Adjunctive Therapy In Adults Research Articles

Eslicarbazepine acetate: A novel agent for the adjunctive treatment of epilepsy

Eslicarbazepine acetate, a novel antiepileptic agent, has recently been marketed as an adjunctive therapy in adults with partial onset seizures with or without secondary generalization. Its mode of action is not fully elucidated but it is believed that it and its metabolites stabilize the inactivated state of voltage-gated sodium channels, preventing their return to the inactivated state. Eslicarbazepine acetate is extensively converted to eslicarbazepine, its major active metabolite. Its pharmacokinetic profile is unaffected by food, gender, age or moderate hepatic impairment; clearance is dependent on renal function and dose reduction is recommended in patients with a creatinine clearance < 60 ml/min. Eslicarbazepine acetate does not induce its own metabolism or clearance. Clinical trials have demonstrated efficacy in short and long term studies (up to 1 year) together with improvements in quality of life outcomes and depressive symptoms where these existed at baseline. Most adverse events were mild to moderate in intensity and occurred early in treatment; the most frequently reported events were dizziness, somnolence and headache. Trials using eslicarbazepine acetate as monotherapy are ongoing.

Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures

To evaluate the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy in adults with partial-onset seizures. Double-blind, placebo-controlled, parallel-group, multicenter study consisting of an 8-week baseline period, after which patients were randomized to placebo (n = 87) or once-daily ESL 800 mg (n = 85) or 1200 mg (n = 80). Patients received half dose during 2 weeks preceding a 12-week maintenance period. Seizure frequency over the maintenance period was significantly (P < 0.05) lower than placebo in both ESL groups. Responder rate was 23% (placebo), 35% (800 mg), and 38% (1200 mg). Median relative reduction in seizure frequency was 17% (placebo), 38% (800 mg), and 42% (1200 mg). The most common adverse events (AEs) (>10%) were dizziness, somnolence, headache, and nausea. The majority of AEs were of mild or moderate severity. Once-daily treatment with ESL 800 and 1200 mg was effective and generally well tolerated.

Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial‐Onset Seizures

To evaluate the efficacy and safety of lacosamide when added to 1 or 2 antiepileptic drugs (AEDs) in adults with uncontrolled partial-onset seizures, and assess plasma concentrations of concomitant AEDs to determine any potential for drug interactions. During this multicenter, double-blind, placebo-controlled trial, patients were randomized to placebo or lacosamide 200, 400, or 600 mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments of 100 mg/day over 6 weeks and maintained for 12 weeks. Results were analyzed on an intention-to-treat basis. Four hundred eighteen patients were randomized and received trial medication; 312 completed the trial. The median percent reduction in seizure frequency per 28 days was 10%, 26%, 39%, and 40% in the placebo, lacosamide 200, 400, and 600 mg/day treatment groups, respectively. The median percent reduction in seizure frequency over placebo was significant for lacosamide 400 mg/day (p=0.0023) and 600 mg/day (p=0.0084). The 50% responder rates were 22%, 33%, 41%, and 38% for placebo, lacosamide 200, 400, and 600 mg/day, respectively. The 50% responder rate over placebo was significant for lacosamide 400 mg/day (p=0.0038) and 600 mg/day (p=0.0141). Adverse events that appeared dose-related included dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus. Lacosamide did not affect mean plasma concentrations of concomitantly administered AEDs. In this trial, adjunctive lacosamide significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures. Along with favorable pharmacokinetic and tolerability profiles, these results support further development of lacosamide as an AED.

Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures

Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures

Pregabalin: A novel γ-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders

Background: The US Food and Drug Administration (FDA) approved pregabalin in December 2004 for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Pregabalin is the first drug approved in the United States and in Europe for both conditions. In June 2005, pregabalin was approved as an adjunctive treatment in adults with partial-onset seizures. The FDA currently is considering the approval of pregabalin as adjunctive therapy in adults with generalized anxiety disorder (GAD) or social anxiety disorder (SAD). Objectives: The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of pregabalin; review its approved uses in the management of neuropathic pain and refractory partial-onset seizures; and investigate its potential use in patients with GAD or SAD. Methods: Relevant English-language literature was identified through a search of MEDLINE (1993–June 2006) and International Pharmaceutical Abstracts (2000–June 2006). The search terms included pregabalin, Lyrica, S-(+)-3 isobutylgaba, PN, DPN, diabetic peripheral neuropathy, PHN, postherpetic neuralgia, partial seizures, epilepsy, generalized anxiety disorder, and CI-1008. Results: In 4 clinical trials in a total of 1068 patients with diabetic peripheral neuropathy, the patients receiving pregabalin 300 to 600 mg/d had significantly greater improvement in mean pain scores than placebo recipients ( P ≤ 0.01). Patients with postherpetic neuralgia receiving pregabalin 450 to 600 mg/d had significantly greater improvement in relief of pain and pain-related sleep interference than placebo recipients ( P ≤ 0.002). Patients with refractory partial-onset seizures who received pregabalin 150 to 600 mg/d (divided into 2 or 3 doses) concomitantly with antiepileptic drugs had significantly fewer seizures than placebo recipients ( P ≤ 0.001). In the 3 studies that evaluated the efficacy of pregabalin in patients with GAD or SAD, the patients receiving pregabalin 200 to 600 mg/d (divided into 2 or 3 daily doses) had a significantly greater reduction in mean pain scores on the Hamilton Anxiety Scale than placebo recipients ( P ≤ 0.01). Across all the reviewed clinical trials, the most commonly reported adverse effects (AEs) were those affecting the central nervous system, including somnolence (≤50%), dizziness (≤49%), and headache (≤29%). AEs resulted in withdrawal from the study in ≤32% of patients. Conclusions: Pregabalin appears to be an effective therapy in patients with diabetic peripheral neuropathy, postherpetic neuralgia, and adults with refractory partial-onset seizures. The available data suggest that pregabalin may be beneficial as an adjunctive therapy in adult patients with GAD or SAD.

Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy

To compare the cognitive effects of lamotrigine vs topiramate as adjunctive therapy in adults with epilepsy. A multicenter, double-blind, randomized, prospective study was conducted in adults with partial seizures. Lamotrigine or topiramate was introduced as an adjunctive therapy to carbamazepine or phenytoin and titrated over 8 weeks to target doses. These drugs were maintained another 8 weeks (maintenance phase) without dosage changes. The primary endpoint was change from screening to the end of the maintenance phase in a combined analysis of standardized measures of cognition (Controlled Oral Word Association Task [COWA]; Stroop Color-Word Interference; Digit Cancellation; Lafayette Grooved Pegboard, dominant hand; Rey Auditory Verbal Learning Test, delayed recall; and Symbol-Digit Modalities test). For the primary endpoint, cognitive performance at the end of the maintenance phase was better with lamotrigine than with topiramate (415.3 vs 315.1; p < 0.001). On the individual cognitive tests, performance was better with lamotrigine than with topiramate in mean changes from screening on the COWA (p < 0.001), Stroop Color-Word Interference (p = 0.038), and Symbol-Digit Modalities tests (p < 0.001). The treatment effect exceeded the minimum clinically important difference for the COWA and the Symbol-Digit Modalities test. Mean changes from screening in the Performance-On-Line test simulating driving skills reflected better performance with lamotrigine than with topiramate (p = 0.021). The median percentage change from baseline in seizure frequency was lower with lamotrigine than with topiramate during the escalation phase (-80% vs -100%; p = 0.028) but not during the maintenance phase (-75% vs -100%; p = 0.062). The frequencies of cognitive adverse events and of premature withdrawals related to cognitive decline were higher with topiramate than with lamotrigine (6% vs 0%; p = 0.013). Lamotrigine had significantly less impact than topiramate on measures of cognition when used as adjunctive therapy for partial seizures.

Dexamethasone in Adults with Community-Acquired Bacterial Meningitis

Bacterial meningitis in adults is a severe disease with high fatality and morbidity rates. Experimental studies have shown that the inflammatory response in the subarachnoid space is associated with an unfavourable outcome. In these experiments, corticosteroids, and in particular dexamethasone, were able to reduce the inflammatory cascades in the subarachnoid space. The use of corticosteroids as adjunctive therapy in adults with bacterial meningitis has been evaluated in six studies, performed over a time period of 40 years. Most studies on adjunctive dexamethasone therapy in adults with bacterial meningitis were limited by methodological flaws. In 2002, a study with sufficient statistical power to show significant differences was published. This European Dexamethasone Study showed that adjunctive dexamethasone therapy reduced the rate of unfavourable outcomes in adults with bacterial meningitis from 25% to 15%. In this study, adjunctive treatment with dexamethasone was given before or with the first dose of antibacterials, without serious adverse effects. A quantitative review showed a consistent beneficial effect of dexamethasone on mortality and a borderline statistical beneficial effect on neurological sequelae. On the basis of the available evidence, adjunctive dexamethasone therapy should be initiated before or with the first dose of antibacterials and continued for 4 days in all adults with suspected or proven bacterial meningitis, regardless of bacterial aetiology. In patients with both meningitis and septic shock, dexamethasone therapy cannot be unequivocally recommended, but the use of lower doses seems reasonable at present. Since prompt use of dexamethasone and appropriate antibacterials improves the prognosis of adults with bacterial meningitis, hospitals will require protocols to include dexamethasone with the initial antibacterial therapy.

Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): Characterization by dynamic liver function tests

Levetiracetam is an antiepileptic drug approved for use as adjunctive therapy in adults with partial-onset seizures. We sought to investigate possible changes in the pharmacokinetics of levetiracetam and its metabolite ucb L057 in patients with liver cirrhosis, who may require dose adjustments. A single dose of levetiracetam was administered to 5 healthy subjects and to patients with Child-Pugh class A (n = 5), B (n = 6), or C (n = 5) alcohol-induced cirrhosis. The pharmacokinetics of levetiracetam and ucb L057 was measured and correlated with biochemical liver function parameters, with creatinine clearance, and with kinetics of caffeine, lidocaine, and d -sorbitol as probes for specific liver functions. Dynamic liver function tests revealed a deterioration of liver function. The pharmacokinetics of levetiracetam and its metabolite did not differ between healthy subjects and those with class A or B cirrhosis. However, in patients with class C cirrhosis, levetiracetam total clearance was reduced by 57% (90% confidence interval [CI], 43%-67%; P < .001). The geometric mean ratio of the area under the plasma concentration-time curve for levetiracetam, Child-Pugh class C versus control, was 2.41 (90% CI, 1.80-3.23), and the geometric mean of the half-life ratio was 2.27 (90% CI, 1.74-2.97). This was explained by the deterioration of renal function in patients with severe hepatic disease. In pharmacokinetic studies of hepatic impairment, including all classes of cirrhosis may be more revealing than including only selected classes of liver failure. No dose adjustment of levetiracetam is necessary in patients with mild to moderate liver impairment; however, patients with severe cirrhosis should initially receive only half of the commonly recommended dose.

Overview of the Clinical Pharmacokinetics of Oxcarbazepine

Oxcarbazepine (GP 47680, 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine- 5-carboxamide) is an antiepileptic drug registered worldwide by Novartis under the trade name Trileptal((R)). Trileptal((R))is approved as adjunctive therapy or monotherapy for the treatment of partial seizures in adults and in children. In the US, Trileptal((R)) is approved as adjunctive therapy in adults and in children >/=4 years of age and as monotherapy in adults and in children.Trileptal((R))is currently marketed as 150, 300 and 600mg film-coated tablets for oral administration. A 60 mg/mL (6%) oral suspension formulation has also been registered worldwide.Oxcarbazepine and its pharmacologically active metabolite, 10-monohydroxy derivative (MHD; 10,11-dihydro-10-hydro-carbamazepine; GP 47779) show potent antiepileptic activity in animal models comparable to that of carbamazepine (Tegretol((R))) and phenytoin. Oxcarbazepine and MHD have been shown to exert antiepileptic activity by blockade of voltage-dependent sodium channels in the brain.Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is responsible for the pharmacological effect of the drug. This step is mediated by cytosolic arylketone reductases. MHD is eliminated by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidised to the pharmacologically inactive dihydroxy derivative (DHD). The absorption of oxcarbazepine is complete. In plasma after a single oral administration of oxcarbazepine the mean apparent elimination half-life (t((1/2))) of MHD in adults was 8-9h. Food has no effect on the bioavailability of the highest strength of the final market image tablet (600mg). At steady state MHD displays predictable linear pharmacokinetics at doses ranging from 300 to 2400mg. In children with normal renal function, renal clearance of MHD is higher than in adults, with a corresponding reduction in the terminal t((1/2)) of MHD. Consequently, although no special dose recommendation is needed, an increase in the dose of oxcarbazepine may be necessary to achieve similar plasma levels to those in adults. In patients with moderate to severe renal impairment (creatinine clearance <30 mL/min), the elimination t((1/2)) of MHD is prolonged with a corresponding 2-fold increase in area under the concentration-time curve. Therefore, a dose reduction of at least 50% and a prolongation of the titration period is necessary in these patients. Mild-to-moderate hepatic impairment does not affect the pharmacokinetics of MHD. Based on in vitro and in vivo findings and compared with antiepileptic drugs such as carbamazepine, phenytoin and phenobarbital, oxcarbazepine has a low propensity for drug-drug interactions. In vitro, MHD inhibits the cytochrome P450 (CYP) 2C19 (ki [inhibition constant] = 88 micromol/L). At oxcarbazepine doses above 1.2g, a 40% increase in the concentration of phenytoin and a 15% increase in phenobarbital levels were observed. Oxcarbazepine/MHD at high doses may slightly increase phenobarbital and phenytoin plasma concentrations. Therefore, when using high doses of oxcarbazepine an adjustment in the dose of phenytoin may be required. In vitro, MHD is only a weak inducer of uridine diphospate (UDP)-glucuronyltransferase (UDPGT) and therefore is unlikely to have an effect on drugs that are mainly eliminated by conjugation through the UDPGT enzymes (e.g. valproic acid and lamotrigine). Weak interactions between MHD and antiepileptic drugs that are strong inducers of CYP enzymes have been identified. Carbamazepine, phenobarbital and phenytoin have been shown to reduce MHD levels by 30-40% when coadministered with oxcarbazepine, with no decrease in efficacy. Oxcarbazepine decreases the plasma hormone levels (ethinylestradiol and levonorgestrel) of oral contraceptives and may therefore have the potential to cause oral contraception failure.

Levetiracetam: its use in partial-onset seizure

Levetiracetam is one of the newer antiepileptic drugs released within the past decade and is indicated for use as adjunctive therapy in adults with partial-onset seizures. It is a novel antiepileptic drug with a unique activity profile and is chemically unrelated to existing antiepileptic drugs. The mechanism of action of levetiracetam does not involve conventional modulation of any of the three main mechanisms underlying classical antiepileptic drug activity. Levetiracetam pharmacokinetics are linear and time invariant. In addition, levetiracetam has shown clinical efficacy in randomized controlled trials for treatment of partial-onset seizures. Levetiracetam also has favorable pharmacokinetic and safety profiles. The purpose of this article is to examine the drug profile of levetiracetam, based on information derived from its preclinical and clinical studies. Furthermore, this article seeks to highlight key characteristics of levetiracetam that clinicians should consider in order to deliver individualized care to patients with epilepsy.

Integrating clinical trial data into clinical practice.

During the past decade, eight new antiepileptic medications (AEDs), including felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS), have been approved in the United States. In multicenter controlled clinical trials, each of these new AEDs has demonstrated efficacy as adjunctive therapy in adults with refractory partial seizures,1-18⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ and some have shown efficacy as monotherapy in adults with partial seizures.19-27⇓⇓⇓⇓⇓⇓⇓⇓ Although large amounts of data have emerged from these trials, the challenge for clinicians who treat adults with epilepsy has been to integrate these data into their clinical practices. Clinicians who treat children with epilepsy have faced greater obstacles. Only a handful of multicenter controlled clinical trials involving the newer AEDs have been conducted in children with epilepsy. In addition, these studies have focused on answering regulatory questions rather than addressing routine clinical issues. However, it is possible to extract practical and clinically useful information from these multicenter trials by systematically examining specific aspects of the efficacy, safety, and serum concentration trial data. An important factor in evaluating clinical trial data is to determine whether the study’s efficacy data demonstrate the potential usefulness of an AED for children with epilepsy. Direct application of adult clinical trial data to children has many potential hazards. There are a variety of differences between pediatric and adult epilepsy, including age-related seizure types and epilepsy syndromes, etiologic differences in partial seizures between adults and children, and a higher frequency of localization-related epilepsy syndromes in children.28 Therefore, only data from pediatric studies are included in this analysis. The design of the clinical trial is the critical factor determining the potential …

Oxcarbazepine

Oxcarbazepine (OXC) (Trileptal®, Novartis) is one of the recently introduced anti-epileptic drugs (AEDs) in the US. This drug has demonstrated efficacy as adjunctive therapy in adults and children, and as monotherapy in adults for the treatment of seizures of partial onset. There is also convincing evidence of its efficacy in patients with newly diagnosed and refractory trigeminal neuralgia. In addition, the initial efficacy results of oxcarbazepine in other neuropathic pain conditions and in bipolar disorders are encouraging. In this review, recommendations on the optimal clinical use of OXC are given based on its pharmacokinetic profile, efficacy and tolerability in those various conditions.

A review of high-dose intravenous immunoglobulin treatment for atopic dermatitis.

Atopic dermatitis generally responds to topical therapy; however, small numbers of patients have severe resistant disease despite second line therapies. High-dose intravenous immunoglobulin (HdIVIg) which is being used increasingly for dermatological indications has been suggested to be of benefit in a small number of uncontrolled trials and case reports. The mode of action is via a number of immunomodulatory mechanisms and it is not associated with the many side-effects of steroids and other immunosuppressive agents. There are now reports of 32 atopic dermatitis patients treated with HdIVIg, and this review aims to make a critical assessment of the current data. These have been obtained from a Medline search of the English literature from 1966 to 2001 for intravenous immunoglobulin and atopic dermatitis/eczema. Taken together an improvement was observed in 61% of atopic dermatitis patients treated with HdIVIg. Adults appeared less likely to respond (48%) than children (90%) and the duration of response was also more prolonged in children. Adjunctive therapy in adults was more effective than monotherapy (59% vs 0%), whereas monotherapy was effective in 90% of children. HdIVIg may offer a safe potential therapeutic avenue for resistant cases of atopic dermatitis, particularly in children, but should be further assessed using double-blind placebo-controlled trials.

Oxcarbazepine in the treatment of epilepsy.

Oxcarbazepine is a new antiepileptic drug (AED) that has been registered in more than 50 countries worldwide since 1990 and recently received approval in the United States and the European Union. Oxcarbazepine is a keto analog of carbamazepine and has a more favorable pharmacokinetic profile. It is rapidly absorbed after oral administration and undergoes rapid and almost complete reductive metabolism to form the pharmacologically active 10-monohydroxy derivative. Oxcarbazepine exhibits linear pharmacokinetics, no autoinduction, and minimal interaction with other AEDs. Ten controlled trials demonstrated that oxcarbazepine is safe and efficacious in the treatment of partial seizures across a wide range of ages (children to adults), situations (recent onset to treatment-resistant epilepsy), and uses (monotherapy and adjunctive therapy). The most common treatment-emergent adverse events are related to the central nervous system. Treatment-emergent hyponatremia (defined as serum sodium level < 125 mEq/L) occurred in 3% of patients treated with oxcarbazepine in clinical trials. According to the efficacy and safety profile established in the controlled trials, oxcarbazepine represents an important new treatment option indicated for monotherapy and adjunctive therapy in adults with partial seizures and as adjunctive therapy in children aged 4 years or older with partial seizures. Although structurally similar to carbamazepine, significant differences exist in the pharmacokinetics, drug interaction potential, adverse-effect profile, and dosage and titration between these two agents, and they should be considered distinct therapeutic agents.

Oxcarbazepine

Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) is a 10-keto analogue of carbamazepine with anticonvulsant activity. In newly diagnosed adult patients, oxcarbazepine monotherapy is as effective as phenytoin and vaiproic acid at reducing generalised tonic-clonic and partial seizure frequency. Furthermore, oxcarbazepine 2400 mg/day as monotherapy has also proved effective in the treatment of refractory partial seizures in adult patients. Oxcarbazepine 600, 1200 and 2400 mg/day as adjunctive therapy significantly reduced seizure frequency compared with placebo in 692 patients with refractory partial seizures. The efficacy of oxcarbazepine monotherapy is similar to that of phenytoin in the treatment of children and adolescents with newly diagnosed partial or generalised tonic-clonic seizures. Additionally, adjunctive therapy with oxcarbazepine was significantly more effective than placebo at reducing seizure frequency in children and adolescents with refractory partial seizures. The most commonly reported adverse events associated with oxcarbazepine monotherapy and/or adjunctive therapy in adults and/or children are somnolence, dizziness, headache, nausea and vomiting. Oxcarbazepine monotherapy is better tolerated than phenytoin (in both adults and children) and valproic acid (in adults), and although 75 to 90% of adult patients in 5 recent monotherapy studies reported adverse events while receiving oxcarbazepine, <8% withdrew from treatment because of them. Acute hyponatraemia, although usually asymptomatic, develops in 2.7% of patients treated with oxcarbazepine. Adverse events most likely to resolve upon switching to oxcarbazepine therapy from treatment with carbamazepine are undetermined skin reactions (rashes, pruritus, eczema), allergic reactions and a combination of malaise, dizziness and headache. Although oxcarbazepine does have a clinically significant interaction with some drugs (e.g. phenytoin and oral contraceptives), it has a lower propensity for interactions than older antiepileptic drugs (AEDs) because its major metabolic pathway is mediated by noninducible enzymes. Oxcarbazepine as monotherapy is a viable alternative to established AEDs in the treatment of partial and generalised tonic-clonic seizures in adults and children. Furthermore, it is also effective as adjunctive therapy in the treatment of refractory partial seizures in both age groups. In addition, the drug is tolerated better than the older, established AEDs, and has a lower potential for drug interactions. These attributes make oxcarbazepine an effective component in the initial treatment of newly diagnosed partial and generalised tonic-clonic seizures, and also as an adjunct for medically intractable partial seizures in both adults and children.

Oxcarbazepine (Trileptal). An effective and well tolerated new drug as first choice in treatment of focal seizures

Oxcarbazepin (OXC; 10,11-dihydro-10-oxo-5H-dibenz-[b,f]azepin-5-carboxamid, trade name Trileptal) is a new antiepileptic drug for treatment of mono- and adjunctive therapy of partial seizures with or without secondary generalization for adults and children above 6 years of age. It was developed through structural variation of carbamazepine. Extensive postmarketing use includes more than 200,000 patient years. The mechanism of action mainly involves blockage of sodium currents. The recommended daily starting dose of oxcarbazepin for both mono- and adjunctive treatment is 8-10 mg/kg (600 mg/day for adults) in two doses and can be titrated according to clinical benefit up to 2400 mg/day. Oxcarbazepin undergoes reductive metabolism at its keto moiety to form MHD, which is glucuronidated and excreted in the urine, with minimal involvement of the hepatic cytochrome P450-dependent enzymes. Thus, OXC has limited drug interactions and does not require slow titration, allowing for better tolerability. Oxcarbazepin compares favorably to presently available new anticonvulsants of the second generation for two reasons: it is available immediately for both mono- and adjunctive therapy in adults and children, and extensive postmarketing experience from many countries is already available. In addition, OXC has been thoroughly tested in an unusually large clinical development program and been shown to be similarly effective as standard antiepileptic drugs.

Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults.

Six double-blind, placebo-controlled trials were conducted with topiramate (TPM) initiated as adjunctive therapy in adults with treatment-resistant partial-onset seizures with or without secondary generalization. Because protocols and study populations were similar, data from the studies were pooled and analyzed for 527 patients treated with TPM and 216 treated with placebo. Seizures were reduced > or =50% in 43% of TPM-treated patients and in 12% of placebo-treated patients (p < 0.001); 5% of TPM-treated patients, but no placebo-treated patients, were seizure free during 11-19 weeks of double-blind treatment (p < 0.001). The therapeutic effect was consistent regardless of seizure type, age, gender, baseline seizure rate, or concomitant antiepileptic drug (AED). With 100 mg/day TPM as a starting dosage and weekly dosage increments of 100-200 mg/day added to maximally tolerated dosages of AEDs, the most common treatment-emergent adverse events (TEAEs) were dizziness, somnolence, fatigue, psychomotor slowing, nervousness, paresthesia, ataxia, memory difficulty and speech problems. These central nervous system effects were generally mild to moderate in severity, usually occurred early in treatment, often during titration, and resolved with continued treatment. Other notable TEAEs were weight loss and, in a small percentage of patients, renal calculi.

Population pharmacokinetics of lamotrigine adjunctive therapy in adults with epilepsy.

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18-64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme-inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in non-whites and increased by 13% in patients receiving more than one concomitant enzyme-inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme-inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme-inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.

Topiramate use in pediatric patients.

Topiramate (TPM), a new antiepileptic medication, is efficacious as adjunctive therapy in adults with partial onset seizures. Its efficacy as adjunctive therapy in children was evaluated in two randomized double-blind placebo-controlled trials involving childhood epileptic encephalopathy (the Lennox-Gastaut syndrome) and partial onset seizures. In these studies, topiramate adjunctive therapy resulted in a significant reduction in drop attacks (tonic or atonic seizures) in patients with the Lennox Gastaut syndrome and a significant reduction in partial onset seizures in children with refractory partial epilepsy. In both trials, TPM's efficacy improved as the dose escalated from the double-blind phase to the open-label portion. The minimally effective topiramate dose for adjunctive therapy in children with refractory epilepsy appears to be 6 mg/kg/day. Topiramate was well tolerated with mild or moderate side effects, predominantly related to the central nervous system. Practical tips are provided that may increase the chance that topiramate will be effective and well tolerated. The most important advice is a "start low, go slow" approach. An initial TPM dose of 0.5-1 mg/kg/day followed by weekly increments of 0.5-1 mg/kg is usually well tolerated. Based on these studies, topiramate appears to be an important addition to our pediatric AED armamentarium.

The Optimum Use of Intravenous Immunoglobulin for Prophylaxis of Opportunistic Infection in HIV-Infected Adults

Immunoglobulin therapy is well established in the treatment of HIV-infected children with frequent bacterial infections or recurrent severe bacterial infections, and the beneficial effects are well demonstrated. Such clear recommendations regarding intravenous immunoglobulin (IVIG) therapy are currently not available for adults. Several studies have been performed in adults to determine the effects of IVIG therapy in different dosages on the frequency and severity of infections, as well as on survival. Although most studies suffer from problems in design and low patient numbers, some conclusions can be drawn. The therapy is well tolerated and does not seem to have adverse effects on patients' immune functions. Most studies demonstrate beneficial results of IVIG treatment, especially on frequency and severity of infections in patients with advanced HIV disease. However, overall survival is, if at all, only slightly prolonged. Despite the observed beneficial effects, it is unclear whether these benefits justify the high costs of continuous IVIG therapy. The role of IVIG therapy could be further altered by the recent improvements in antiviral drug therapy. Taken together, the available data suggest an individualised usage of IVIG as adjunctive therapy in adults with advanced HIV infection and severe or recurrent bacterial infections.