Vigabatrin: a novel therapy for seizure disorders.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of vigabatrin and its role in the management of seizure disorders. METHODS: A MEDLINE search of English-language literature from January 1993 through January 1999 was conducted using vigabatrin as a search term to identify pertinent studies and review articles. Additional studies were identified from the bibliographies of reviewed literature. The manufacturer provided postmarketing surveillance data. Priority was given to randomized, double-blind, placebo-controlled studies. FINDINGS: Vigabatrin is a selective and irreversible inhibitor of gamma-aminobutyric acid transaminase. In controlled clinical trials of vigabatrin add-on therapy in patients with uncontrolled partial seizures, 24-67% of patients achieved a < or =50% reduction in seizure frequency. Data from two comparative trials with carbamazepine monotherapy indicate that vigabatrin monotherapy reduces the frequency of partial seizures in patients with newly diagnosed epilepsy. Vigabatrin also controls infantile spasms, particularly those associated with tuberous sclerosis. Vigabatrin is more effective in patients with partial seizures than in those with generalized seizures. The drug is generally well tolerated. Headache and drowsiness were the most common adverse effects observed in controlled clinical trials; visual field defects, psychiatric reactions, and hyperactivity also have been reported. There are no known clinically significant drug interactions. CONCLUSIONS: Vigabatrin improves seizure control as add-on therapy for refractory partial seizures and may produce therapeutic benefits in the treatment of infantile spasms. Vigabatrin is generally well tolerated, with a convenient administration schedule, a lack of known significant drug interactions, and no need for routine monitoring of plasma concentrations.

Lamotrigine: an antiepileptic agent for the treatment of partial seizures.

OBJECTIVE: To review the current literature on lamotrigine and its use as an antiepileptic drug (AED). DATA SOURCES: MEDLINE and bibliographic literature searches pertaining to lamotrigine were performed. Additionally, Burroughs Wellcome provided a comprehensive bibliography, data on file, and investigator's brochure. DATA SELECTION: The selection of reported data for this review includes both controlled and uncontrolled studies as well as case reports and unreported data from both European and US trials. DATA SYNTHESIS: Lamotrigine is effective as an adjunctive agent in the treatment of complex and simple partial seizures with or without secondary generalization. Anecdotal reports suggest that the spectrum of activity may include other seizure types, but controlled studies substantiating these reports are needed. Lamotrigine has a favorable pharmacokinetic profile, including a long half-life, low serum protein binding, and lack of mixed-function oxidase enzyme induction. It is likely that the drug induces metabolism through the glucuronidation pathway, although probably not to a clinically significant extent. Concurrent use of enzyme-inducing AEDs increase lamotrigine's clearance, whereas valproic acid decreases it. Adverse effects are primarily central nervous system-related, with dizziness, diplopia, ataxia, and somnolence reported in at least 10% of the patients treated. The incidence of these effects is higher in patients treated concomitantly with carbamazepine and may represent a pharmacodynamic interaction. The occurrence of rash may limit lamotrigine's use and was the most common cause for discontinuation in clinical trials (2.3%). The incidence of rash is higher in patients comedicated with valproic acid. CONCLUSIONS: Lamotrigine appears to be a safe and effective new AED for patients with refractory partial seizures when used as an adjunctive agent. It has a favorable pharmacokinetic profile allowing for once- or twice-daily dosing and adverse effects appear mild and transient. Additional studies are required to confirm efficacy in other seizure types.

Autism and associated behavioral disorders: pharmacotherapeutic intervention.

OBJECTIVE: To review the literature on autism and pervasive developmental disorders (PDDs) as well as their respective pharmacotherapies. DATA SOURCES: An Index Medicus, MEDLINE, and bibliographic search of the literature pertaining to autism, PDDs, and respective treatments. STUDY SELECTION: Because of the paucity of literature on the treatment of autism and PDDs, the selection of reported data for this review included both controlled and uncontrolled studies, as well as case reports and any other information reported in the literature on the treatment of these disorders. DATA SYNTHESIS: Autism and PDDs are severe developmental disabilities defined by behavioral criteria. These disorders are lifelong in nature and present in varying severity of clinical manifestations. Behavioral manifestations of patients with autism include core deficits in social interaction, communication, and imaginative activities, with a restricted repertoire of activities and interests. The present understanding of the neurochemical basis of the disorder is limited. The role of pharmacotherapy in the management of autism and PDDs is to ameliorate behavioral symptoms that interfere with the patient's ability to participate in educational, social, work, and family systems. Agents that have shown positive clinical effects in the treatment of children with autism and PDDs are reviewed in this article. CONCLUSIONS: Autism is a complex developmental disorder representing a heterogeneous group of individuals with similar symptomatologies and multiple biologic etiologies. Present pharmacotherapeutic intervention seeks to resolve behavioral symptoms. Treatment of autism and PDDs requires appropriate delineation of the behaviors and neurobiologic disorders associated with each patient. No single therapeutic agent, or combination thereof, is appropriate for the treatment of all children and adults with autism or PDDs.

Developmental principles of antiepileptic drug therapy.

Antiepileptic drug therapy in children can be challenging because seizure semiology and drug disposition change dramatically over time. Close monitoring of drug clearance is required in early life because of the rapid ontogenesis of drug-eliminating organs. Large variations in serum peak and trough antiepileptic drug concentrations increase the risk for both adverse drug effects and unsatisfactory seizure control. Antiepileptic drug adverse effects also differ, probably relative to different receptor sensitivities in children. Failure to appreciate the developmental differences between children and adults can result in medication noncompliance, breakthrough seizures, and unacceptable adverse effects.

Medical intractability in children evaluated for epilepsy surgery.

We assessed the value of therapeutic reevaluation and additional pharmacotherapy in medically intractable children referred for epilepsy surgery. In 21 children with antiepileptic drug treatment omissions, correcting the omission was ineffective in 19 (90%). Two children (10%), both of whom had structural lesions, achieved significant seizure control with high-dose carbamazepine monotherapy. Therapeutic reevaluation is indicated in all medically intractable children prior to epilepsy surgery.

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.

Carbamazepine toxicity resulting from generic substitution.

Generic substitution is practiced widely in both hospital and community settings. There have been several reports of reduced serum concentrations and seizure exacerbation following generic substitution of Tegretol. We describe the first 2 cases of carbamazepine toxicity resulting from the substitution of Tegretol with Epitol. Two 6-year-old children experienced increases in the maximum serum carbamazepine concentration, one of 22% and one of 41%. Both became asymptomatic when their serum concentrations were lowered and had no residual effects.

Drug disposition in neonates with patent ductus arteriosus.

OBJECTIVE: To review the literature on the physiologic changes created by neonatal patent ductus arteriosus (PDA) and the potential impact on drug disposition in these infants. DATA SOURCES: An Index Medicus and bibliographic search of the English-language literature pertaining to neonatal PDA and drug usage in newborns. DATA SYNTHESIS: PDA in premature infants is associated with a variety of physiologic changes that could alter drug disposition. Perfusion of drug-elimination organs (i.e., liver and kidney) may be diminished, resulting in decreased drug elimination. Further, the general fluid overload state associated with PDA may result in larger volumes of distribution (Vd), and dilutional effects for many drugs. Drug absorption, Vd, tissue penetration, and clearance may be affected by the physiologic changes incurred by a PDA. Although the pharmacokinetics of several categories of therapeutic agents may be affected by a PDA, disposition changes with the aminoglycosides and indomethacin have been the best documented. The most reliable pharmacokinetic change appears to be related to drug Vd. The interpretation of many of these studies is confounded by a potential drug interaction with the concurrent administration of indomethacin for PDA closure. CONCLUSIONS: Close therapeutic drug monitoring is indicated in newborns with PDAs as abrupt changes in drug disposition can occur with PDA closure. PDA-induced changes in specific pharmacokinetic parameters of agents such as the aminoglycosides, indomethacin, and perhaps vancomycin may prove to be a valuable diagnostic adjunct for the identification of babies with undiagnosed PDA. More research into this pharmacophysiologic aspect of pharmacokinetics is warranted.

Changes in plasma levels of oxygen radical scavenging enzymes during extracorporeal membrane oxygenation in a lamb model.

We studied levels of superoxide dismutase, glutathione, reductase, glutathione peroxidase and lipoperoxides in 12 healthy lambs below 1 year of age (8-19 kg) under therapy with extracorporeal membrane oxygenation (ECMO). Plasma levels of these free oxygen radical scavenging enzymes and lipoperoxides were taken 1 day before the ECMO experiment, at the beginning of ECMO after the first rotations of the roller pump, during, and after ECMO. The pre-ECMO results of days 1 and 2 were compared with the during-ECMO results and those with the post-ECMO results using the t test for paired samples. We found a significant decrease of both superoxide dismutase and glutathione reductase on ECMO, a trend to increased lipoperoxide levels, and unchanged levels of glutathione peroxidase. After discontinuing bypass the levels began to normalize again. We conclude that ECMO reduces some oxygen radical scavenging enzyme levels and exhibits a trend to increased lipoperoxide levels. Near total lung collapse with consecutive reperfusion injury might be harmful considering these results. However, the nonsignificant increase in lipoperoxide levels excludes considerable oxygen toxicity during this short ECMO trial.

Effect of extracorporeal membrane oxygenation on tobramycin pharmacokinetics in sheep.

BACKGROUND AND METHODS: Critically ill infants undergoing extracorporeal membrane oxygenation (ECMO) therapy often receive multiple pharmacologic agents. Although the disposition of many drugs has been assessed in patients undergoing cardiopulmonary bypass and in patients receiving mechanical ventilation, only limited data exist for selected medications in patients undergoing ECMO. To evaluate the potential influence of ECMO on aminoglycoside pharmacokinetics, we studied the disposition of tobramycin in ten sheep before and during ECMO therapy. Each sheep received a single iv dose of tobramycin during a control period before ECMO and on a study day during ECMO. Identically timed serial blood samples over 4 hrs were obtained after each tobramycin dose. Paired serum tobramycin concentrations were obtained pre- and postmembrane oxygenator during ECMO in six sheep. RESULTS: Alterations in specific pharmacokinetic variables for tobramycin were observed as a result of ECMO. Estimates of elimination half-life and volume of distribution for tobramycin were significantly increased during ECMO as compared with control (pre-ECMO) values (1.8 +/- 0.3 vs. 2.7 +/- 0.8 [SD] hrs [p < .01] and 0.3 +/- 0.1 vs. 0.5 +/- 0.2 L/kg [p < .005], respectively). Tobramycin body clearance was unaffected by the procedure (1.8 +/- 0.8 vs. 1.7 +/- 0.4 mL/min/kg). Paired serum tobramycin concentrations obtained pre- and postmembrane oxygenator demonstrated no drug removal. CONCLUSIONS: These data suggest that ECMO circuitry does not sequester tobramycin and that the prolonged elimination half-life observed during ECMO therapy is not due to a change in drug clearance but is due to an ECMO-induced increase in tobramycin volume of distribution. To achieve and maintain preselected target tobramycin serum concentrations during ECMO, the usual dosage interval should remain unchanged, but the dose should be increased to compensate for the alteration in the drug's volume of distribution. The clinical applicability of these findings needs to be confirmed in carefully controlled clinical studies involving infants receiving ECMO therapy.

Carbamazepine dosing for pediatric seizure disorders: the highs and lows.

Carbamazepine (CBZ) has become a commonly used antiepileptic agent in the pediatric population. It is considered a drug of choice for not only partial seizures but also for primary generalized tonic-clonic seizures. Although this agent is very effective, regulation of serum drug concentrations can sometimes be problematic in children. CBZ elimination is more rapid in children, necessitating the need for higher mg/kg doses than are commonly employed in adults. The accumulation of the pharmacologically active metabolite carbamazepine-10,11-epoxide is often higher in children due to more rapid conversion of the parent compound and may elicit either a better therapeutic response or neurotoxicities. CBZ absorption can also be somewhat altered in children and may be related in part to the dosage form used in small children. This article is intended to discuss some of the obstacles that may be encountered in CBZ therapy in children and to offer suggestions for improved therapy with this agent.

Therapeutic drug monitoring in the neonate and paediatric age group. Problems and clinical pharmacokinetic implications.

Therapeutic drug monitoring should encompass not only serum concentration monitoring but also assessments of organ and clinical functions. This is especially important in children, in whom receptor drug concentration or sensitivity may be different from that seen in the adult population. Therapeutic end-points should be identified and serum drug concentrations adjusted to meet these goals. This is further complicated by the added impact of pharmacokinetic idiosyncrasies displayed by children, coupled with the routine pitfalls of therapeutic drug monitoring seen in any patient population. Neonates and infants present the additional challenge of having a set of mechanisms whose degree of maturation sometimes changes on a day-to-day basis with alarming rapidity. It is this phenomenon which makes the definition of pharmacokinetic parameters following a single dose so unreliable and potentially hazardous. Therapy should be based not only on the capacity of the infant to eliminate and respond to a particular agent, but also on the understanding of the dynamic changes that will occur on an ongoing maturational basis. A basic familiarity with the patient population under study is essential in obtaining relevant data for pharmacokinetic analysis. Special consideration in children should focus on potential problems with drug administration, drug absorption, metabolite patterns, changing drug disposition, idiosyncratic reactions, receptor sensitivity and chronopharmacokinetics. As with other patient populations, serum drug concentration monitoring is only a small part of the clinical scenario, the whole of which must be the basis for therapeutic decisions and pharmacodynamic titration.

Rapid sequential phenobarbital treatment of neonatal seizures.

The optimal serum concentration of phenobarbital in newborns and its safety at high doses are not well established. The dose response relationship of rapid sequential phenobarbital loading in the newborn was examined and the efficacy of high-dose monotherapy was compared with the addition of a second anticonvulsant for persistent seizure activity. A single loading dose of phenobarbital 15 to 20 mg/kg was initially administered to 120 newborns. Nonresponders received sequential bolus doses of 5 to 10 mg/kg until seizures ceased or a serum concentration of 40 micrograms/mL was obtained. Infants with refractory seizures received additional phenobarbital to a maximum serum concentration of 100 micrograms/mL. The seizures of 48 babies (40%) were controlled after initial loading and 37 of the remaining 72 subjects (51%) responded at serum concentrations of as great as 40 micrograms/mL. The seizures of only seven subjects were controlled at greater concentrations. A second anticonvulsant controlled seizures in 13 of the 28 subjects (46%) whose seizures were refractory to phenobarbital. A gestational age of less than 32 weeks was associated with a significantly better response to phenobarbital. Serum phenobarbital concentrations greater than 50 micrograms/mL produced only occasional feeding difficulty and sedation. It was concluded that sequentially administered IV phenobarbital controls seizures in both term and preterm newborns (77%). This therapeutic effect is dose dependent but plateaus at a serum concentration of 40 micrograms/mL. At greater serum concentrations, unresponsive patients should receive a second antiepileptic agent.

Valproic acid efficacy, toxicity, and pharmacokinetics in neonates with intractable seizures.

Six neonates with prolonged, intractable seizures were treated with valproic acid (VPA). Each patient had received maximum doses of phenobarbital (greater than 40 micrograms/ml), and five patients received at least two additional anticonvulsants, without success. Seizure activity was controlled in five of six (83%) cases. In four cases, all other anticonvulsants could be withdrawn, and seizures were controlled on VPA monotherapy. VPA was discontinued in three patients because of VPA-induced hyperammonemia. VPA pharmacokinetic measurements were as follows: for total VPA, volume of distribution (V) = 0.40 l/kg (range, 0.36 to 0.47 l/kg), serum clearance (Cl) = 14.4 ml/h/kg (5.5 to 18.2 ml/h/kg), half-life (T1/2) = 26.4 hours (8.6 to 48.5); for unbound VPA, V = 2.02 l/kg (1.14 to 2.44 l/kg), Cl = 108.9 ml/h/kg (42.0 to 252.0 ml/h/kg). T1/2 = 17.6 hours (6.7 to 34.2). VPA free fraction ranged from 11.3 to 31.6% (mean, 19.2%).

Inadequacy of FDA dosing guidelines for theophylline use in neonates.

The efficacy of the FDA guidelines for theophylline dosing in newborns was evaluated retrospectively in 224 patients who had clearance data available. Mean projected post loading dose serum concentration was 4.1 +/- 1.0 mg/L in 160 patients. Mean projected steady-state concentration was 4.8 +/- 1.6 mg/L in 189 patients receiving intravenous aminophylline and 4.2 +/- 1.3 mg/L in 35 patients on oral therapy. Projected serum concentrations were subtherapeutic (less than 6.0 mg/L) in 181 of the 224 patients analyzed. There was a statistically significant difference in serum concentrations between asphyxiated and nonasphyxiated patients (p less than 0.001). There was no significant difference in mean projected serum concentrations between patients age 26-41 weeks (postconceptional age). This study suggests that the FDA dosing guidelines for theophylline in infants is inadequate and results in subtherapeutic (less than 6.0 mg/L) serum concentrations in the majority of newborns.