Therapeutic drug monitoring (TDM) may be very useful in the clinical management of antiepileptic drug therapy for multiple reasons, such as individual variability, metabolism, genetic factors or drug-drug or drug-food interactions. In addition, TDM is helpful to study the variation in pharmacokinetics that occurs between individuals. Here, we describe a rapid assay using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry to measure the antiepileptic drugs lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide. After the addition of internal standards (ISs) and protein precipitation of serum or plasma, 1μl of sample was separated on a 2.1×50mm reverse phase column (Waters, Acquity UPLC BEH Phenyl, 1.7μm). Analytes were then ionized and detected by electrospray ionization mass spectrometry with multiple reaction monitoring. Runtime was 2.5min per injection. Matrix effects were investigated by systematical ion suppression and in-source fragmentation experiments. The calibration curves of the 6 antiepileptic drugs were linear over the working range between 0.05 and 50mg/L (r>0.99). The limit of detection (LOD) was <0.05mg/L, whereas the limit of quantification (LLOQ) was 0.10mg/L of all drugs measured in the assay. The intraassay and interassay coefficients of variation for all compounds were <15% for very low concentration (0.1mg/L) and <8% in the clinically relevant concentration range (>1.0mg/L). Mean recoveries were between 87.8 and 98.6% for all drugs. There were no significant ion suppressions detected at the elution times of the analytes. The mean differences between serum and heparinized plasma values were less than 6% for the 6 antiepileptic drugs. All drugs were stable in serum at -20°C, 4°C, and even at RT for at least 1 month. In summary, a specific and sensitive stable isotope dilution UPLC-MS/MS method was developed and validated for routine clinical monitoring of lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide.

The solid phase FTIR and FT-Raman spectra of primidone were recorded in the regions 4000-400cm(-1) and 4000-100cm(-1), respectively. The vibrational spectra were analysed and the observed fundamentals were assigned and analysed. The experimental wavenumbers were compared with the theoretical scaled vibrational wavenumbers determined by DFT methods. The Raman intensities were also determined with B3LYP/6-31G(d,p) method. The total electron density and molecular electrostatic potential surface of the molecule were constructed by using B3LYP/6-311++G(d,p) method to display electrostatic potential (electron+nuclei) distribution. The HOMO and LUMO energies were measured. Natural bond orbital analysis of primidone has been performed to indicate the presence of intramolecular charge transfer. The (1)H and (13)C NMR spectra were recorded and the chemical shifts of the molecule were calculated.

A sensitive and fast high-performance liquid chromatographic method coupled with ultraviolet detection is herein reported for the simultaneous determination of human plasma concentration of six antiepileptic drugs frequently used in clinical practice [phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC)] and some of their main metabolites, carbamazepine-10,11-epoxide (CBZ-E), 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (trans-diol) and licarbazepine (Lic). Sample preparation consisted of a deproteinization step with methanol followed by a solid-phase extraction procedure. Chromatographic separation was achieved in approximately 15 min on a reversed-phase C18 column using a mobile phase composed by water-methanol-acetonitrile-triethylamine (68.7:25:6:0.3, v/v/v/v; pH 6.5) pumped isocratically at 1.0 mL/min. The detector was set at 237 nm. Calibration curves were linear with regression coefficients greater than 0.992 over the concentration ranges 0.25-100 μg/mL for PB, 0.4-50 μg/mL for PRM, 0.5-50 μg/mL for PHT, 0.1-50 μg/mL for CBZ, LTG and CBZ-E, 0.1-25 μg/mL for OXC, 0.25-10 μg/mL for trans-diol and 0.15-80 μg/mL for Lic. Inter- and intra-day imprecision did not exceed 12.15% and inaccuracy was within ±14.91%. Absolute mean recoveries ranged from 78.49 to 101.04% and no interferences were observed at the retention times of the analytes and internal standard (ketoprofen). This bioanalytical method was successfully applied to real plasma samples from epileptic patients and it seems to be a suitable tool for routine therapeutic drug monitoring and also to support other clinical pharmacokinetic-based studies.

A 7.5-year-old girl who was treated with phenobarbital (PHB) for epilepsy was admitted with decreased levels of consciousness. She had been known to have high PHB levels of unknown cause, without symptoms. Her PHB levels were very high, as expected, but primidone levels were also detected although she and her parents denied history of primidone administration. We wished to rule out intentional unprescribed use of primidone. Our retrospective review showed 3 other children with high PHB concentrations where primidone was also detected when PHB levels were over 130 μmol/L. Complementary studies confirmed that high-dose PHB can convert to its prodrug primidone, which has not been reported previously.

Essential tremor (ET) is one of the most common tremor disorders in the world. Despite this, only two medications have received Level A recommendations from the American Academy of Neurology to treat it (primidone and propranolol). Even though these medications provide relief to a large group of ET patients, up to 50% of patients are non-responders. Additional medications to treat ET are needed. This review discusses some of the methodological issues that should be addressed for quality clinical drug development in ET.

To study prevalence, specific patterns and response to treatment of tremor in dementia with Lewy bodies (DLB), in comparison with other tremulous disorders prevalence, qualitative and quantitative features of tremor were studied in an incident cohort of 67 dopaminergic treatment naive DLB, 111 Parkinson's Disease (PD) and 34 Essential Tremor (ET) patients. Tremulous DLB patients (tDLB) were compared with tremulous PD (tPD) and ET patients and followed for 2 years. Double blind placebo-controlled acute drug challenge with L-Dopa and alcohol was performed in all ET, 24 tDLB and 27 tPD. Effects of dopaminergic chronic treatment in all tDLB and tPD patients and primidone in 8 tDLB were also assessed. Tremor occurred in 44.76 % of DLB patients. The tDLB patients presented a complex pattern of mixed tremors, characterized by rest and postural/action tremor, including walking tremor and standing overflow in 50 % tDLB. Standing tremor with overflow was characteristic of tDLB (p < 0.001). Head tremor was more frequent in tDLB than tPD and ET (p = 0.001). The tDLB tremors were reduced by acute and chronic dopaminergic treatments (p < 0.01) but not by alcohol or primidone. Tremor occurs commonly in DLB patients with a complex mixed tremor pattern which shows a significant response to acute and chronic dopaminergic treatments. Recognizing that there is a clinical category of tremulous DLB may help the differential diagnosis of tremors.

Blood (serum/plasma) antiepileptic drug (AED) therapeutic drug monitoring (TDM) has proven to be an invaluable surrogate marker for individualizing and optimizing the drug management of patients with epilepsy. Since 1989, there has been an exponential increase in AEDs with 23 currently licensed for clinical use, and recently, there has been renewed and extensive interest in the use of saliva as an alternative matrix for AED TDM. The advantages of saliva include the fact that for many AEDs it reflects the free (pharmacologically active) concentration in serum; it is readily sampled, can be sampled repetitively, and sampling is noninvasive; does not require the expertise of a phlebotomist; and is preferred by many patients, particularly children and the elderly. For each AED, this review summarizes the key pharmacokinetic characteristics relevant to the practice of TDM, discusses the use of other biological matrices with particular emphasis on saliva and the evidence that saliva concentration reflects those in serum. Also discussed are the indications for salivary AED TDM, the key factors to consider when saliva sampling is to be undertaken, and finally, a practical protocol is described so as to enable AED TDM to be applied optimally and effectively in the clinical setting. Overall, there is compelling evidence that salivary TDM can be usefully applied so as to optimize the treatment of epilepsy with carbamazepine, clobazam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and zonisamide. Salivary TDM of valproic acid is probably not helpful, whereas for clonazepam, eslicarbazepine acetate, felbamate, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin, the data are sparse or nonexistent.

Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative-hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.

Primidone is a minor first-generation antiepileptic drug, little currently prescribed for this indication, but except marketing authorization, remains a first-line treatment of essential tremor. Although it is metabolized in phenyl-ethyl-malondamide and phenobarbital, active metabolites that contribute also to its action, primidone is not a prodrug and is active by itself. The rate of conversion of primidone to phenobarbital is highly variable according to the subject. Generally accepted therapeutic range for primidone is between 5 and 10 mg/L (23-46 mmol/L). The therapeutic drug monitoring (TDM) of primidone must be accompanied by the determination of phenobarbital concentrations. The level of proof of the interest of the TDM primidone was estimated to be "probably useless". Phenobarbital, a very ancient anticonvulsant, is much less used today, for the benefit of other more recent compounds. It remains prescribed in neonatology and is one of the compounds used in status epilepticus. It is a molecule with a long half-life, metabolized in p-hydroxy-phenobarbital. It is a potent inducer of CYP3A4. Several side effects, especially drowsiness, are concentration-dependent. Generally accepted therapeutic range for phenobarbital is between 10 and 40 mg/L (43 - 172 mmol/L), without considering the type of crise. The level of proof of the interest of TDM of phenobarbital was evaluated as "recommended".

Many essential tremor patients continue to require tremor suppressing medications following deep brain stimulation. The true incidence of medication usage in the years following surgery remains unclear, and the use of medications has not been included in the post-operative analyses of tremor severity and also quality of life.Among 28 essential tremor patients treated with deep brain stimulation at a single center between January 2002 and April 2010, we analyzed the prevalence and dosage of pre-operative tremor suppressing medications versus post-operative medications at 12 and 36 months following surgery. We also assessed the influence of medication continuation on clinical outcome measures, such as the Fahn-Tolosa-Marin Tremor Rating Scale, and the 36 item short-form health quality of life survey.Both unilateral and bilateral deep brain stimulation resulted in a decrease in primidone use (p = 0.0082, 0.046, respectively), and bilateral deep brain stimulation patients used less tremor suppressing medications 36 months following surgery (p = 0.02). The decision to discontinue primidone after surgery resulted in a non-significant long-term improvement in tremor motor score (23 points versus 15 points, p = 0.19), and did not significantly influence the physical and mental composite quality of life scores (p = 0.81, 0.23, respectively).Bilateral deep brain stimulation effectively eliminated the need for tremor suppressing medications, while unilateral stimulation was not as effective in reducing medication usage. Clinicians and patients should be aware that discontinuation of primidone after surgery may worsen tremor in unilateral deep brain stimulation cases, but discontinuation will not likely impact quality of life.