbamazepine induces the metabolism of other antiepileptic drugs, enhancing the clearance of phenytoin, primidone, valproic acid, clonazepam, and ethosuximide. (3) Other drugs added to the epileptic patient's drug regimen may induce the metabolism of carbamazepine, causing increased serum concentrations. (4) Inhibition of carbamazepine metabolism by other drugs can also occur; symptoms of drug intoxication rapidly follow. Interactions occur between carbamazepine and macrolide antibiotics, cimetidine, propoxyphene, and isoniazid. Drug-drug interactions are preventable.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbamazepine↗
PubMedDate not supplied

Combined administration of carbamazepine and phenobarbital: effect on anticonvulsant activity and neurotoxicity.

Despite the trend towards single drug therapy of epilepsy, patients resistant to monotherapy are commonly treated with more than one antiepileptic drug. As part of an investigation on the experimental background for antiepileptic drug combinations, the effect of the pharmacodynamic interactions between carbamazepine and phenobarbital on the toxicity/efficacy ratio was studied in mice. All results were expressed in terms of drug concentrations in the brain to exclude possible pharmacokinetic interactions from the analysis. A purely additive interaction was found for the anticonvulsant as well as for the neurotoxic effect of the drugs. The combination of carbamazepine and phenobarbital has therefore no advantage over each drug alone in this model. Based on these and previous results, there is no experimental evidence in favor of any combination between the four main drugs against partial seizures, i.e., carbamazepine, phenytoin, phenobarbital, and primidone.

Animals↗
PubMed1988

Adjunctive therapy in resistant epilepsy.

It is now established that the overall prognosis for epilepsy is good and that remission will occur in at least 75% of patients following adequate treatment with monotherapy. Patients who fail to respond to monotherapy, who are not suitable for surgery, and who continue to have frequent seizures may have to be considered for an alternative drug regimen. A review of the literature indicates that complete seizure control with adjunctive treatment is rare, but improved seizure control can be obtained in up to 40% of patients. In a study of clobazam as adjunctive treatment, 60% (N = 20) of our patients responded to treatment initially and 33% maintained an improvement over an 18-month period. In 31 patients who failed to respond to carbamazepine as monotherapy, primidone (N = 16) or valproate (N = 15) were prescribed as adjunctive treatment. One patient obtained complete freedom from seizures and 14 (45%) had a greater than 50% reduction in seizure frequency. Suggested indications for the use of additive treatment in epilepsy are discussed.

Anti-Anxiety Agents↗
PubMedDate not supplied

Controlled trial of lamotrigine (Lamictal) for refractory partial seizures.

The antiepileptic effect of lamotrigine (LTG) was assessed in a double-blind, placebo-controlled crossover trial in 24 adult patients with refractory partial seizures. LTG or placebo was added to existing antiepileptic drugs (AEDs). The dose of LTG varied from 75 to 400 mg daily. Three patients did not complete the trial. One was withdrawn from the trial with ataxia, tiredness, dyspnea, and diplopia while receiving LTG and died 18 days later of invasive carcinoma involving the liver. A second patient was withdrawn during baseline for contravening admission criteria, and a third received LTG in error during both treatment periods. Twenty-one patients (12 men and 9 women) completed the trial. An analysis of seizure counts in the 12-week treatment period with LTG showed a statistically significant reduction in seizures as compared with placebo for total seizures (p less than 0.002), partial seizures (p less than 0.002), and secondarily generalized seizures (p less than 0.05). The analysis of total seizure days showed a significant reduction during LTG treatment (p less than 0.002). There were no statistically significant changes in plasma concentrations of phenytoin (PHT), carbamazepine (CBZ), primidone (PRM), or phenobarbital (PB) between the two treatment periods. The most common adverse events reported during the trial were diplopia, drowsiness, tiredness, ataxia, and headache, but although these were more frequent during LTG treatment, the differences from placebo were not statistically significant. No hematological or biochemical changes were noted.

Adolescent↗
PubMedDate not supplied

Possible induction of systemic lupus erythematosus by valproate.

Two patients developed clinical and laboratory evidence of systemic lupus erythematosus (SLE) during treatment with valproate (VPA) preparations. The first patient, a 47-year-old man, had fever, malaise, and thrombocytopenia 1 month after VPA was added to phenytoin (PHT) and primidone (PRM). He developed high titers of antinuclear antibodies (ANA) and anti-DNA antibodies, and hypocomplementemia. After discontinuation of PHT and VPA, steroid and immunoglobulin treatment was required for 4 weeks before his condition improved. The second patient, a 28-year-old woman, had been followed for idiopathic leukopenia for 3 years and had previously experienced fever and lymphadenopathy from PHT. After 4 months of divalproex therapy, she developed confusion, joint pain, and a dramatic increase in seizure frequency. She also developed high titers of ANA and anti-DNA antibodies and hypocomplementemia, along with a further decrease in white blood cell (WBC) count. These responded to steroid therapy and withdrawal of divalproex. Three months later, reintroduction of divalproex was followed by a return of ANA in low titer, which resolved after discontinuation. We believe that VPA may have caused true SLE in these patients, one of whom was probably predisposed.

Adult↗
PubMed1992

Drug interactions in epilepsy.

The abolition of seizures using a single antiepileptic agent can be expected in more than 80% of patients, although not necessarily with the first drug tried. The remainder often receive polypharmacy, and current evidence suggests that perhaps only around 10% of these benefit significantly in terms of improved seizure control. Many more experience complicated drug interactions. Carbamazepine, phenytoin, phenobarbital, and primidone (metabolized in part to phenobarbital) all induce the synthesis of hepatic monooxygenase and conjugating enzymes. This will result in an acceleration in the metabolism of other lipid-soluble drugs with likely attenuation of their pharmacological effects. Valproate, on the other hand, is a minor enzyme inhibitor. Pharmacokinetic interactions are almost invariable when more than one antiepileptic drug is coprescribed. The extent and direction of interactions with combinations of these drugs are varied and unpredictable. Discontinuation of an enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s). Pharmacodynamic interactions also cause problems in epileptic patients. A number of commonly prescribed psychoactive drugs, such as tricyclic antidepressants and neuroleptics, can worsen seizure control by reducing the convulsion threshold. In addition, there seems little doubt that ethanol abuse and withdrawal can precipitate seizures in susceptible patients. Antiepileptic polypharmacy is more likely to impair cognitive function than the same drugs used singly. In addition, the more antiepileptic drugs received by a patient in the first trimester of pregnancy, the higher the risk of teratogenesis in the exposed infant. Drug interactions prolong and complicate the process of new drug assessment, particularly when introduced in treated patients with refractory epilepsy. The candidate antiepileptic drug may alter the concentration of concomitant therapy, or its own breakdown may be influenced by coprescribed enzyme inducers or inhibitors. Even if the new drug is excreted unchanged by the kidney, unexpected interactions can be uncovered. Pharmacodynamic interactions need not always be detrimental. Currently, there is no rational approach to the treatment of intractable epilepsy. As more new drugs with single mechanisms of action become available, the potential exists for combining these synergistically. This approach may revolutionize the pharmacological management of the epileptic patient in the 21st century.

Anticonvulsants↗
PubMed1992

Pregnancy and the risk of teratogenicity.

One in every 250 newborns is exposed to antiepileptic drugs (AEDs) in utero. Various studies have attributed a teratogenic effect to these AEDs, mainly consisting of major malformations, minor anomalies, intrauterine or postnatal growth failure, and psychomotor retardation. Prospective studies confirm the increased risk of major malformations. The absolute risk of 7-10% is about 3-5% higher than that in the general population. Barbiturates and phenytoin (PHT) are particularly associated with congenital heart malformations, facial clefts, and some other malformations. Valproate (VPA) and carbamazepine (CBZ) are associated predominantly with spina bifida aperta (1-2 and 0.5-1.0% risk, respectively) and hypospadias. Bilateral radial aplasia is a rare but specific effect of VPA. Several studies identified additional risk factors, i.e., high daily AED dosage, high maternal serum AED concentrations, low folate levels, or polytherapy [phenobarbital (PB) plus primidone (PRM) plus PHT or CBZ plus VPA plus PB with or without PHT]. The few prospective studies controlled for socioeconomic factors or that considered parental findings indicate that risk of specific cognitive defects rather than risk of overall mental retardation may be increased, that early growth retardation is followed by a catch-up growth to normal, and that ocular hypertelorism and nail hypoplasia are the only minor anomalies causally related to PHT exposure. However, no final conclusions can be made. Genetic predisposition to the teratogenic side effects of AEDs plays a role, codetermining the recurrence risk if the woman has previously given birth to a child with a major malformation. The molecular genetic basis of this predisposition is unclear.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗