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Emilio Perucca

Publications and source records attributed to Emilio Perucca.

At least 37 records · Page 2Linked to original sources
PubMed2005

An introduction to antiepileptic drugs.

In recent years, the number of commercially available antiepileptic drugs (AEDs) has increased steadily. Although this may complicate management choices, it also offers welcome new options to individualize treatment more effectively. Because each of the available AEDs differs from others in many clinically relevant properties, opportunities to tailor drug treatment to the characteristics of the individual patient have never been greater. Properties that are especially important in drug selection in patients with epilepsy include spectrum of efficacy in different seizure types, adverse effects profile, pharmacokinetic properties, susceptibility to cause or be a target of clinically important drug-drug interactions, ease of use, and cost. Other factors that need to be considered in tailoring drug choice include availability of user-friendly pediatric formulations, and potentially favorable effects on co-morbid conditions. In fact, a number of AEDs are efficacious and widely prescribed in additional indications, particularly psychiatric disorders, migraine prophylaxis, and neuropathic pain. Recently, advances have been made in understanding the mechanisms of actions of AEDs at the molecular level. While a fully mechanistic approach to the clinical use of these agents is not yet feasible, knowledge of mechanisms of action offers useful clues in predicting their efficacy profile and spectrum of potential adverse effects.

Adult↗
PubMed2005

Influence of CYP2C9, 2C19 and 2D6 genetic polymorphisms on the steady-state plasma concentrations of the enantiomers of fluoxetine and norfluoxetine.

The antidepressant fluoxetine is administered as racemic mixture of two enantiomers (S- and R-fluoxetine). While S- and R-fluoxetine are equipotent in blocking serotonin reuptake, the enantiomers of the demethylated metabolite, norfluoxetine, show marked differences in pharmacological activity, S-norfluoxetine being about 20 times as potent as R- norfluoxetine as a serotonin reuptake inhibitor. In vitro and in vivo data suggest that the metabolism of fluoxetine to norfluoxetine is stereoselective and mediated, at least in part, by the polymorphic cytochrome P450 (CYP) isoenzymes CYP2D6, CYP2C9 and CYP2C19. In the present study, the influence of CYP2D6, CYP2C9 and CYP2C19 polymorphisms on the steady-state plasma concentrations of fluoxetine and norfluoxetine enantiomers was evaluated in 78 patients receiving chronic fluoxetine treatment (10-60 mg/day). The plasma concentrations of fluoxetine and norfluoxetine enantiomers were measured and CYP2D6, CYP2C9 and CYP2C19 genotypes were analyzed. No statistically significant relationship was identified between CYP2D6 or CYP2C19 genotypes and the dose normalised plasma concentrations of any of the enantiomers or the active moiety (i.e. the sum of S-fluoxetine, R-fluoxetine and S-norfluoxetine). However, the plasma concentration of S-norfluoxetine was very low in the only CYP2D6 poor metaboliser. Furthermore, the median S-norfluoxetine/S-fluoxetine ratios were higher in homozygous than in heterozygous extensive metabolisers (P<0.05). Among homozygous extensive metabolizers for CYP2D6, patients homozygous for CYP2C9*1 had lower dose-normalized R-fluoxetine concentrations and lower active moiety levels compared with those carrying detrimental CYP2C9 alleles (P<0.05). These results suggest that CYP2D6 and CYP2C9 polymorphisms contribute to the interindividual variability in fluoxetine pharmacokinetics at steady-state.

Adolescent↗
PubMed2005

Topiramate pharmacokinetics in children and adults with epilepsy: a case-matched comparison based on therapeutic drug monitoring data.

OBJECTIVE: To compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting. STUDY DESIGN: Retrospective, case-matched pharmacokinetic evaluation. PATIENTS: Seventy children (aged 1-17 years) with epilepsy and 70 adult controls (aged 18-65 years) with epilepsy, matched for sex and comedication. METHODS: Topiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney's U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed. RESULTS: In the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 +/- 21.0 vs 28.4 +/- 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 +/- 35.1 vs 46.1 +/- 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis. CONCLUSION: Topiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.

Administration, Oral↗
PubMed2005

Overtreatment in epilepsy: how it occurs and how it can be avoided.

In pharmacotherapy, overtreatment may be defined as an excessive drug load (that is, excessive drug dosages or unnecessary polypharmacy) leading to a suboptimal risk-to-benefit ratio. The risk of overtreatment in the pharmacological management of epilepsy is substantial and may have serious consequences in terms of a greater incidence and severity of adverse effects. These effects can range from subtle CNS impairment to overt toxic effects, including teratogenicity. Overtreatment also causes increased treatment costs and may even lead to a paradoxical deterioration in seizure control. The prevention and correction of overtreatment requires a thorough understanding of the situations and mechanisms that lead to inappropriate prescribing of antiepileptic drugs. These include initiating treatment in conditions where it is not indicated (for example, long-term prophylaxis after head trauma or supratentorial surgery in seizure-free patients), use of excessively fast titration rates, prescription of excessively high initial target dosages, failure to consider conditions associated with reduced dosage requirements (for example, old age or comorbidities associated with impaired drug clearance), and failure to consider the dose-response characteristics of the selected drug. Many patients whose seizures do not respond to the initially prescribed medication can be optimally managed by switching to monotherapy with an alternative agent; premature use of combination therapy represents another common form of overtreatment. Overtreatment may also result from a failure to adjust the dosage to prevent or compensate for adverse pharmacokinetic or pharmacodynamic drug interactions, and from a failure to reduce drug load in patients who have not benefited from high dosages or polypharmacy. While the measurement of drug concentrations can aid in minimising adverse effects, there is also a danger of overtreatment resulting from inappropriate interpretation of drug concentration data. Continuation of drug therapy in seizure-free patients in whom the risk-benefit ratio is in favour of gradual withdrawal may also be regarded as overtreatment. Tailoring therapy to the needs of the individual patient is the key to the successful management of epilepsy. Even though the importance of complete seizure control cannot be overemphasised, no patient should be made to suffer more from the adverse effects of treatment than from the manifestations of the seizure disorder.

Anticonvulsants↗
PubMed2005

Can drug resistance in epilepsy be minimized? Challenging commonly held beliefs.

Until more efficacious antiepileptic drugs (AEDs) that can tackle the challenge of drug-refractory epilepsy are developed, the best way to minimize inadequate seizure control is to exploit at best available treatments. There are however, discrepancies between commonly held opinions on several aspects of drug therapy, and the body of scientific evidence which exists to support them. This article highlights a few examples, discussing evidence that, contrary to common belief, (i) a significant proportion of patients with newly diagnosed epilepsy respond to concentrations of AEDs below the "therapeutic range" quoted in the literature; (ii) only a small group of patients unresponsive to low to moderate AED dosages become seizure-free after increasing dosage up to the limit of tolerability; (iii) knowledge of mechanisms of AED action can aid in the rational use of AEDs in the clinic; (iv) monitoring serum levels of new generation AEDs can be usefully exploited to improve management, and (v) at least in a subgroup of patients, successful epilepsy surgery cannot be regarded as curative, because seizure control may be dependent upon continuation of AED therapy. It is hoped that increased awareness of these issues could eventually contribute not only to improved clinical outcome, but also to high quality studies in many areas where gaps in knowledge prevent application of truly evidence-based management.

Anticonvulsants↗
PubMed2004

Epilepsy after head injury.

PURPOSE OF REVIEW: The purpose of this short review is to provide an update on the epidemiology of posttraumatic epilepsy, associated risk factors, data from prevention studies, and recent breakthroughs in experimental research. RECENT FINDINGS: There is increasing evidence that neuroimaging findings, stratification by neurosurgical procedures performed, and genomic information (e.g. apolipoprotein E and haptoglobin genotypes) may provide useful predictors of the individual risk of developing posttraumatic epilepsy. While antiepileptic drug prophylaxis can be effective in protecting against acute (provoked) seizures occurring within 7 days after injury, no antiepileptic drug treatment has been found to protect against the development of posttraumatic epilepsy and therefore long-term anticonvulsant prophylaxis is not recommended. Glucocorticoid administration early after head injury also has not been found to reduce the risk of posttraumatic epilepsy. At the basic research level, there have been advances in the understanding of pathophysiological changes in posttraumatic excitatory and inhibitory synapses, and the critical period for epileptogenesis after head injury has been better defined. Finally, the development of a novel animal model, which mimicks more closely human posttraumatic epilepsy, may facilitate efforts to characterize relevant epileptogenic mechanisms and to identify clinically effective antiepileptogenic treatments. SUMMARY: Despite the continuing lack of clinically effective agents for posttraumatic epilepsy prophylaxis, recent advances in basic and clinical research offer new hope for success in the development of new strategies for prevention and treatment.

Animals↗
PubMed2004

Navigating toward fetal and maternal health: the challenge of treating epilepsy in pregnancy.

A rational approach to the treatment of women of childbearing potential with epilepsy has been hampered by the lack of conclusive data on the comparative teratogenic potential of different antiepileptic drugs (AEDs). Although, several cohort studies on birth defects associated with AED use during pregnancy have been published, these have generally failed to demonstrate differences in malformation rates between AEDs, probably mainly due to insufficient power. In particular, pregnancies with new generation AEDs have been too few. In recent years, pregnancy registries have been introduced to overcome this problem--EURAP (an international collaboration), the North American, and the U.K. AED and pregnancy registries are observational studies that prospectively assess pregnancy outcome after AED exposure using slightly different methods. Each has enlisted 3-5,000 pregnancies in women with epilepsy, and the North American and the U.K. have released preliminary observations. Thus the U.K. registry reported a higher malformation rate with valproate, 5.9% (4.3-8.2%; 95% CI), than with carbamazepine, 2.3% (1.4-3.7%), and lamotrigine, 2.1% (1.0-4.0%). Most of the more recent cohort studies have also identified a nonsignificant trend toward a higher teratogenicity with valproate. These signals need to be interpreted with some caution since none of the studies to date have fully assessed the impact of possible confounders, such as type of epilepsy, family history of birth defects, etc. However, with increasing number of pregnancies it should be possible in the near future for the pregnancy registries to take such confounding factors into account and thus make more reliable assessments of the causal relationship between exposure to specific AEDs and teratogenic risks. While awaiting more conclusive results, it appears reasonable to be cautious in prescribing valproate to women considering to become pregnant if other suitable treatment alternatives, and with less teratogenic potential, are available. Any attempt to change treatment should, however, be accomplished well before conception. The importance of maintained seizure control must also be kept in mind, and the woman who needs valproate to control her seizures should not be discouraged from pregnancy, provided that counseling at the best of available knowledge is given.

Abnormalities, Drug-Induced↗
PubMed2003

Improved enantioselective assay for the determination of fluoxetine and norfluoxetine enantiomers in human plasma by liquid chromatography.

A simple and innovative assay is described which allows the chiral separation of the four enantiomers of fluoxetine and norfluoxetine, with performance characteristics adequate for therapeutic drug monitoring. The assay requires liquid-liquid extraction into acetonitrile/n-hexane/isopropylic alcohol and re-extraction into phosphoric acid for clean-up. The acidic layer is injected onto the HPLC system after filtering. Separation of the analytes is achieved with a Chiralcel ODR column and a mobile phase consisting of potassium hexafluorophosphate/acetonitrile. Detection is made by ultraviolet absorbance at 227 nm. Standard curves are linear for each enantiomer (r(2)>/=0.992) over the range of 10-1000 ng/ml with a limit of quantification of 10 ng/ml for each enantiomer. Within-day and between-day CV% are </=10% for each enantiomer.

Fluoxetine↗
PubMed2003

Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial.

OBJECTIVE: To evaluate the value of alternative monotherapy versus adjunctive therapy in partial epilepsy refractory to single antiepileptic drug (AED) therapy. DESIGN AND METHODS: In a multicentre, parallel-group, open-label study, patients with cryptogenic or symptomatic partial epilepsy not controlled after single or sequential AED monotherapies were randomised to monotherapy with an alternative AED or to adjunctive therapy with a second AED. The AED to be added/substituted and dose adjustments were determined by the physician's best judgement. Patients were followed up until withdrawal from the allocated treatment or for 12 months, whichever first. Outcome measures included proportion of patients continuing on the assigned treatment strategy, proportion of patients seizure-free after achieving the target maintenance dose, and adverse effects rates. Data were analysed by actuarial life tables, Kaplan-Meier survival analysis and Cox proportional hazard regression model. RESULTS: Of a total of 157 patients (including 94 previously exposed to only one AED), 76 were randomised to alternative monotherapy and 81 to adjunctive therapy. The two groups were balanced in clinical characteristics. The 12-month cumulative probability of remaining on the assigned treatment was 55% in patients randomised to alternative monotherapy and 65% in those randomised to adjunctive therapy (P=0.74). The 12-month probability of remaining seizure-free was 14 and 16%, respectively (P=0.74). Adverse effects were similar in the two groups. No significant differences in outcome within or between groups were identified based on etiology of epilepsy and previous AED exposure. CONCLUSIONS: Although these findings should be interpreted with caution due to the low statistical power resulting from the relatively small sample size, alternative monotherapy and adjunctive therapy were associated with similar outcomes. Further work is required to determine whether outcome could be improved through identification of specific AED combinations with synergistic activity.

Adolescent↗
PubMed2003

Translating monotherapy trials into clinical practice: a look into the abyss.

To be approved for monotherapy by regulatory authorities, new antiepileptic drugs (AEDs) must first be tested in well-controlled studies in refractory patients (conversion to monotherapy trials) or in patients with newly diagnosed epilepsy. However, the applicability of the information obtained in these trials to day-to-day clinical practice is limited. Clinical trials in newly diagnosed patients, particularly those allowing dose flexibility, offer more useful information, but a close scrutiny of methodological details is required to avoid misinterpretation of the findings. In many instances, the neurologist has a drug with a label, but lacks critical information on optimal titration rates, optimal target and maintenance dosages, response rates in populations with different epilepsy syndromes, different age ranges and comorbidities, and long-term safety data. Such information becomes available only through general clinical experience, well-designed phase IV studies, and postmarketing surveillance.

Anticonvulsants↗
PubMed2003

Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs.

There are two types of interactions between drugs, pharmacokinetic and pharmacodynamic. For antiepileptic drugs (AEDs), pharmacokinetic interactions are the most notable type, but pharmacodynamic interactions involving reciprocal potentiation of pharmacological effects at the site of action are also important. By far the most important pharmacokinetic interactions are those involving cytochrome P450 isoenzymes in hepatic metabolism. Among old generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone induce the activity of several enzymes involved in drug metabolism, leading to decreased plasma concentration and reduced pharmacological effect of drugs, which are substrates of the same enzymes (eg, tiagabine, valproic acid, lamotrigine, and topiramate). In contrast, the new AEDs gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, vigabatrin, and zonisamide do not induce the metabolism of other AEDs. Interactions involving enzyme inhibition include the increase in plasma concentrations of lamotrigine and phenobarbital caused by valproic acid. Among AEDs, the least potential interaction is associated with gabapentin and levetiracetam.

Anticonvulsants↗
PubMed2003

Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs.

Antiepileptic drugs (AEDs) are commonly prescribed for long periods, up to a lifetime, and many patients will require treatment with other agents for the management of concomitant or intercurrent conditions. When two or more drugs are prescribed together, clinically important interactions can occur. Among old-generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone are potent inducers of hepatic enzymes, and decrease the plasma concentration of many psychotropic, immunosuppressant, antineoplastic, antimicrobial, and cardiovascular drugs, as well as oral contraceptive steroids. Most new generation AEDs do not have clinically important enzyme inducing effects. Other drugs can affect the pharmacokinetics of AEDs; examples include the stimulation of lamotrigine metabolism by oral contraceptive steroids and the inhibition of carbamazepine metabolism by certain macrolide antibiotics, antifungals, verapamil, diltiazem, and isoniazid. Careful monitoring of clinical response is recommended whenever a drug is added or removed from a patient's AED regimen.

Animals↗
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

Serum carbamazepine concentrations in elderly patients: a case-matched pharmacokinetic evaluation based on therapeutic drug monitoring data.

PURPOSE: To assess the influence of aging on the steady-state pharmacokinetics of carbamazepine (CBZ) in a large population of patients evaluated in a therapeutic drug monitoring (TDM) setting. METHODS: The database of a large TDM service was used to identify retrospectively steady-state serum CBZ concentrations in 157 elderly patients with epilepsy (65 years and older) treated with CBZ alone or in combination with phenobarbital (PB). CBZ apparent oral clearance (CL/F) values were calculated and compared with those determined in an equal number of controls aged 20 to 50 years, and matched for gender, body weight, and comedication. RESULTS: Compared with corresponding controls, mean CBZ CL/F values were 23% and 24% lower, respectively, in the groups of elderly patients receiving monotherapy (57.1 +/- 20.6 vs. 74.6 +/- 28.3 ml/h/kg; p < 0.0001) and PB comedication (74.7 +/- 25.5 vs. 98.7 +/- 34.9 ml/h/kg; p < 0.01). Within each age group, patients comedicated with PB showed significantly higher CBZ CL/F values than those on monotherapy. A negative correlation between CL/F and age was found both within the monotherapy and the PB comedicated groups. In addition, CL/F values showed a positive relation with the administered daily dosage, which persisted within subgroups homogeneous for age and comedication. The independent influence of age, CBZ dosage, and comedication on CBZ CL/F was confirmed by multiple regression analysis. CONCLUSIONS: CBZ CL/F is decreased in an age-dependent manner in elderly patients compared with younger subjects, presumably because a reduction in the rate of CYP3A4-mediated drug metabolism. Elderly patients retain their sensitivity to dose-dependent autoinduction and to heteroinduction by enzyme-inducing AEDs, but their metabolic rates remain considerably below those observed in matched controls. As a result of this, patients in old age will require lower CBZ dosages to achieve serum concentrations comparable with those found in nonelderly adults.

Adult↗