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Objective Medical management of brain tumor-related epilepsy is complicated by interactions between antiepileptic and chemotherapeutic drugs. We studied the effect of temozolomide therapy on the disposition of the new antiepileptic drugs topiramate (TPM) or oxcarbazepine (OXC). Methods Fifteen patients chronically treated with TPM or OXC in monotherapy starting a chemotherapeutic treatment with temozolomide were enrolled in the study, of which ten were available for the final analyses. Blood samples were collected before temozolomide treatment (T0), at its end (T7) and after further 1–3 weeks (T14–T28). For each patient, more than one treatment cycle was studied. Topiramate and OXC mono-10-hydroxy derivative (MHD) plasma concentrations were determined by hplc coupled with ion spray mass spectrometer (TPM) or ultraviolet (MHD) detection. Results Mean TPM concentrations were 5.4 ± 2.4 μg/ml at T0 vs. 5.5 ± 2.4 μg/ml at T7 (n = 14), and 5.4 ± 2.4 μg/ml at T0 vs. 5.6 ± 2.8 μg/ml at T14–T28 (n = 14). Mean MHD concentrations were 16.4 ± 7.6 μg at T0 vs. 18.5 ± 9.0 μg/ml at T7 (n = 5), and 16.8 ± 7.0 μg/ml at T0 vs. 18.0 ± 8.7 μg/ml at T14–T28 (n = 8) (all comparisons not statistically significant; Student’s t-test for paired samples). Conclusion Temozolomide treatment did not affect TPM plasma concentrations in chronically treated patients. Data for MHD in OXC-treated patients were similar, but, due to the small sample size, results should be interpreted cautiously.These findings confirm that TPM (and possibly OXC) are a reasonable choice of antiepileptic drug in patients with brain tumor-related epilepsy.

The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years. In view of the importance of the issue, the Italian League against Epilepsy (LICE) set up an ad hoc working group whose task was to assess available evidence on the efficacy and safety of generic AEDs in the treatment of epilepsy and to produce recommendations on their use. A careful review of the literature revealed no adequately powered randomized controlled trials that assessed the risk/benefit ratio of generic substitution. Although there have been reports of loss or worsened seizure control, or appearance of adverse events, following the switch from brand products to generics, a critical assessment of the evidence generally does not allow us to establish a cause-effect relationship between the switch and a change in clinical status. Overall, the working group concluded that generic AEDs meeting current regulatory criteria for bioequivalence represent a valuable choice in the management of epilepsy by allowing a substantial reduction of treatment costs, particularly in patients initiating monotherapy or adjunctive treatment and in those with persistent seizures. The working group considered that in patients who achieved seizure freedom a modest change in plasma drug levels, which may occasionally occur even after substitution of products that meet bioequivalence criteria, could in rare cases lead to seizure breakthrough. Therefore, generic substitution is not recommended in patients who achieved seizure remission. Switches between a particular generic and another generic should also be preferably avoided. Finally, sustained-release AED formulations should not be used interchangeably with immediate-release brand or generic products. Patients need to be informed about the stringent criteria that currently govern the approval of generic products and about the implications of the use of generic AEDs, and their opinion should be taken into consideration at the time of prescribing.

Objectives: To assess the potential association between dopamine transporter (DAT) genotype, single photon emission CT (SPECT) measures using [ 1 2 3 I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([ 1 2 3 I]-FP-CIT) of striatal dopaminergic function, and oral levodopa response pattern in a cohort of patients with Parkinson disease. Methods: Thirty-six patients at different disease stages enrolled in the study. Each patient was examined by [ 1 2 3 I]-FP-CIT SPECT and a standardized oral levodopa test on 2 separate days in a randomized order within 3 weeks. The main outcome variables were the specific-to-nonspecific tracer uptake ratio in the contralateral putamen for SPECT analysis; latency, duration, and magnitude of the motor effect; and presence of dyskinesias for the levodopa test. The variable number of tandem repeat (VNTR) polymorphisms of the gene coding for DAT were detected for each patient by standard methods. Results: Contralateral putamen [ 1 2 3 I]-FP-CIT uptake ratios were similar in the patients carrying the 9-copy allele (n = 20) of the DAT VNTR compared with 10-repeat homozygotes (n = 16). No significant difference was found in levodopa main outcome variables and dyskinesia incidence between the two groups of patients stratified by DAT VNTR polymorphism. Conclusions: The study did not identify clinically relevant in vivo DAT neurochemical function phenotypes or levodopa response patterns associated with the DAT polymorphism.

A rapid and simple liquid chromatographic method with photodiode array detection was developed for the simultaneous determination of six antiepileptic drugs (oxcarbazepine, carbamazepine, lamotrigine, phenobarbital, primidone and phenytoin) and two metabolites (10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine, the main active metabolites of carbamazepine and oxcarbazepine, respectively) in human plasma. Separation of the analytes was achieved in less than 11.5 min on a C18 column (150×4.0 mm, i.d. 4.5 μm) with a mobile phase composed of methanol, acetonitrile and a pH 3.0, 15 mM phosphate buffer containing 0.63% triethylamine (19.2:16.8:64.0, (v/v/v)), at 1 ml min−1 flow rate. Two procedures were tested for the pretreatment of human plasma samples: protein precipitation with perchloric acid, and solid-phase extraction. The protein precipitation procedure did not allow for the analysis of 10,11-dihydro-10,11-epoxycarbamazepine. On the contrary, solid-phase extraction with hydrophilic–lipophilic balance cartridges gave good results in terms of extraction efficiency and reproducibility and allowed for the determination of all analytes. The HPLC-DAD method developed, coupled to a careful SPE procedure, seems to be suitable for the plasma level determination of simultaneously administered antiepileptic drugs.

Background As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. Methods Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. Results Two hundred sixty-seven GBM patients (median age, 64 y; range, 29–84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2–12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0–18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248–0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388–0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328–0.986; P = .0446). Conclusions The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.

Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim of testing their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day transplant-related mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36 ± 570.06 vs. 838.10 ± 282.40 mMol*min) and higher post-transplant bilirubin serum levels (3.280 ± 0.422 vs. 1.874+0.197 mg/dL). In vitro, busulfan elicits pro-inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. It is worthy of note that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism.

Objective: The aim of the study was to investigate the potential effect of short, moderate intensity (e70% maximum heart rate) cyclette exercise on levodopa (LD)/dopa decarboxylase inhibitor bioavailability and motor response in a subgroup of Parkinson disease (PD) patients presenting a moderate-to-severe delay in fasting morning LD dose absorption and matched motor response. Methods: Ten patients underwent an oral LD instrumental kinetic-dynamic test based on simultaneous serial measurements of plasma LD concentrations, finger tapping motor effects, dyskinesia ratings plus Unified Parkinson Disease Rating Scale Motor Section (section III) evaluation after ingestion of their usual fasting first morning LD dose, on 2 occasions, 2 weeks apart, according to an intrasubject randomized cross-over design: once receiving their oral LD test dose immediately before a 15-minute cycling and once at seated rest. The main LD pharmacokinetic variables were time to peak, peak plasma concentration, and the area under the 4-hour plasma concentration-time curve. The main LD pharmacodynamic variables were the latency, duration of the motor effect elicited by the LD test dose, and the area under the 4-hour tapping effect-time curve. Results: The LD pharmacokinetics and pharmacodynamics did not differ between the 2 sessions. Conclusions: We found no significant effect of a moderate, clinically practical exercise on LD rate and extent of absorption and matched motor response in a subgroup of patients with delayed LD kinetic-dynamic effect.

Dopamine receptor agonists were originally developed as adjunctive therapies to ‘smooth out’ motor response fluctuations to levodopa in patients with advanced Parkinson’s disease. However, they are now used in the early stages of the disease, in monotherapy or combination with low doses of levodopa, to delay the onset of levodopa therapy and its complications. Oral dopamine agonists currently available worldwide for Parkinson’s disease include the older ergot derivatives bromocriptine and pergolide and the second generation non-ergoline compounds ropinirole and pramipexole. Other dopamine agonists that are used less frequently include cabergoline (a new ergoline drug, only recently released in some European countries as an antiparkinsonian drug), lisuride (an ergot derivative) and piribedil (an older non-ergot compound). Data on the pharmacokinetics of oral dopamine agonists, especially the older ergot derivatives, are scarce and mostly refer to small groups of healthy young individuals. All these agents, with the exception of pramipexole, are subject to extensive enterohepatic first-pass metabolism. Their bioavailability is low and shows high intra- and interindividual variability. The pharmacodynamic properties of dopamine agonists relevant to their antiparkinsonian effect have not been clearly defined. As a result, an optimal dosage schedule for the treatment of Parkinson’s disease is generally identified using highly individualised empirical assessment. This involves considerable time expenditure and creates difficulty for patients, who have to follow complex titration schedules. Dopamine agonists appear to have a low potential for pharmacokinetic interaction with levodopa. Few data have been reported on the effect of coadministration on the pharmacodynamics of levodopa. The available data indicate that pergolide and bromocriptine significantly increase the duration of the motor response to levodopa, while baseline motor effects and the magnitude of motor response are substantially unchanged. Cabergoline also significantly prolongs the motor response to a dose of levodopa in patients experiencing motor fluctuations, but baseline motor scores are also significantly improved, suggesting a long-lasting effect. Subcutaneous apomorphine is currently the only non-oral formulation of a dopamine agonist available; it is used as add-on rescue therapy for patients who have advanced Parkinson’s disease and a wide spectrum of complex motor, sensory, autonomic and cognitive ‘wearing-off ’ phenomena not controlled by optimal oral dopaminergic therapy. Attempts to deliver apomorphine and other soluble dopamine agonists by more practical non-oral routes, such as intranasally or transdermally, have so far been of limited clinical utility or are currently still under investigation.

Objective: The aim of the study was to assess the effect of the time of ingestion of a meal on the pharmacokinetics and pharmacodynamics of a levodopa/carbidopa controlled-release formulation in parkinsonian patients on chronic levodopa therapy. Methods: The kinetic-dynamic profile of one tablet of controlled-release levodopa/carbidopa 200/50 mg was monitored in eight patients, according to an intrasubject randomized cross-over design in two different sessions. A standard meal was consumed by the patients after they had fasted for 15–17 h, on one occasion 30 min before the ingestion of the test dose, and on the other occasion 2 h after the ingestion of the same drug dose. Blood venous samples for analysis of plasma levodopa and its metabolite 3-O-methyldopa were drawn at 20-min intervals up to 6 h after dosing. Motor response to the levodopa test dose was assessed by the finger tapping and walking speed tests at the same times as blood was drawn. Results: Controlled is release levodopa intake after meals resulted in a significant delay in drug absorption, with an almost twofold increase in time of initial appearance of levodopa in plasma and time to peak plasma concentration. Peak plasma drug concentrations were not significantly different in the two experimental conditions; the area under the 6-h plasma concentration-time curve showed an average reduction of 24% in the fed condition, partly reflecting the incomplete assessment of levodopa absorption, within the 6 h of examination, due␣to 5-h delayed peak plasma levodopa concentration␣in two patients. With reference to levodopa pharmacodynamics, time to onset of motor response was significantly delayed and duration of motor response significantly curtailed in the fed condition, while the magnitude and overall extent of motor effect were unchanged. Conclusions: In keeping with previous findings on levodopa standard-release preparations, these data show that time of meal ingestion is an important determinant of levodopa disposition, even from controlled-release preparations in parkinsonian patients. From a clinical point of view, these results help to explain some of the delayed, curtailed and even lacking responses that often complicate afternoon motor performances in patients at the more advanced stages of the disease.

We conducted a 3-year prospective assessment of the relationship between levodopa (L-DOPA) plasma concentration and both dyskinesias and tapping motor response after a standard oral L-DOPA dose in 11 parkinsonian patients, Hoehn & Yahr (H & Y) stages 2-3, with L-DOPA therapeutic response complicated by involuntary movements. Over the 3-year period, duration of the tapping effect significantly decreased, while that of dyskinesias showed minor changes. Initially, the L-DOPA therapeutic response significantly outlasted the dyskinesia effect and progressively shortened to parallel the dyskinesia profile at the more advanced clinical stage. According to kinetic-dynamic modeling, L-DOPA concentrations producing 50% of maximum therapeutic and toxic effects (EC50) also changed independently. EC50 for dyskinesias did not vary over time. EC50 for the tapping effect was, at the first observation, significantly lower than that of the matched value for dyskinesias and progressively rose to values similar to the EC50 for dyskinesias by the third year of follow-up. These data suggest a dissociation of the kinetic-dynamic relationship of L-DOPA motor and dyskinesia effects, possibly reflecting different cerebral handling of exogenous levodopa-derived dopamine with disease progression.

Lacosamide (LCM) is one of the newer antiepileptic drugs (AEDs) licensed as add-on treatment for partial epilepsy. Data on LCM pharmacokinetics and interactions are limited and partly contradictory. The purpose of this study was to assess the effect of concomitant AED therapy on steady state plasma concentrations of LCM in a population of patients with epilepsy.Steady state plasma concentrations of LCM were assessed in a cohort of 75 consecutive patients with epilepsy referred to the Laboratory of Clinical Neuropharmacology for AED therapeutic monitoring over 16 months. Plasma LCM concentrations were measured by high-performance liquid chromatography with spectrophotometric detection.Median morning trough plasma concentration-to-weight-adjusted dose ratio of LCM [(mg/L)/(mg/kg/d)] was significantly reduced (0.94 versus 1.35, P < 0.001) in patients treated with LCM plus AED strong inducers of cytochrome P450 metabolism, namely, carbamazepine, phenobarbital, and phenytoin (group A, n = 33), compared with a pool of patients not comedicated with AED strong inducers, predominantly including oxcarbazepine, levetiracetam, lamotrigine, and valproic acid (group B, n = 42). The 2 groups were comparable for age, gender, weight, LCM daily dose, and dosing frequency. LCM plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 75 to 600 mg/d, although, at a given drug dose, a large interpatient variability was observed in matched, plasma drug concentration.Our findings confirm, in a real-patient clinical setting, preliminary evidence from randomized, clinical trials showing that carbamazepine, phenobarbital, or phenytoin significantly reduces the overall systemic exposure to LCM. From a practical point of view, patients on concomitant AED strong inducers may require a 30\% higher dose of LCM compared with patients not receiving strongly inducing AED cotherapy, to achieve the same plasma drug concentration.

Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial beta-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

We investigated the relationship between the rate of motor response after a standard levodopa oral dose and drug dynamic variables and disease-related factors in 66 patients with Parkinson's disease. Time to maximum finger tapping effect was positively correlated with matched duration of levodopa dose response and fell from a median 120 minutes in patients at Hoehn and Yahr stage I and II to 60 minutes in stage IV patients (p < 0.001). The accelerated response to levodopa dose with the advancement of disease was also apparent as an increased steepness of the tapping effect versus time curve, with a shift from a hyperbolic to a sigmoid profile. The rate of motor response to oral levodopa may reflect the rate of dopamine interaction with the postsynaptic receptors, providing an indirect objective index of presynaptic dopaminergic homeostasis.

We systematically assessed the potential effects of disease severity and acute levodopa dosing on body balance by a stable force measuring platform in 56 patients with Parkinson's disease, and compared them to 34 healthy volunteers. Postural sway variables were significantly higher in both patient groups without (Hoehn and Yahr 1–2) and with (Hoehn and Yahr 3–4) a clinically evident deficit of postural stability compared to controls. Levodopa dosing significantly increased postural sway 1 and 2 hours post-dose. The standardization of static posturography with respect to the clinical characteristics and drug schedule of patients may improve the sensitivity of the test, disclosing abnormalities of postural stance even at the early stages of the disease and revealing possible acute drug effects.

Despite the burden of chronic daily headache (CDH), general practitioners’ (GPs) ability to recognize it is unknown. This work is a sub-study of a population-based study investigating GPs’ knowledge on their CDH patients. Patients diagnosed with CDH through the screening questionnaire were interviewed by their GPs who indicated if subjects were known as patients suffering from CDH with medication overuse (MO), CDH without MO, episodic headache (EH) or non-headache sufferers. Our study showed that 64.37 % of CDH sufferers are misdiagnosed by their GPs. However, overusers are better known to GPs.

We aimed to compare apparent steady-state oral clearance (CL/F) of the antiepileptic drug levetiracetam (LEV) in elderly (66-80 years, n=105) and very elderly (81-96 years, n=70) vs nonelderly (30-65 years, n=97) patients with epilepsy. Median weight-normalized CL/F (mLmin(-1)kg(-1)) decreased from 1.23 (nonelderly) to 0.83 (elderly) and 0.59 (very elderly) (p

We assessed the nature of foot strike and the potential effect of acute levodopa dosing in Parkinsonian patients with mild to severe fluctuations of motor performances in comparison with healthy volunteers. Forty-eight patients were enrolled in the study and compared with 33 age and gender matched controls. Each patient was assessed by a computerized electropodographic system before levodopa dosing and 1 and 2-h after intake of a standard fasting morning dose of levodopa plus benserazide. Twelve foot strikes (six right, six left) were analysed per patient. The controls underwent three repeated examinations at 1-h intervals. Patients' motor response to acute levodopa dosing was evaluated at fixed times by a battery of motor tests. Foot strike dynamics differed between patients and controls: in particular, first ground contact of the foot was significantly shifted from heel to forefoot in patients compared to controls. The forward shift in footprint during walking was more marked on the more affected body side but was unrelated to the severity and duration of Parkinsonism and unresponsive to levodopa dosing. Tapping and walking tests were overall responsive to acute levodopa intake. The system seemed suitable to detect irregular patterns of foot strike even at the early stages of Parkinsonism, when lower limb disorder was not clinically overt, and might be useful in the search for clinical markers of Parkinsonian gait.

Summary: Free and total carnitine and acylcarnitine in plasma and urine samples was measured in 22 epileptic patients before and after 15 and 45 days of valproate (VPA) therapy and in 16 healthy volunteers on a single occasion. Carnitine plasma concentration and renal excretion observed in epileptic patients before VPA therapy did not differ from control values. After VPA was started, free and total plasma concentration decreased significantly (p < 0.05) from 49 ± 17 to 35 ± 16 at 15 days and to 35 ± 13 nmol/ml at 45 days of therapy (free carnitine) and from 60 ± 18 to 50 ± 18 at 15 days and to 55 ± 14 nmol/ml at 45 days of therapy (total carnitine), whereas acylcarnitine increased significantly (p < 0.05) from 10 ± 8 to 14 ± 8 at 15 days and to 18 ± 16 nmol/ml at 45 days of therapy. Free carnitine urinary excretion decreased significantly (p < 0.05) from 200 ± 135 to 115 ± 76 and 118 ± 75 μmol/24 h, whereas acylcarnitine urinary excretion increased significantly (p < 0.05) from 78 ± 56 to 154 ± 98 and 155 ± 89 μmol/24 h after VPA therapy was started. As a consequence, acylcarnitine renal clearance increased significantly (+ 30%, p < 0.05) whereas free carnitine renal clearance did not change during VPA therapy. No difference was detected between 15 and 45 days of therapy. No patients experienced symptoms of VPA toxicity. Our results suggest that VPA in patients increases both formation and renal clearance of acylcarnitine. ReSUMe Les taux plasmatiques et urinaires de carnitine libre, totale et d'acylcarnitine ont ete mesures chey 22 patients epileptiques avant et 15 et 45 jours apres traitement par valproate (VPA), ainsi qu'une seule fois chez 16 volontaires sains. La concentration plasmatique de carnitine et l'excretion renale observees chez les patients epleptiques avant traitement par VPA ne differaient pas des valeurs controles. Apres mise en route d'un traitement par VPA, la concentration libre et totale a diminue significativement (p < 0.05) de 49 ± 17 B 35 ± 16 a 15 jours et B 35 ± 13 nmol/ml a 45 jours de traitement (pour la carnitine libre) et de 60 ± 18 B 50 ± 18 B 15 jours et B 55 ± 14 nmol/ml B 45 jours de traitement (carnitine totale), alors que l'acylcarnitine augmentait significativement (p < 0.05) de 10 ± 8 B 14 ± 8 15 jours et 18 ± 16 nmol/ml B 45 jours de traitement. L'excrCtion urinaire de carnitine libre a diminut significativement (p < 0.05) de 200 ± 135 a 115 ± 76 et 118 ± 75 pmo1124H00, alors que l'excrCtion urinaire d'acylcarnitine augmentait significativement (p < 0.05) de 78 ± 56 B 154 ± 98 et 155 ± 89 p, mo1/24H00 apres mise en route du traitement par VPA. La clearance rCnale de l'acylcarnitine a donc augmente significativement (+30% p < 0.05), alors que la clearance rtnale de la carnitine libre n'a pas ete modifiee sous traitement par VPA. Il n'y a pas eu de differences entre le 15 eme et le 45 meme jour de traitement. Aucun patient n'a presente de symptbmes de toxicit/ au VPA. Ces resultats suggerent que le VPA augmente la formation et la clearance rCnale d'acylcarnitine chez les patients epileptiques. RESUMEN Se han determinado los niveles plasmaticos y de orina de acilcarnitina libre y total en 22 pacientes antes de 15 y 45 dias de tratamiento con valproato (VPA) y en 16 voluntarios normales en una sola ocasion. Las concentraciones plasmeticas de carnitina y la excreccion renal observadas en los enfermos epilepticos antes de la terapia con VPA no se diferenciaron de los valores control. Despues de iniciar el VPA las concentraciones libre y total plasmaticas se redujeron significativamente (p < 0.05) de 49 ± 17 a 35 ± 16 a los 15 dias y de 35 ± 13 nmol/ml a los 45 dias de tratamiento (carnitina libre), de 60 ± 18 a 50 ± 18 a los 15 dias y a 55 ± 14 nmol/ml a los 45 dias de tratamiento (carnitina total) mientras que la acilcarnitina se incremento significativamente (p < 0.05) de 10 ± 8 a1 14 ± 8 y a los 15 y a 18 ± 16 nmol/ml a los 45 dias del tratamiento. La excreccion urinaria de carnitina libre se redujo significativamente (p < 0.05) de 200 ± 135 a 115 ± 76 y 118 ± 75 μmo1/24 h mientras que la excreccion urinaria de acilcarnitina se incremento significativamente (p < 0.05) de 78 ± 56 a 154 ± 98 y de 155 ± 89 μmo1/24 h despues de iniciar la terapia con VPA. Como consecuencia el aclaramiento renal de acilcarnitina se incremento significativamente (+30%; p < 0.05) mientras que el aclaramiento renal de carnitina libre no cambio durante el tratamiento con VPA. No se observaron diferencias entre 15 y 45 dias de tratamiento. Ningun paciente experimento sintomas de toxicidad a1 VPA. Los resultados sugieren que el VPA en pacientes incrementa tanto la formacion como el aclaramiento renal de acilcarnitina. ZUSAMMENFASSUNG Bei 22 epileptischen Patienten wurden das freie, das gesamte und das Acylcarnitin in Plasma und Urin vor und nach 15 und 45 Tagen unter Valproat-Therapie gemessen, sowie bei 16 gesunden Freiwilligen in einer einmaligen Probe. Die Carnitin Plasmakonzentration und renale Ausscheidung bei epileptischen Patienten vor der Valproat-Therapie unterschieden sich nicht von den Kontrollwerten. Unter Valproat sank die gesamte und freie Plasmakonzentration signifikant (p < 0.05) von 49 ± 17 auf 35 ± 16 (Tag 15) und auf 35 ± 13 nmol/ml (Tag 45) ab (freies Carnitin) und von 60 ± 18 auf 50 ± 18 (Tag 15), bzw. auf 55 ± 14 nmol/ml (Tag 45) (Gesamtcarnitin), wahrend Acylcarnitin signifikant (p < 0.05) von 10 ± 8 auf 14 ± 8 (Tag 15) bzw. 18 ± 16 nmol/ml (Tag 45) anstieg. Die freie Carnitinurinaus scheidung fie1 signifikant (p < 0.05) von 200 ± 135 auf 115 ± 76, bzw 118 ± 75 pmo1/24 Std., wahrend die Acylcarnitinurinausscheidung signifikant (p < 0.05) von 78 ± 56 auf 154 ± 98 bzw. 155 ± 89 pmo1/24 Std. nach Beginn der Valproat-Therapie anstieg. Die renale Acylcarnitin Clearance stieg signifikant (+30%; p < 0.05) an, wahrend die renale freie Carnitin Clearance sich unter der Therapie nicht anderte. Zwischen Tag 15 und Tag 45 wurden keine Unterschiede gefunden. Kein Patient zeigte Symptome einer Valproat-Toxizitat. Diese Ergebnisse zeigen, daβ Valproat sowohl die Bil-dung als auch die renale Clearance von Acylcarnitin erhoht.

The effect of aging on carbamazepine (CBZ) plasma level/dose ratio was evaluated retrospectively in 15 children who were receiving CBZ monotherapy and who were followed up for at least 3 years. Subjects of the study were selected from a population of roughly 4,500 patients attending our therapeutic drug monitoring service during a 12-year period. Results showed that the CBZ plasma level/dose ratio increases within subject during childhood, in agreement with data obtained in between-patient studies. However, the increase is not linear with age, the greatest modifications being observed between 9 and 13 years of age. Weight gain alone does not seem to explain this finding, implicating the involvement of complex physiological changes occurring during puberty.

We present an implementation of a method we previously reported allowing the newer antiepileptic drugs (AEDs) rufinamide (RFN) and zonisamide (ZNS) to be simultaneously determined with lamotrigine (LTG), oxcarbazepine's (OXC) main active metabolite monohydroxycarbamazepine (MHD) and felbamate (FBM) in plasma of patients with epilepsy using high performance liquid chromatography (HPLC) with UV detection. Plasma samples (250 microL) were deproteinized by 1 mL acetonitrile spiked with citalopram as internal standard (I.S.). HPLC analysis was carried out on a Synergi 4 microm Hydro-RP, 250 mm x 4.6 mm I.D. column. The mobile phase was a mixture of potassium dihydrogen phosphate buffer (50 mM, pH 4.5), acetonitrile and methanol (65:26.2:8.8, v/v/v) at an isocratic flow rate of 0.8 mL/min. The UV detector was set at 210 nm. The chromatographic run lasted 19 min. Commonly coprescribed AEDs did not interfere with the assay. Calibration curves were linear for both AEDs over a range of 2-40 microg/mL for RFN and 2-80 microg/mL for ZNS. The limit of quantitation was 2 microg/mL for both analytes and the absolute recovery ranged from 97% to 103% for RFN, ZNS and the I.S. Intra- and interassay precision and accuracy were lower than 10% at all tested concentrations. The present study describes the first simple and validated method for RFN determination in plasma of patients with epilepsy. By grouping different new AEDs in the same assay the method can be advantageous for therapeutic drug monitoring (TDM).

Serial plasma samples collected after an acute administration of valproic acid, (VPA, 15 mg/kg as oral solution) in epileptic patients were selected for this study. The plasma samples were selected from three different groups of patients; patients on phenobarbital and phenytoin with clinical VPA intolerance (group A); patients on phenobarbital and phenytoin without clinical VPA toxicity (group B); and patients without phenobarbital and phenytoin and without clinical VPA toxicity (group C). Plasma samples from 6 patients per group were analyzed for carnitines and ammonia. Ammonia levels during acute study increased significantly (P less than 0.05) in patients who experienced VPA intolerance, while no changes were found in the other patients. After acute VPA administration, total carnitine was unchanged but free carnitine was decreased (P less than 0.05) and carnitine esters were increased (P less than 0.05) in all groups of patients studied. No difference in carnitine profiles was seen between patients with or without evidence of VPA administration has an important effect on carnitine metabolism. However, unlike the acute effect on ammonia metabolism, this acute effect does not seem to be correlated with any associated antiepileptic therapy, nor does it predict clinical VPA intolerance.

We present a simple, fast and validated method for the determination of the new generation antiepileptic drug (AED) levetiracetam (LEV) in plasma of patients with epilepsy using high performance liquid chromatography (HPLC) with UV detection. Plasma sample (500 microL) pretreatment was based on simple deproteinization by methanol spiked with the internal standard (I.S.). HPLC analysis was carried out on a Synergi 4-microm Hydro-RP, 150 mm x 4 mm I.D. column. The mobile phase was a mixture of potassium dihydrogen phosphate buffer (50 mM, pH 4.5) and acetonitrile (94:6, v/v) at an isocratic flow rate of 1.5 mL/min. The UV detector was set at 205 nm. Calibration curves were linear (mean correlation coefficient=0.999) over a range of 4-80 microg/mL. The quantitation limit was 2 microg/mL and the absolute recovery was >90% for LEV and the I.S. Both intra and interassay precision and accuracy were lower than 7.5%. The chromatographic run lasted 13 min. The present procedure omitting expensive solid phase or time-consuming liquid-liquid extraction and drying steps is cheaper, faster and simpler than mostly published analytical methods for levetiracetam. Applied to a large population of patients with epilepsy this assay proved very practical in our therapeutic drug monitoring setting (TDM).

Objective:The aim of the study was to explore the potentialeffect of the catechol-O-methyltransferase inhib-itor entacapone coadministration on the rate ofabsorption and matched latency to motorresponse of an oral test dose of levodopa/benser-azide in the treatment of Parkinson disease (PD).Methods:Fourteen PD patients (Hoehn and Yahr stages2Y2.5) entered the study protocol. They underwentan oral levodopa instrumental kinetic-dynamictest on 2 occasions, 4 weeks apart, according toan intrasubject open comparative design: at thefirst examination, while receiving their usuallevodopa/benserazide therapy, and at the secondone after a 4-week entacapone (200 mg) dosingconcomitantly with usual first morning levodopa/benserazide intake.Results:Entacapone coadministration was associated witha median 15-minute lengthening ( P G 0.05) of timeto peak levodopa plasma concentration comparedwith levodopa/benserazide alone but failed tohave a statistically significant effect on matchedlatency to drug motor effect. Levodopa peakplasma concentration was nearly identical in the2 treatments.Conclusions:Overall, the delayed latency to single-dose peakplasma levodopa concentration on entacaponecotreatment was modest and of negligible clinicalsignificance in a cohort of moderately affected PDpatients.Key Words: levodopa, Parkinson disease, COMTinhibitors, entacapone, kinetics-dynamics

Epilepsy is a common clinical problem in patients with brain tumours, strongly affecting patients' quality of life. Tumour-related seizures are often difficult to control, and the clinical picture is complicated by frequent interactions between antiepileptic drugs (AEDs) and antineoplastic agents. We studied the safety and efficacy of levetiracetam (LEV), a new AED with a different pharmacological profile from traditional anticonvulsants, in 19 patients (6 females; age range 28-70 years, mean 48 years) with supratentorial gliomas and epilepsy. Seizure types were simple partial in four patients, complex partial in 4, complex partial with secondary generalization in 7, and generalized tonic-clonic in 4. LEV was added to the existing AED treatment on account of persisting seizures, and titrated at dosages of 1,000-3,000 mg/day. Patients were seen at the Outpatient's Centre every 1-3 months, and followed-up for 7-50 months (mean 25 months, median 20 months). At the end of the observation period, nine patients were seizure free (seizure free period ranging from 7 to 33 months, mean 16, median 12) and five patients reported an improvement in seizure-frequency from daily to weekly (n=1) or from weekly to monthly (n=3). Seizure frequency was unmodified in four patients and increased (from monthly to weekly) in one. No LEV-related adverse effects were observed. LEV plasma concentrations monitored in 12 subjects ranged from 11.9 to 82.1 microg/ml. Our preliminary open data indicate that add-on treatment with LEV in patients with brain tumours is safe and appears to be effective in reducing seizure frequency. Controlled studies on larger populations are warranted to confirm these open observations.

Sleep-related eating disorder (SRED) is characterized by recurrent arousals from sleep associated with compulsive ingestion of food. No controlled therapeutic trials are available for SRED. We assessed the safety, tolerability and efficacy of pramipexole, a dopamine D3-receptor agonist, in the treatment of SRED. Eleven consecutive patients with SRED in the absence of concurrent daytime eating disorders underwent actigraphic recording and subjective sleep diary evaluation for a week before and every week for 2 weeks of treatment with pramipexole 0.18-0.36 mg or placebo, administered in a double-blind crossover randomized sequence. The primary outcomes of the trial were actigraphic measures of night sleep parameters (sleep efficiency, motor activity mean and median, number and duration of wake episodes), secondary outcomes were the number of good sleep nights/weekly, number and duration of nocturnal awakenings/night, and visual analogue preference score. Pramipexole was well tolerated without any patient withdrawing from the study. Pramipexole reduced night-time activity median (P = 0.02) and increased the number of nights of good sleep/week (P = 0.02). All other measurements remained unaffected. Pramipexole at low doses was well tolerated, improving some measures of sleep quality and reducing median night activity in SRED. Further studies with higher dosages and for longer time-periods are warranted.

We explored the potential effect of catechol-O-methyltransferase (COMT) genetic polymorphism on the pharmacokinetics and pharmacodynamics of a standard oral dose of levodopa in patients with Parkinson's disease (PD). We prospectively collected blood samples for COMT genotyping from a population of 104 PD patients. Each patient was examined by a standard oral levodopa/benserazide test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects and dyskinesia ratings, up to 4 hours after dosing. The main levodopa pharmacokinetic outcome variables were time to peak and peak plasma concentration, plasma elimination half-life, and the area under the plasma concentration-time curve. The main outcome levodopa pharmacodynamic variables were latency, duration, and magnitude of the motor effect elicited by the levodopa test dose, the area under the tapping effect-time curve, and the presence of dyskinesias. Nineteen patients (18%) harbored the low-activity homozygous COMT genotype (A/A), 63 patients (61%) carried the intermediate-activity heterozygous COMT genotype (A/G) and 22 patients (21%) had the high-activity homozygous COMT genotype (G/G). The three groups were comparable for vital and clinical characteristics. No significant difference was found in levodopa main pharmacokinetic-pharmacodynamic variables and dyskinesia incidence among the three subgroups of patients. We failed to identify clinically relevant levodopa pharmacokinetic-pharmacodynamic response patterns associated with the COMT polymorphism in PD patients.

A very simple and fast method has been developed and validated for simultaneous determination of the new generation antiepileptic drugs (AEDs) lamotrigine (LTG), oxcarbazepine's (OXC) main active metabolite monohydroxycarbamazepine and felbamate in plasma of patients with epilepsy using high-performance liquid chromatography (HPLC) with spectrophotometric detection. Plasma sample (500 microL) pre-treatment was based on simple deproteinization by acetonitrile. Liquid chromatographic analysis was carried out on a Synergi 4 microm Hydro-RP, 150 mm x 4 mm I.D. column, using a mixture of potassium dihydrogen phosphate buffer (50mM, pH 4.5) and acetonitrile/methanol (3/1) (65:35, v/v) as the mobile phase, at a flow rate of 1.0 mL/min. The UV detector was set at 210 nm. Calibration curves were linear (mean correlation coefficient >0.999 for all the three analytes) over a range of 1-20 mg/mL for lamotrigine, 2-40 microg/mL for monohydroxycarbamazepine and 10-120 microg/mL for felbamate. Both intra and interassay precision and accuracy were lower than 7.5% for all three analytes. Absolute recoveries ranged between 100 and 104%. The present procedure describes for the first time the simultaneous determination of these three new antiepileptic drugs. The simple sample pre-treatment, combined with the fast chromatographic run permit rapid processing of a large series of patient samples.

We report a case of recurrence of absence seizures possibly induced by low doses of amitriptyline. A patient with juvenile absence epilepsy on chronic valproic acid monotherapy and seizure-free for a period of 6 years experienced a recurrence of absence seizures on starting a headache prophylaxis with a low dose of amitriptyline (0.3 mg/kg). Seizures disappeared immediately after the addition of ethosuximide to antiepileptic therapy in spite of continuing amitriptyline. After stopping amitriptyline (3 months later) ethosuximide was also stopped and the patient remained, as before, seizure-free on valproic acid monotherapy.

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new anti-epileptic drug (AED) levetiracetam in a cohort of 100 adult patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two groups, otherwise comparable for age, gender, weight-adjusted daily dose of levetiracetam, and dosing frequency: group A (n = 65), receiving levetiracetam plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin; group B (n = 35), receiving levetiracetam plus AEDs without inducing properties of CYP metabolism, namely valproic acid and lamotrigine. Plasma levetiracetam concentrations were measured by HPLC with spectrophotometric detection. Median morning trough levetiracetam plasma concentrations were significantly lower in patients of group A than in patients of group B (10.4 microg/mL versus 14.7 microg/mL, P0.001). Median weight-normalized levetiracetam apparent oral clearance (CL/F) was 1.3-fold in patients receiving AED inducers compared with patients on AED noninducers (1.93 versus 1.45 mL x min(-1) x kg, P0.001). No gender-related difference was observed in CL/F values. Levetiracetam plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 500 to 5000 mg/d, although at a given daily dose an appreciable interpatient variability was observed in matched plasma drug concentrations. Concomitant AED inducers can contribute to variability in levetiracetam disposition in patients with epilepsy. The observed differences were moderate and possibly of minor clinical significance.

We examined the potential sex-related differences in levodopa pharmacokinetics and their relation with the pres- ence of dyskinesias in a group of 115 patients (67 men, 49 women) with Parkinson's disease. The patients were given a standard oral dose of levodopa plus benserazide (100/25 mg). The area under the levodopa plasma concentration time curve, corrected for the levodopa test dose (in mg/kg body weight), (AUCw) was significantly higher in women than in men, with a reduced oral clearance. No difference in the proportion of men and women experiencing dyskinesias was observed.

The authors performed 72-hour polysomnography, including a levodopa-placebo-controlled choice reaction time test with continuous monitoring of cardiovascular variables in two patients with Parkinson's disease complaining of excessive daytime sleepiness on levodopa monotherapy. The subacute levodopa challenge was accompanied by physiologic sleep episodes, worsened reaction times, and a reduction in mean blood pressure and heart rate over baseline values, linked temporally to the sleep episodes.

Levodopa pharmacokinetic-phamacodynamic (PK-PD) modeling may be able to test the functional integrity of the nigrostriatal dopaminergic system in Parkinson's disease (PD). [(123)I]-FP-CIT SPECT imaging of striatal dopamine transporters has also been introduced for the evaluation of presynaptic dopaminergic homeostasis. We aimed to assess the intrapatient relation between levodopa PK-PD and SPECT measures of dopaminergic function in PD. Thirty-five PD patients, 1 to 4 on the Hoehn and Yahr (HY) scale, enrolled in the study. Each patient was examined by levodopa PK-PD modeling and SPECT imaging. Primary measure outcomes were the levodopa half-life in the effect compartment (t1/2(eq)) for PKPD modeling and the ratio of specific to non specific (SP/NSP) tracer striatal uptake for SPECT. Levodopa t1/2(eq) was highly significantly correlated with HY scale (r = -0.815, p0.0001), Unified Parkinson's disease Rating Scale (UPDRS) (r = -0.691, p0.0001) and PD symptom duration (r = -0.647, p0.0001). SPECT contralateral putamen SP/NSP ratio showed the most significant correlations with clinical indicators of disease severity: HY, r = -0.526, p0.002; UPDRS, r = -0.523, p0.002; symptom duration, r = -0.513, p0.002. Significant correlations were observed between levodopa t1/2(eq) and putamen SP/NSP ratios, yielding the closest correlation for the contralateral region (r = 0.522, p0.002). An indirect PK-PD dopaminergic functional variable and direct SPECT measures of presynaptic dopaminergic system homeostasis were in close agreement with clinical data and correlated to each other. Levodopa PK-PD modeling can be a practical clinical tool indirectly assessing the functional integrity of the nigrostriatal dopaminergic system in PD patients.

The authors describe a case of a rare, potentially fatal multisystem reaction, recently called drug rash with eosinophilia and systemic symptoms (or DRESS) resulting from phenobarbitone. They highlight the main characteristics of this syndrome and the diagnostic difficulties.

The authors report preliminary findings on the potential contribution of CYP2C19 isoenzyme to the human metabolism of N-desmethylclobazam (N-CLB), the main active metabolite of clobazam (CLB), a benzodiazepine frequently used as add-on therapy in patients with refractory epilepsy. Two children on CLB treatment showing extremely high plasma concentration/dose ratio (C/D) of N-CLB and metabolite/parent drug ratio (N-CLB/CLB), suggestive of a putative poor metabolizer (PM) phenotype, were tested for CYP2C19 polymorphisms. Eleven epileptic patients on stable CLB therapy were included for reference values of CLB and N-CLB metabolic variables and tested for possible CYP2C19 polymorphisms. Detection of the CYP2C19*2, CYP2C19*3, and CYP2C19*4 mutations was performed in the genomic DNA by PCR amplification and enzyme digestion procedures. In the two presumed CYP2C19 PM patients, the N-CLB/CLB ratio was 10- to 27-fold higher than matched median values of the control epileptic patients. According to CYP2C19 genotyping, one patient was homozygous for CYP2C19*2, while the second presented only one copy of the same mutation, a genotype also found in three control patients. These observations provide further indirect in vivo evidence of CYP2C19 isoenzyme involvement in the metabolism of the CLB main metabolite. According to genotyping, subjects carrying one or two copies of the defective CYP2C19*2 allele might develop markedly elevated steady-state plasma concentrations of N-CLB and be at higher risk of adverse effects.

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new antiepileptic drug (AED) topiramate and the potential relation between topiramate plasma levels and side effects in a cohort of 116 patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two subgroups, otherwise comparable for age and weight-adjusted daily dose of topiramate. Group A (n = 73) received topiramate plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin. Group B (n = 43) received topiramate plus AEDs without inducing properties of CYP metabolism (namely valproic acid and lamotrigine). Weight-normalized topiramate clearance values, calculated as dosing rate/steady-state plasma drug concentration, were about 1.5-fold in patients receiving AED inducers compared with patients receiving AED noninducers. Topiramate plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 25 to 800 mg/d, although, at a given daily dose, a large interpatient variability was observed in matched plasma drug concentrations within each group of patients. Thirty-nine patients (34%) reported side effects associated with topiramate, mostly central nervous system effects. No consistent relation was observed between topiramate plasma concentrations and adverse effects, either in the cohort of patients as a whole or within each subgroup. From a clinical point of view, patients receiving concurrent treatment with enzyme-inducing AEDs can show twofold lower topiramate plasma concentrations compared with patients receiving valproic acid or lamotrigine, and appropriate topiramate dosage adjustments may be required when concomitant AED inducers are either added or withdrawn. Due to the observed variability in topiramate metabolic variables and the complex spectrum of possible pharmacokinetic and pharmacodynamic interactions with the most commonly coprescribed AEDs, monitoring of plasma topiramate concentrations may help the physician in the pharmacokinetic optimization of the drug dosage schedule in individual patients.

The authors assessed differences in both therapeutic and dyskinesia-matched concentrations of levodopa by kinetic-dynamic modeling in a large cohort of patients with Parkinson disease grouped by severity of symptoms. The goal was to provide a kinetic-dynamic approach to levodopa therapy monitoring to assist treating physicians in rationalizing patients' drug schedules in line with disease progression. Eighty-six patients, grouped according to HoehnYahr (HY) clinical stage (HY I, n = 23; II, n = 25; III; n = 25; IV, n = 13) enrolled in the study. After a 12-hour levodopa washout each patient was examined using a standard oral levodopa test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects, and dyskinesia ratings. The kinetic-dynamic modeling for both effects was carried out according to the "link" effect compartment model and sigmoidal pharmacodynamic model. Levodopa plasma kinetics did not differ among patient groups. Duration of motor response was significantly (p0.001) curtailed in patients in advanced clinical stages whereas dyskinesia duration showed minor changes among the three affected groups (HY II, III, and IV). Median effective concentrations (EC 50 ) were increased at the more advanced clinical stage (p0.001), from a median 0.2 microg/mL in patients at HY stage I to 0.9 microg/mL in patients at HY stage IV, whereas the maximum effect showed less consistent changes among the four groups. Intrasubject levodopa therapeutic concentrations were lower than values for dyskinesias in patients at the moderate stage of the disease, equaling dyskinesia-matched drug concentrations in the more affected patients. These findings are in line with previous observations of major changes in levodopa concentration-effects relationship with disease progression and support a stratification of patients with Parkinson disease according to kinetic-dynamic modeling. From a practical point of view, knowledge of individual patients' kinetic-dynamic variables can help the physician assess patients' clinical needs objectively and optimize levodopa dosing according to disease progression.

A high-performance liquid chromatographic method with UV detection for the simultaneous analysis of the antiepileptic drug carbamazepine and five of its metabolites in human plasma has been developed. The analysis was carried out on a reversed-phase column (C8, 150x4.6 mm I.D., 5 microm) using acetonitrile, methanol and a pH 1.9 phosphate buffer as the mobile phase. Under these chromatographic conditions, carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine, 10,11-dihydro-10,11-dihydroxycarbamazepine, 2-hydroxycarbamazepine, 3-hydroxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine are baseline separated in less than 18 min. The extraction of the analytes from plasma samples was performed by means of an original solid-phase extraction procedure using Oasis HLB cartridges. The method requires only 250 microl of plasma for one complete analysis. The repeatability (RSD%2.4), intermediate precision (RSD%3.5) and extraction yield (84.8-103.0%) were very good for all analytes. The method is suitable for reliable therapeutic drug monitoring of patients undergoing chronic treatment with carbamazepine and for kinetic-metabolic studies of this drug.

Taste disorders can occur during different pharmacologic treatments.1,2⇓ Among antiepileptic drugs (AED), carbamazepine (CBZ), felbamate (FBM), and phenytoin (PHT) have been reported to induce taste abnormalities. IV fosphenytoin and valproic acid (VPA) have occasionally been associated with dysgeusia. To our knowledge, taste abnormalities related to lamotrigine (LTG) have never been recorded. We describe three patients with drug-resistant partial epilepsy who had dysgeusia during treatment with LTG. A 65-year-old man with frontal lobe epilepsy since childhood added LTG treatment, up to 100 mg/d, to his stable phenobarbitone (PB) (25 mg/d), CBZ (1200 mg/d), and VPA (1500 mg/d) polytherapy. One year later, as seizures improved, the patient reduced VPA treatment to 900 mg/d, and gradually (over 3 months) withdrew CBZ. Twenty days after complete CBZ withdrawal, the patient started to complain of severe dysgeusia, characterized by a marked bitter taste and hypersalivation, which interfered with eating and caused …

We present a simple and fast method for the determination of the novel antiepileptic drug topiramate in human plasma by high-performance liquid chromatography coupled with turbo ion spray mass spectrometry. Plasma sample pre-treatment was based on simple deproteinization by acetonitrile. Liquid chromatographic analysis was carried out on a reversed-phase column (C18, 125x4 mm I.D., 5 microm) using acetonitrile-ammonium acetate buffer, pH 6.3 as the mobile phase, at a flow-rate of 0.8 ml/min. Retention time for topiramate was 2.1 min. The detector was a single quadrupole mass spectrometer coupled to a turbo ion spray ion source and a heated nebulizer probe, operating in the positive ion mode. Ion source temperature was off; voltage was +5800 V; nebulizer and curtain gas flow-rates were 6 and 10 ml/min, respectively. Calibration curves for topiramate were linear over the range 1 to 20 microg/ml. Absolute recovery ranged between 92 and 95%. Intra- and inter-assay precision was4%. The present procedure, omitting extraction and drying steps, is faster and simpler than the previously reported analytical methods for topiramate and was demonstrated to possess adequate sensitivity for routine therapeutic drug monitoring in plasma from patients with epilepsy.

Felbamate (FBM) is a novel antiepileptic drug (AED) currently undergoing clinical evaluation in the United States. During a controlled clinical trial conducted at the National Institutes of Health Clinical Center, FBM was added to constant carbamazepine (CBZ) monotherapy. CBZ total concentrations were reduced during active FBM treatment (mean reduction 25%, range 10-42%, p less than 0.001). The effect was evident after the first week of treatment and reached a plateau in 2-4 weeks. To clarify the interaction mechanism, free and total concentrations of CBZ and its plasma metabolites were determined by high-performance liquid chromatography (HPLC) and ultrafiltration in four patients. In these patients, FBM treatment reduced CBZ concentrations and increased CBZ-epoxide (CBZ-E) concentrations (p less than 0.01). Free fractions of all compounds were unmodified. FBM appears to be capable of inducing CBZ metabolism. CBZ-FBM interaction may be clinically relevant.

The authors report preliminary findings on the effect of the new generation antiepileptic drug (AED) felbamate (FBM) on steady state plasma concentrations of clobazam (CLB), a benzodiazepine (frequently used as add-on therapy in patients with refractory epilepsy) and its active metabolite n-desmethyl-clobazam (N-CLB). The authors prospectively collected plasma samples from 66 children and adults with epilepsy receiving chronic CLB therapy. On the basis of concomitant AEDs, patients were divided into three subgroups otherwise comparable for age and weight-adjusted daily dose of CLB: group A (n = 22), receiving CLB monotherapy or CLB plus AEDs without inducing properties of cytochrome P450 (CYP) metabolism, namely valproic acid (VPA) or lamotrigine (LTG); group B (n = 28), receiving CLB plus AED inducer polytherapy (carbamazepine, phenobarbital, phenytoin), even associated with VPA (n = 9) or LTG (n = 12); group C (n = 16), receiving CLB plus FBM, associated with AED inducers, VPA or LTG. Level to weight-adjusted dose ratio (L/D) of CLB in groups B and C was twofold lower compared to group A (p < 0.001). L/D of N-CLB was twofold higher in group B and fivefold in group C compared to group A (p < 0.00 1). The metabolite-to-parent drug ratio shifted from a median value of 2.8 in group A to 13 in group B, and up to 29 in patients receiving polytherapy with FBM (p < 0.001). These data confirm previous reports of a significant increase in CLB clearance in patients receiving AED inducers, leading to an accumulation of its main metabolite. They also provide novel evidence of a further marked increase in N-CLB plasma concentrations in patients receiving FBM cotherapy. From a clinical point of view, this finding should be kept in mind in explaining possible toxicity in patients on complex AED polytherapy. Furthermore, knowledge of the in vivo interaction between CLB and FBM could help in identifying the CYP isoforms involved in the metabolism of both CLB and N-CLB.

Objective: The aims of the study were to follow prospectively the intrasubject progression of idiopathic PD in a cohort of patients using levodopa kinetic-dynamic modeling and to assess the relation between the rate of progression of the disease and patients' different clinical characteristics.Methods: Thirty-four patients (Hoehn and Yahr stages 1 to 3) enrolled in the longitudinal follow-up. Each patient was examined at 1-year intervals over a median 4 years by a standardized oral levodopa test. The primary measure outcome was the computed half-life of levodopa in the "effect compartment" (t1/2eq), a proposed indicator of nigrostriatal dopaminergic functionality and integrity.Results: Values of levodopa t1/2eq correlated negatively with severity of symptoms (r = -0.652, p < 0.0001) and decreased over the years together with a worsening of patients' clinical stage (p < 0.0001). The rate of reduction in drug t1/2eq was more rapid in patients at the earlier stages of the disease compared with the more advanced ones, falling from a median annual reduction of 37 minutes in patients at initial Hoehn and Yahr stage 1 to 6.5 minutes in stage 3 patients (p < 0.001). Patients without tremor at onset, otherwise comparable to patients with tremor for baseline values of levodopa t1/2eq, disease severity, duration, and daily dose of levodopa, tended to show a higher rate of reduction in levodopa t1/2eq than patients with tremor. Overall, patients' annual reduction in levodopa t1/2eq over baseline values averaged 17 ± 9%.Conclusions: These results are in keeping with PET findings on the objective assessment of idiopathic parkinsonism evolution, and they support the suggestion that levodopa pharmacodynamic modeling may offer a practical clinical tool to assess indirectly the functional integrity of the nigrostriatal dopaminergic system over time in parkinsonian patients.

2048 Background: The impact on the general population of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) was assessed in the context of the Registry of the Project of the Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in the field of neuro-oncology. Methods: Patients (pts) meeting the following inclusion criteria were evaluated: age ≥18 years; PS 0-3; histologically confirmed GBM, no previous or concomitant non-glial tumoral disease, residence in the Emilia Romagna region. The data were collected prospectively. Results: Study accrual, started on January 1 2009, was closed, as planned, on December 31 2010. Two hundred sixty-eight pts (F=111, M=157; median age, 63.5 [range 29-34] years) were studied. mOS was 10.7 months (95%CI: 9.2 – 12.3). MGMT status, assessed in 186 (89%) of 210 pts who had at least radiotherapy was evaluable in 174 pts (83%), being methylated in 76 (43.7%), and unmethylated in 98 (56.3%) pts. mOS for pts with MGMT methylated status was 18.5 months (95%CI: 14.4-22.6), and 12.4 months for those with MGMT unmethylated status (95%CI: 10.5 - 14.3, p

The current symptomatic treatment of Parkinson's disease mainly relies on agents which are able to restore dopaminergic transmission in the nigrostriatal pathway, such as the dopamine precursor levodopa or direct agonists of dopamine receptors. Ancillary strategies include the use of anticholinergic and antiglutamatergic agents or inhibitors of cerebral dopamine catabolism, such as monoamine oxidase type B inhibitors. Levodopa is the most widely used and effective drug. Its peculiar pharmacokinetics are characterised by an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme aromatic-amino acid decarboxylase and rapid adsorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both drug intestinal absorption and delivery to the brain and clinical effect include standardisation of levodopa administration with respect to meal times and a controlled dietary protein intake. The levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, with swings in the therapeutic response ('wearing-off' phenomena). 'Wearing-off' phenomena can be also associated, at the more advanced disease stages with a 'negative', both parkinsonism-exacerbating and dyskinetic effect of levodopa at subtherapeutic plasma concentrations. Dyskinesias may be also related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone, and simultaneous monitoring of levodopa concentration-effect relationships may prove useful to disclose the underlying mechanism and in planning the correct pharmacokinetic management. Controlled-release levodopa formulations have been developed in an attempt to smooth out fluctuations in plasma profiles and matched therapeutic responses. The delayed levodopa absorption and lower plasma concentrations which characterise controlled-release formulations compared with standard forms must be taken into account when prescribing dosage regimens and can be complicating factors in the management of the advanced disease stages. The pharmacokinetic and pharmacodynamic characterisation of the other antiparkinsonian agents is hampered by the lack of sensitive and specific analytical methods to measure their very low plasma drug concentrations and by the difficulty in quantitatively assessing overall moderate drug clinical effects. In clinical practice an optimal dosage schedule is still generally found for each patient on an empirical basis. Future strategies should focus on the search for pharmacological agents with a better kinetic profile, particularly a higher and reproducible bioavailability and a predictable relationship between plasma drug concentration and clinical response. Treatments aimed not only at controlling the symptoms, but also at slowing the neurodegenerative process, are currently under intensive investigation.

Ticlopidine is an antiplatelet agent used in the prophylaxis of peripheral and cerebrovascular diseases, [1-3] ischemic heart disease, [1,3] and vascular complications of diabetes mellitus. [4] In healthy volunteers ticlopidine reduces the clearance of theophylline [5] and antipyrine, [6] probably by inhibiting the activity of cytochrome P450 enzymes. On the basis of these observations, the package insert in some countries contains a warning advising caution when ticlopidine is introduced in patients receiving therapy with highly metabolized drugs. We report a case of metabolic phenytoin-ticlopidine interaction in which phenytoin plasma concentrations increased and CNS toxicity appeared when ticlopidine was added to the therapeutic regimen. A 65-year-old man had a history of complex partial seizures, sometimes with secondary generalization, which started at the age of 52 years. A brain CT scan obtained at this time was normal. He had been treated with different antiepileptic regimens for about 10 …

Objective: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson’s disease using parametric, non-linear mixed effect modelling with the program NONMEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid EMax representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. Results: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets. Conclusion: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug’s beneficial motor activity in patients with mild to severe Parkinson’s disease (Hoehn and Yahr status I–IV).