Valproic Acid Sodium Research Articles

The Management of Epilepsy in the 1990s

The pharmacological treatment of epilepsy has made considerable progress during the last decade, due to improved knowledge of the clinical pharmacology of individual drugs, acquisition of new information on the factors affecting response and need for drug treatment, and development of promising new agents. Once a clinical diagnosis of epilepsy has been made (which generally requires the occurrence of more than one seizure), treatment should be started with a single drug selected on the basis of seizure type and tolerability profile. Although there are important regional differences in prescribing patterns and individual circumstances may dictate alternative choices, carbamazepine is generally regarded as the preferred treatment for partial seizures (with or without secondary generalisation) while valproic acid (sodium valproate) is usually the first choice in most forms of generalised epilepsies. To achieve therapeutic success, the daily dosage must be tailored to meet individual needs, and there is suggestive evidence that in some patients the dosage prescribed initially may be unnecessarily large. Plasma antiepileptic drug concentrations may aid in the individualization of dosage, but should not be regarded as a substitute for careful monitoring of clinical response. Although overall about 70% of patients can be completely controlled, response rate is influenced by a number of factors, the most important of which are seizure type and syndromic form. The importance of a correct syndromic classification for rational drug selection has been poorly assessed and represents a major area for future research. Patients who do not respond to the highest tolerated dose of the initially prescribed drug may be switched to monotherapy with an alternative agent or may be given add-on treatment with a second drug. Appropriate prospective trials are required to assess the merits of either strategy. If add-on therapy is selected and the patient becomes seizure free, it may be possible to discontinue the drug prescribed initially and reinstitute monotherapy. Only a minority of patients are likely to require multiple drug therapy, and it remains to be established whether specific drug combinations are more effective than others. Until further information becomes available, the new agents should be reserved for patients failing to respond to the conventional treatments of first choice. Patients whose seizures cannot be controlled by available drugs should be reassessed, and polytherapy should be maintained only when there is clear evidence that benefits outweigh possible adverse effects. In many patients who have been seizure free for at least 2 years it may be possible to gradually discontinue all medications.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic administration of sodium valproic acid slows pubertal maturation in inbred DBA/2J mice: skeletal, histological, and endocrinological evidence.

Sodium valproic acid (VPA) has been reported to occasionally delay pubertal maturation in children. In the current study, we sought to establish a valid animal model with which to further investigate the neuroendocrinological sequelae of VPA administration. Male and female DBA/2J mice were weaned at 2 weeks of age and administered either VPA (17-20 mg/kg/day) or control solution via drinking water. Animals were weighed and sacrificed via decapitation at 4, 6, or 8 weeks of age. Testes and ovaries were prepared for histological analyses. In addition, the length of the left humerus bone from each animal was obtained as an index of skeletal growth, and trunk blood was assayed for circulating follicle-stimulating hormone (FSH) and prolactin (PRL). For males, testicular weights of the animals receiving VPA were significantly lower than those of control animals at all three sampling ages. No between-group differences were found for body weight at any sampling age, and yet the rate of skeletal maturation (as indexed by humerus length) was decreased significantly for the VPA-treated males at all three sampling periods. Additionally, while hormone levels did not consistently differ, histological analyses of the gonadal tissue demonstrated significantly decreased rats of spermatogenesis at all sampling points for VPA-treated animals. For females, chronic VPA administration led to a significant reduction in uterine weight at the 4 and 6 week sampling periods, and yet by 8 weeks of age the uterine weights for the two groups did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)

Nimodipine

Nimodipine is indicated for a variety of conditions in elderly patients. Elderly patients often have multiple morbidity and receive treatment with a variety of drugs. Therefore, it is important to investigate the possible pharmacokinetic and pharmacodynamic interactions of nimodipine with various drugs commonly prescribed for elderly patients. There were no clinically relevant interactions of nimodipine with any of the following specific agents studied: the antiarrhythmics mexiletine, propafenone, disopyramide or quinidine, digoxin, the beta-adrenoceptor antagonists propranolol or atenolol, nifedipine, warfarin, diazepam, indomethacin, ranitidine or glibenclamide (glyburide). However, there were some notable interactions. In epileptic patients taking the anticonvulsants carbamazepine, phenobarbital (phenobarbitone) and/or phenytoin, there was a 7-fold decrease in the area under the plasma concentration versus time curve (AUC) and an 8- to 10-fold decrease in the maximum plasma concentration of nimodipine. These effects were to be expected, considering the hepatic enzyme-inducing properties of these anticonvulsant drugs. Therefore concomitant use of these agents with oral nimodipine is not recommended. In contrast, epileptic patients treated with nimodipine and valproic acid (sodium valproate) showed an increase in both the AUC (approximately 50%) and maximum plasma concentrations (approximately 30%) of nimodipine, which may be explained by valproic acid inhibiting the presystemic oxidative metabolism of nimodipine. Concomitant administration of cimetidine produced an approximate doubling of the bioavailability of nimodipine. This again was to be expected, considering the known inhibitory effect of cimetidine on cytochrome P450. However, no changes in haemodynamics, clinical or laboratory status or tolerability were observed, and dose adjustment did not appear to be clinically necessary.

Antiepileptic Agents and Birth Defects

An association exists between maternal use of antiepileptic drugs (AEDs) during pregnancy and birth defects in offspring. The overall malformation rate is 11.1% in offspring of AED-treated epileptic mothers, while it is 5.7% in the offspring of untreated epileptic mothers and 4.8% in those of the general population. Cardiovascular defects, facial cleftings and skeletal anomalies are the most frequently occurring AED-associated malformations. No firm patterns of specific AEDs inducing particular birth defects have been established. Nevertheless, neural tube defects may be specific malformations in infants exposed to both valproic acid (sodium valproate) and/or carbamazepine. Several minor anomalies are influenced by genetic factors. From prospective studies a number of primary risk factors for increased incidences of congenital malformations in the offspring of epileptic mothers receiving AEDs have been identified. These include high drug dosage, high serum drug concentration, the use of AEDs with high teratogenicity potency [primidone > valproic acid > phenytoin > carbamazepine > phenobarbital (phenobarbitone)] and AED polypharmacy (especially combinations of valproic acid and carbamazepine, and phenytoin and/or carbamazepine with or without barbiturates). The mechanism of teratogenicity of AEDs is still being investigated, but it is postulated that epoxide intermediates and other toxic metabolites of AEDs might be involved. In addition, the folate deficiency and impaired folate metabolism caused by AEDs may contribute to the teratogenicity of these drugs. To prevent birth defects, the use of the lowest effective AED dosage and a change from polypharmacy to monotherapy are recommended before conception. A decrease in serum AED concentrations during pregnancy does not in itself justify an increase in drug dosage. The high risk of neural tube defects in offspring exposed to valproic acid (or carbamazepine) warrants prenatal examination in pregnant women receiving this drug, such as ultrasound and amniotic fluid α-fetoprotein investigations. To reduce the risk of this malformation, replacement of conventional formulations of valproic acid with controlled release formulations and the use of folate supplementation are recommended.

The New Anticonvulsant Drugs

Several new antiepileptic drugs offer a worthwhile alternative when standard antiepileptic drugs have failed. Suggestions have been made to improve the risk-benefit ratio of the new antiepileptic agents. More specifically, vigabatrin, which is a very useful and well tolerated new antiepileptic drug for refractory partial epilepsy, should be started at a low dosage of 0.5 g/day with increments of 0.5 g/day every week. Daily dosages exceeding 3 g/day should be restricted to patients with improvement. If necessary, the daily dosage of vigabatrin should be withdrawn slowly, i.e. by not more than 1 g/week. Lamotrigine is also a beneficial new drug for refractory partial and generalized seizures. However, the drug is associated with rash. In patients also receiving valproic acid (sodium valproate) [which inhibits the metabolism of lamotrigine], the incidence of rash can be reduced by slow titration of 25mg every other day for the first week and 25mg per day for the second week. Rare hypersensitivity reactions, e.g. Stevens-Johnson syndrome, remain a problem. The risk-benefit ratio of felbamate has recently been compromised by fatal aplastic anaemia and fatal liver disease in a number of patients. In general, patients should be withdrawn from felbamate, if possible, until further clarification of its definitive risk-benefit ratio. Finally, gabapentin is a very safe add-on medication. Its remarkably low potential to cause adverse effects makes it a welcome addition for the treatment of refractory partial epilepsy.

Pharmacokinetic-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly prescribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compounds like phenylbutazone, oxyphenbutazone and azapropazone are most prone to pharmacokinetic interactions, the use of these compounds should be avoided where possible. Acidic NSAIDs interact with bile acid-binding resins, resulting in decreased concentrations of NSAIDs in the blood. In earlier reports it was suggested that the absorption of NSAIDs was affected by antacids and sucralfate. More recently, it was shown that there is delayed absorption of these drugs, but there is no difference in the extent of absorption. Only salicylates had their urinary secretion enhanced by antacids, which increase the urinary pH to values > 7. Histamine H2-receptor antagonists can be combined safely with NSAIDs. The concomitant administration of probenecid increased the blood concentration of NSAIDs, so an enhanced anti-inflammatory effect can be expected when these 2 drugs are combined. More importantly, NSAIDs can cause pharmacokinetic drug-drug interactions with other drugs. As can be expected, interactions with drugs that have a small therapeutic window are most likely to be of clinical significance. For example, lithium, medium to high dose methotrexate and, to a lesser extent, cyclosporin may be affected by concomitant administration of an NSAID. Aspirin (acetylsalicylic acid) and/or pyrazoles interact with oral anticoagulants, oral antihyperglycaemic agents and the anticonvulsants phenytoin and valproic acid (sodium valproate). Elevation of blood concentrations of these agents can be potentially dangerous. Similarly, NSAIDs interact with digoxin. This interaction is most likely to occur in the elderly, in neonates or in patients with renal impairment. Indomethacin can influence the blood concentrations of aminoglycosides in neonates. Unfortunately, this effect seems unpredictable, so practical therapeutic recommendations cannot be made. When NSAIDs are combined with salicylates or diflunisal, the blood concentrations of the salicylate or diflunisal may increase. However, the clinical relevance of this increase in drug concentration seems to be of minor importance. Gastrointestinal bleeding caused by NSAIDs is the most dangerous when it results from a mixed pharmacokinetic/pharmacodynamic interaction; however, patients are also at risk when pharmacodynamic interactions only are involved.

Evaluation of antiepileptic drug efficacy. A review of clinical trial design.

Up to 30% of patients with epilepsy are not adequately treated with currently available antiepileptic drugs. Despite a need for new agents, few were developed after valproic acid (sodium valproate), which appeared in the 1970s. This picture has changed recently. A number of new antiepileptic drugs have been approved for marketing, and additional approvals are expected soon. The evidence in the form of adequate and well controlled studies supporting the efficacy of each of these new drugs has included (and in some cases been wholly composed of) placebo-controlled add-on trials, showing the viability of that design. Add-on trials, which compare a new drug with placebo in the presence of a stable regimen of antiepileptic drug therapy, can be conducted as parallel or cross-over designs. These designs have been considered insensitive because they are conducted in patients refractory to available antiepileptic drugs, but add-on trials have proved able to identify effective new drugs. They also permit long term evaluation and provide information, including drug interaction data, in one of the major clinical contexts where a new antiepileptic drug may be used. New designs now allow the evaluation of antiepileptic effectiveness in other clinical contexts, including monotherapy, and provide alternatives when drug interactions obscure add-on trial interpretation. The key feature of this class of monotherapy designs is basing patients' trial duration on their seizure activity rather than on a fixed time period. This is accomplished by defining 'therapeutic failure' criteria which serve to assess efficacy of the test agent while protecting patient safety.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of Antiepileptic Drugs in Schizophrenia

During the last 20 years, research has indicated that antiepileptic drugs such as carbamazepine, valproic acid (sodium valproate) and clonazepam have therapeutic effects in disorders other than epilepsy. These agents are beneficial in patients with manic and depressive disorders, and have a mood-stabilising effect in schizophrenic and schizoaffective disorders that present with comorbid affective symptoms, such as excitation and aggression. Furthermore, a prophylactic effect on the recurrence of mood disorders is also observed.

Childhood Epilepsy : Current Therapeutic Recommendations.

The pharmacotherapy of epilepsy in children must account for a number of specific issues. The nature of epileptic disorders found in children differs from that in adults. For example, epilepsies of childhood are more likely to be developmentally or genetically based than those found in adults. Children also differ from adults in indications for antiepileptic drugs. Indeed, some types of childhood epilepsy do not require specific pharmacological treatment since prognosis is often excellent without therapy. This is especially true for children who are neurologically nonnal and those with benign epilepsy syndromes that have a characteristic electroclinical presentation, such as febrile seizures. In contrast, children with evidence of brain damage or those with serious epilepsy syndromes must be treated promptly.Once it has been decided that treatment is necessary, the choice of treatment should be based on a comparison of efficacy and tolerability of individual antiepileptic agents. The spectrum of toxicity is often different in younger patients from that in adults, and adverse effects that are acceptable in adults may be cause for discontinuation of therapy in children. Intellectual, cognitive and behavioural toxicity are particularly unacceptable.Establishing sustained therapeutic serum concentrations in children also requires specific attention. Rapid gastrointestinal transit times and interactions with milk and infant formulas may pose special management problems. Toxic metabolites of antiepileptic drugs are frequently produced in children. This can lead to drug hypersensitivity and other possible conditions, such as valproic acid (sodium valproate)-induced hepatotoxicity.Unless specific paediatric data are obtained, recommendations for the treatment of epilepsies in children will continue to be based on studies in adults and on anecdotal observations. Given the high prevalence and significant morbidity of childhood epilepsies, further studies of treatments are urgently needed.

Antiepileptic drugs. A review of clinically significant drug interactions.

Approximately 20 to 30% of patients with active intractable epilepsy are commonly treated with polytherapy antiepileptic drug regimens, and these patients may experience complicated drug interactions. Furthermore, because of the long term nature of treatment, the possibility of drug interactions with drugs used for the treatment of concomitant disease is high. Classically, clinically significant drug interactions, both pharmacokinetic and pharmacodynamic, have been considered to be detrimental to the patient, necessitating dosage adjustment. However, this need not always be the case. With the introduction of new drugs (e.g. vigabatrin and lamotrigine) with known mechanisms of action, the possibility exists that these can be used synergistically. The most commonly observed clinically significant pharmacokinetic interactions can be attributed to interactions at the metabolic and serum protein binding levels. The best known examples relate to induction (e.g. phenobarbital, phenytoin, carbamazepine and primidone) or inhibition [e.g. valproic acid (sodium valproate)] of hepatic monoxygenase enzymes. The extent and direction of interactions between the different antiepileptic drugs are varied and unpredictable. Interactions in which the metabolism of phenobarbital, phenytoin or carbamazepine is inhibited are particularly important since these are commonly associated with toxicity. Some inhibitory drugs include macrolide antibiotics, chloramphenicol, cimetidine, isoniazid and numerous sulphonamides. A reduction in efficacy of antibiotic, cardiovascular, corticosteroid, oral anticoagulant and oral contraceptive drugs occurs during combination therapy with enzyme-inducing antiepileptic drugs. Discontinuation of the enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s) and may necessitate dosage readjustment.

Oral contraceptives. Are drug interactions of clinical significance?

There is a large quantity of literature on drug interactions with oral contraceptive (OC) steroids although their incidence is not known. The potential clinical significance of some interactions makes it important for all prescribing doctors and dentists to have some knowledge of the topic. Interactions may be divided into those in which OC effectiveness is impaired, causing breakthrough bleeding or pregnancy, those in which OC activity is enhanced by other drugs and those in which OCs interfere with the metabolism or activity of other therapeutic agents. Consideration of their pharmacology indicates that impairment of OC effect is most likely to be due to interference with ethinylestradiol. This is because this compound is sulphated in the gut wall, hydroxylated and glucuronidated in the liver, and undergoes enterohepatic recirculation. The progestogens are only metabolised in the liver and have no significant enterohepatic recirculation. Protein binding interactions are rarely of clinical importance. OC plasma concentrations may be reduced by induction of hepatic metabolism in the case of griseofulvin, rifampicin (rifampin) and several anticonvulsant drugs; valproic acid (sodium valproate) does not have this effect. Antibiotics may interfere with enterohepatic recirculation of ethinylestradiol and reduce plasma levels of active hormone. This is probably only of significance in a subgroup of women who may sometimes be suspected on history, but cannot be identified by any diagnostic test. Reasons for differences between case reports and formal studies of interactions with antibiotics are discussed. Plasma concentrations of ethinylestradiol may be increased by ascorbic acid (vitamin C) and paracetamol (acetaminophen) which compete with it for sulphation in the gut wall. Theoretically, problems may arise if these agents are stopped suddenly. Imidazole antifungal agents can inhibit ethinylestradiol metabolism and increase its plasma concentrations but the clinical significance of this is unknown. OCs have been shown to inhibit metabolism of many therapeutic drugs and increase their plasma concentrations. This may be of clinical significance in the case of benzodiazepines which are hydroxylated in the liver, but clinical effects are less certain with the other agents. OCs may induce metabolism of other drugs which are glucuronidated, including some benzodiazepines and analgesics. The clinical significance of this type of interaction is also unknown. It is suggested that all prescribers should remember to ask about OCs when taking a drug history and to consider the possibility of interactions with other drugs.

Adverse drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs). Recognition, management and avoidance.

The prevalence and incidence of adverse drug interactions involving nonsteroidal anti-inflammatory drugs (NSAIDs) remains unknown. To identify those proposed drug interactions of greatest clinical significance, it is appropriate to focus on interactions between commonly used and/or commonly coprescribed drugs, interactions for which there are numerous well documented case reports in reputable journals, interactions validated by well designed in vivo human studies and those affecting high-risk drugs and/or high-risk patients. While most interactions between NSAIDs and other drugs are pharmacokinetic, NSAID-related pharmacodynamic interactions may be considerably more important in the clinical context, and prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Prescribing NSAIDs is relatively contraindicated for patients on oral anticoagulants due to the risk of haemorrhage, and for patients taking high-dose methotrexate due to the dangers of bone marrow toxicity, renal failure and hepatic dysfunction. Combination NSAID therapy cannot be justified as toxicity may be increased without any improvement in efficacy. Where lithium or anti-hypertensives are coprescribed with NSAIDs, close monitoring is mandatory for lithium toxicity and hypertension, respectively, and aspirin (acetylsalicylic acid) or sulindac are preferred. Phenytoin or oral hypoglycaemic agents may be administered with NSAIDs other than pyrazoles and salicylates provided that patients are monitored carefully at the initiation and cessation of NSAID treatment. Digoxin, aminoglycosides and probenecid may be coprescribed with NSAIDs, but close monitoring is required, particularly for high-risk patients such as the elderly. Indomethacin and triamterene should be avoided due to the risk of renal failure. High dose aspirin should be replaced by naproxen in patients on valproic acid (sodium valproate) and care is required when corticosteroids are administered to patients taking salicylates long term in high dosage. Interactions between NSAIDs and antacids or cholestyramine are generally avoidable. Adverse drug interactions involving NSAIDs may be limited by rational prescribing and by careful monitoring, particularly for high-risk patients, drugs and therapy periods.

Pharmacokinetic optimisation of anticonvulsant therapy.

Changing attitudes towards the use of antiepileptic drugs have led to an emphasis on monotherapy with serum concentration measurement coupled with standard, weight-adjusted starting and maintenance regimens to guide initial therapy and subsequent dosage titration. Currently, the established anticonvulsants are carbamazepine, valproic acid (sodium valproate) and phenytoin. Phenobarbital is now less commonly prescribed due to its propensity to produce sedation and impair cognitive function. The value of pharmacokinetic optimisation with valproic acid is limited by its wide therapeutic index, large fluctuations in the concentration-time profile and concentration-dependent protein binding. Thus, although serum concentrations are often measured, they are rarely subjected to pharmacokinetic interpretation. Carbamazepine has a flatter concentration-time profile than valproic acid. Its target range is more clearly defined and it undergoes autoinduction of metabolism and interacts with other drugs. Pharmacokinetic principles can, therefore, be more readily applied to carbamazepine, although, in general, a simple clinical approach to its use is usually satisfactory. Phenytoin has required the greatest pharmacokinetic input due to its nonlinear pharmacokinetics and narrow target range. Many different graphical methods, equations and computer programs have been reported, some of which demand 2 steady-state, dose-concentration pairs; others function satisfactorily with only 1. Recent attempts have been made to interpret non-steady-state data. In addition, a number of workers have demonstrated the value of altering the population parameter estimates to account for ethnic differences. A pharmacokinetic approach can also be used to tailor the use of phenytoin in the treatment of status epilepticus. Dosage alterations may be needed for specific patient groups. In particular, children generally require higher dosages on a weight-for-weight basis than adults, while equivalently lower dosages should be given to neonates. Most anticonvulsants are principally cleared by hepatic mechanisms, so dosage adjustment is not usually required in renal disease, although care must be taken in interpreting serum concentrations because of changes in protein binding. Close monitoring is required in the elderly and patients with hepatic impairment, while increased dosages may be needed in critically ill patients and during pregnancy. Pharmacokinetic principles can be used in the treatment of treat self-poisoning with anticonvulsants. There are few data available on the pharmacokinetics of vigabatrin, lamotrigine, oxcarbazepine and gabapentin in patients. Due to its mode of action in binding irreversibly to its target enzyme, serum concentration monitoring of vigabatrin plays no role in optimising therapy. The value of applying pharmacokinetic principles with the other 3 drugs remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)

New Uses of Anticonvulsant Drugs in Psychosis

Psychotic patients not adequately relieved by neuroleptic drugs often improve when anticonvulsants are added. In bipolar disorders and organic psychoses, anticonvulsants can sometimes be used to replace neuroleptics. No individual anticonvulsant is clearly, consistently superior. Patients who fail on one agent may improve on the next. Clonazepam is an excellent adjunct to neuroleptic therapy, but there is little evidence that it is effective as monotherapy. However, it is safe, sedates rapidly, and has an excellent patient tolerability profile. Carbamazepine is the best established drug for patients with bipolar disorders, particularly for rapid cyclers, and is often effective monotherapy. The therapeutic profile of valproic acid (sodium valproate) is similar to that of carbamazepine, but its side effects are quite different and are often preferred. Other anticonvulsants are little studied, but might be chosen to avoid certain side effects, or after better-studied drugs have failed. The pharmacological basis behind using anticonvulsants in psychoses is primarily empirical. In almost every case it has been clinicians who have first noted the beneficial effects of these drugs. Theories such as that of Post have followed.

バルプロ酸ナトリウム徐放性製剤ＫＷ‐６０６６Ｎの薬物動態の検討

バルプロ酸ナトリウム徐放性製剤ＫＷ‐６０６６Ｎの薬物動態の検討

Asymptomatic Hyperammonemia in Patients Receiving Valproic Acid

To determine the frequency of hyperammonemia in asymptomatic patients receiving valproic acid, plasma ammonia concentrations were measured in 55 patients receiving this drug and in 12 patients receiving other anticonvulsants. Twenty-nine of the 55 patients receiving valproic acid and none of the control patients had plasma NH3 levels above the normal range. Ten of the 11 patients receiving both valproic acid and phenytoin sodium in combination had elevated NH3 levels, as did five of six patients receiving both valproic acid and phenobarbital sodium. Elevations in plasma NH3 levels, as high as 140 mumole/L, were well tolerated, and valproic acid dose reductions were not necessary. Based on our findings, hyperammonemia is not an indication for reducing or eliminating valproic acid therapy.

The effect of concurrent administration of valproate sodium on phenobarbital plasma concentration/dosage ratio in pediatric patients

IN EVALUATING the possible interactions between antiepilepfic drugs, 1 the effect of valproic acid or valproate sodium on phenobarbital should be considered as a clinically significant interaction. Many reports ~-6 have indicated a rise in the phenobarbital concentration when valproic acid or valproate sodium was added. Several investigators have provided evidence that valproic acid inhibits phenobarbital metabolism in adult epileptic patients 4, ~ or adult healthy volunteers. 6 To our knowledge, this topic has not been studied in the pediatric age patient. Since several factors that influence the pharmacokinetics of antiepileptic drugs in children are not seen in adults, 7 and since the toxicity of phenobarbital in children, particularly in the younger age group, may be occult, we have retrospectively examined the concentrations of phenobarbital administered concurrently with or without valproate sodium in pediatric patients with seizures.

Plasma GABA levels in neurological patients under treatment with valproic acid

The effect of chronic treatment with valproic acid (VPA), administered as its sodium salt, on the plasma concentrations of GABA was studied in 5 in-patients. Within 2–10 days of treatment with daily doses of 1500–3000 mg sodium VPA GABA levels increased to 30–80 % compared to control days. This increase was transient in 3 out of 5 patients. In 19 epileptic patients under VPA medication plasma GABA levels were 40 % higher than those determined in non-epileptic patients serving as controls. The possibility that the increase in plasma GABA induced by VPA reflects similar increases in brain GABA content is discussed.

Behavioral interactions between opiate and antiepileptic drugs in the mouse

Morphine and related opioid compounds are known to possess proconvulsant activity based upon both electroencephalographic and behavioral criteria. The present authors previously suggested that opiate-related seizures were behaviorally inhibitory, and this was further investigated in the present study. The effects of pretreatment with three pharmacologically distinct compounds (sodium valproic acid, trimethadione, taurine) upon normal behavioral activation to systemic morphine were examined in the mouse. Morphine consistently increased activity levels in comparison with vehicle. Each of the three experimental compounds itself was behaviorally inhibitory; nonetheless both sodium valproate and trimethadione facilitated behavioral responses to morphine. The effects of the same drugs upon activation produced by central administration of a long-lasting enkephalin analog ( d-ala 2-leu-enkephalinamide) were investigated, with similar results. These findings confirm a behavioral interaction between opiate and anticonvulsant drugs, although it may be selective for certain classes of anticonvulsant compounds.