Biomedical subjects

Svein I Johannessen

Publications and source records attributed to Svein I Johannessen.

16 recordsLinked to original sources

PubMed2006

Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII).

The Eigth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT VII, took place in Sitges, Barcelona from the 10th to 14th September, 2006. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference, whose main themes included a focus on status epilepticus (epidemiology, current and future treatments), evidence-based treatment guidelines and the potential of neurostimulation in refractory epilepsy. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on marketed AEDs introduced since 1989. This article summarizes the information presented on drugs in development, including brivaracetam, eslicarbazepine acetate (BIA-2-093), fluorofelbamate, ganaxolone, huperzine, lacosamide, retigabine, rufinamide, seletracetam, stiripentol, talampanel, valrocemide, JZP-4, NS1209, PID and RWJ-333369. Updates on felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine and new extended release oxcarbazepine formulations, pregabalin, tiagabine, topiramate, vigabatrin, zonisamide and new extended release valproic acid formulations, and the antiepileptic vagal stimulator device are also presented.

Anticonvulsants↗

PubMed2006

Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed?

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range. The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured. For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.

Amines↗

PubMed2006

Management of focal-onset seizures: an update on drug treatment.

Focal-onset seizures are manifestations of abnormal epileptic firing of brain cells in a localised area or areas of the brain. The diagnosis of focal-onset seizures initially entails an EEG, a detailed history from the patient and eyewitnesses, as well as computer tomographic or, preferably, magnetic resonance imaging scans. Video EEG to record ictal events may be necessary to establish the correct diagnosis. Focal seizures are classified according to the International Classification of Epileptic Seizures and International Classification of Epilepsies and Epilepsy Syndromes. It is important to try to decide how the seizure event fits into this system in order to successfully evaluate and optimise treatment, as well as to give detailed information to the patient about their seizures and prognosis. Once the decision to treat the seizures has been made, the physician must choose which medication is the most appropriate to begin with. Carbamazepine, phenytoin or valproic acid (sodium valproate) are often rated as first-line drugs, but factors such as adverse-effect profiles, age, possibility of pregnancy, and concomitant diseases and medication also need to be considered. Most of the newer antiepileptic drugs (AEDs) appear to have good efficacy and better tolerability than the older agents, but evidence to support their superiority is scarce and has led to conflicting advice in several guidelines. Among the newer AEDs, lamotrigine, gabapentin, topiramate and oxcarbazepine have obtained monotherapy indication in many countries. The higher costs of the newer AEDs may inhibit their wider use, especially in poorer countries.

Anticonvulsants↗

PubMed2005

Can pharmacokinetic variability be controlled for the patient's benefit? The place of TDM for new AEDs.

The aim of this brief communication is to update our recent review on therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs). The potential value of TDM is discussed in relation to their mode of action and their pharmacokinetic proper-ties. Data on the relationships between serum concentrations and clinical efficacy are limited, and few studies have been designed primarily to study these relationships. As yet there are no generally accepted target ranges for any of the new AEDs. For most drugs a wide range in serum concentration is associated with clinical efficacy,and there is a considerable overlap in serum concentrations related to toxicity and lack of clinical efficacy. Although the available documentation is clearly insufficient, the pharmacological properties of some of the drugs suggest that they may be suitable candidates for TDM. The primary role of TDM for both the newer and established AEDs is to identify an individual's optimum concentration and thus establish a reference value in that patient.

Anticonvulsants↗

PubMed2005

Levetiracetam concentrations in serum and in breast milk at birth and during lactation.

PURPOSE: To study the pharmacokinetics of levetiracetam (LEV) at birth, during lactation, and in the nursed infant. METHODS: Eight consecutive breast-feeding women with epilepsy treated with LEV twice daily and their infants were studied. RESULTS: The mean umbilical cord serum/maternal serum ratio was 1.14 (range, 0.97-1.45) (n = 4). The mean milk/maternal serum concentration ratio was 1.00 (range, 0.76-1.33) at 3 to 5 days after delivery (n = 7). At sampling 2 weeks to 10 months after delivery (n = 5), it was similar (range, 0.85-1.38). At 3 to 5 days after delivery, the infants had very low LEV serum concentrations (<10-15 microM), a finding that persisted during continued breast-feeding. No malformations were detected, and in none of the infants did signs of adverse effects develop. CONCLUSIONS: Our data indicate an extensive transfer of LEV from mother to fetus and into breast milk. However, breast-fed infants had very low LEV serum concentrations, suggesting a rapid elimination of LEV.

Anticonvulsants↗

PubMed2004

Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents and their prevention.

The present review aims at highlighting selective aspects of the medical risks in epilepsy and their prevention. Emphasis is put on accidents and physical injuries, including risk factors and effectiveness of prevention; mortality, its causes, risk factors and prevention of seizure-related deaths, as well as traffic accidents, their risk factors and the effectiveness of prevention. Accidents and injuries are slightly more frequent among people with epilepsy than in the general population. This increased risk is probably most prevalent in patients with symptomatic epilepsy and frequent seizures, most often in combination with associated handicaps. The majority of accidents are trivial and occur at home. The most frequent injuries among patients with epilepsy are contusions, wounds, fractures, abrasions and brain concussions. The standardised mortality ratio (SMR; the ratio of observed number of deaths in a population with epilepsy to that expected, based on age and sex-specific mortality rates in a reference population) in population-based studies of epilepsy is 2-3 compared to the general population. This increased mortality is largely related to the etiology of the epilepsy and is probably not influenced by the treatment of the epilepsy. On the other hand, most fatalities in patients with chronic, therapy resistant epilepsy seem to be seizure-related and often sudden unexpected deaths (SUDEP). The frequency of such seizure-related deaths is most likely to be reduced by intensified treatment aiming at early seizure control, although appropriate studies for definitive evidence are still lacking. Apparently, there is an increased rate of traffic accidents in drivers with epilepsy, even if population-based prospective data are lacking. Many of these accidents are seizure-related. Probably, the extent to which physicians report their patients with uncontrolled epilepsy to the authorities is too low, but this has not yet been explored. Moreover, the preventive measures in legislation may be ignored by many people with epilepsy.

Accidents, Traffic↗

PubMed2004

Levetiracetam in adult patients with and without learning disability: focus on behavioral adverse effects.

Optimal antiepileptic drug treatment in patients with learning disability (LD) represents a particular challenge. These patients are often unable to report toxicity, and side effects may manifest as behavioral problems. The aim of this open study was to compare efficacy and tolerability of levetiracetam (LEV) in patients with LD and those without LD. One hundred eighty-four consecutive adult patients who received LEV were followed for an average of 8.1 months. Fifty-six patients (30%) had LD. Thirty-nine percent of patients with refractory epilepsy (37% with and 40% without LD) had > 50% seizure reduction. Significantly more behavioral side effects (23% vs 10%) and a tendency toward less reported somatic central nervous side effects were found in the LD group. We conclude that LEV is equally effective and well tolerated in both patients with LD and patients without LD. However, behavioral problems are more frequent in patients with LD, whereas the tendency toward seizure increase is not enhanced.

Adolescent↗

PubMed2003

[Oral contraceptives in women with epilepsy].

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Anticonvulsants↗

PubMed2003

[Levetiracetam in the treatment of epilepsy].

BACKGROUND: A proportion of patients with epilepsy are still without seizure control. This open study aims to evaluate the effect and tolerability in consecutive patients treated with the new antiepileptic drug levetiracetam. MATERIALS AND METHODS: 184 adult patients were followed up for an average period of 8.1 months. 166 patients (90%) had refractory epilepsy, defined as having seizures more than once a month despite having tried at least two antiepileptic drugs. RESULTS: 64 (39%) of the patients with refractory epilepsy had at least a 50% reduction of seizure frequency. Of these, 16 (10%) became seizure free. 24 (15%) had at least a 25% increase in seizure frequency. The overall effect was not significantly different for patients with and without learning disability. Levetiracetam also had promising effects in patients with juvenile myoclonic epilepsy and Lennox-Gastaut syndrome. Side effects were reported by 88 (44%) of all patients. Only 10 (5%) discontinued levetiracetam because of side effects. Behavioural effects were more frequent in patients with learning disability. INTERPRETATION: Levetiracetam was well tolerated and effective as add-on treatment in partial and generalised seizures. Some patients experienced an increase in seizure. A possible favourable pharmacodynamic interaction between levetiracetam and carbamazepine should be further explored.

Adolescent↗

PubMed2003

A paradoxical effect of levetiracetam may be seen in both children and adults with refractory epilepsy.

The aim of this prospective, uncontrolled clinical study was to evaluate the tolerability and the efficacy of levetiracetam as add-on treatment in 78 adults and 44 children with intractable epilepsy. The patients' seizure frequency in the 8 weeks baseline period was compared to their seizure frequency after a mean follow-up of 8 months of treatment.A greater than 50% reduction in seizure frequency was achieved in 31 adults (40%) and 9 children (20%), of whom 7 adults (9%) and 3 children (7%) became seizure free. Most often levetiracetam was well tolerated, somnolence being the most frequently reported side effect (18% in adults and 7% in children). However, in 14 adults (18%) and 19 children (43%) levetiracetam was associated with an increase (>25%) in seizure frequency. Such a paradoxical effect, including the development of status epilepticus in three adults and four children, appeared most often in mentally retarded patients during the first 2 months of treatment, and on relatively high doses. Two children developed status epilepticus after 5 and 7 months, respectively. In conclusion, levetiracetam is usually well tolerated as add-on treatment in patients with difficult-to-treat partial onset seizures. By using a lower initial dose and a slower dose escalation than recommended by the manufacturer, a paradoxical effect may perhaps be avoided. In children, doses >20 mgkg(-1) per day should be introduced with caution.

Adolescent↗

PubMed2003

Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data.

PURPOSE: To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs). METHODS: Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy. RESULTS: The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was <11% for MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p < 0.001). Mean accuracy values were <10% for all drugs other than TGB, for which measured values were on average 13.9% higher than spiked values, with a high variability around the mean (45%). No differences in precision and accuracy were found between methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry. CONCLUSIONS: With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.

Anticonvulsants↗

PubMed2003

Therapeutic drug monitoring of the newer antiepileptic drugs.

The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration-effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 micromol/L, 70 to 120 micromol/L, 10 to 60 micromol/L, 35 to 120 micromol/L, 50 to 140 micomol/L, 50 to 250 nmol/L, 15 to 60 micromol/L, 6 to 278 micromol/L, and 45 to 180 micromol/L, respectively. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.

Anticonvulsants↗

PubMed2003

Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study.

To explore possible concentration-effect relationships, gabapentin (GBP) and vigabatrin (VGB) serum concentrations were obtained from patients participating in an add-on dose-titration trial comparing GBP and VGB in partial epilepsy. Patients randomized to GBP started on 1800 mg/d and could have their dosage increased stepwise to 2400 and 3600 mg/d if seizures persisted. Those randomised to VGB started on 1000 mg/d, and the dose could be increased to 2000 and 4000 mg/d. Blood samples were obtained at steady state, at a nonstandardized time, from 27 patients randomized to GBP and from 36 randomized to VGB. Serum samples were analyzed using high-performance liquid chromatography. The treatment effect was expressed as percentage reduction in number of seizures from baseline. In addition, patients were classified as responders (>50% reduction in number of seizures from baseline) or nonresponders. There was no significant correlation between serum concentrations of GBP and seizure reduction at the lowest dosage, 1800 mg/d (r = -0.02, P = 0.94, Spearman-rank), nor between VGB serum levels and seizure reduction at 1000 mg/d of VGB (r = -0.14, P = 0.44). The serum GBP concentrations among responders to GBP 1800 mg/d were 26 +/- 12 micro mol/L (mean +/- SD), which was not different from serum concentrations in nonresponders, 28+/-13 micro mol/L. Nor was there a difference between serum concentrations of responders and nonresponders to VGB 1000 mg/d (32 +/- 23 and 44 +/- 36 micro mol/L, respectively). Hence, with the present study design we were unable to identify specific target ranges of GBP and VGB serum concentrations.

Acetates↗

PubMed2003

Valproate: past, present, and future.

Preclinical studies have been carried out during the past four decades to investigate the different mechanisms of action of valproate (VPA). The mechanisms of VPA which seem to be of clinical importance include increased GABAergic activity, reduction in excitatory neurotransmission, and modification of monoamines. These mechanisms are discussed in relation to the various clinical uses of the drug. VPA is widely used as an antiepileptic drug with a broad spectrum of activity. In patients, VPA possesses efficacy in the treatment of various epileptic seizures such as absence, myoclonic, and generalized tonic-clonic seizures. It is also effective in the treatment of partial seizures with or without secondary generalization and acutely in status epilepticus. The pharmacokinetic aspects of VPA and the frequent drug interactions between VPA and other drugs are discussed. The available methods for the determination of VPA in body fluids are briefly evaluated. At present, investigations and clinical trials are carried out and evaluated to explore the new indications for VPA in other conditions such as in psychiatric disorders, migraine and neuropathic pain. Furthermore, the toxicity of VPA, both regarding commonly occurring side effects and potential idiosyncratic reactions are described. Derivatives of VPA with improved efficacy and tolerability are in development.

Animals↗

PubMed2003

The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come?

The pharmacokinetic properties of a drug are the primary deter-minant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older-generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non-linear kinetics; carbamazepine and valproic acid have relatively short half-lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new-generation AEDs offer a num-ber of pharmacokinetic advantages, particularly in terms of reduced inter-patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.

Acetates↗

PubMedDate not supplied

Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII).

The Seventh Eilat Conference on New Antiepileptic Drugs (AEDs) (EILAT VII) took place in Villasimius, Sardinia, Italy from the 9th to 13th May 2004. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference,whose main themes included advances in pathophysiology of drug resistance, new AEDs in pediatric epilepsy syndromes, modes of AED action and spectrum of adverse effects and a re-appraisal of comparative responses to AED combinations. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on second-generation AEDs. This article summarizes the information presented on drugs in development, including atipamezole, BIA-2-093, fluorofelbamate, NPS 1776, pregabalin, retigabine, safinamide, SPM 927, stiripentol, talampanel,ucb 34714 and valrocemide (TV 1901). Updates on felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine,topiramate, vigabatrin, zonisamide, new oral and parenteral formulations of valproic acid and SPM 927 and the antiepileptic vagal stimulator device are also presented.

Adult↗