Therapeutic Drug Monitoring of Levetiracetam in Different Trimesters of Pregnant Women with Epilepsy in a Tertiary Care Center: A Prospective Study.

BACKGROUND: Levetiracetam is the most commonly used antiepileptic drug in pregnant women due to its low teratogenic risk profile, favorable pharmacokinetic characteristics, and safety profile. Serum levels of levetiracetam vary in epilepsy during pregnancy. Therefore, the aim of the study was to evaluate the serum levels of levetiracetam during different trimesters of pregnancy by using therapeutic drug monitoring (TDM). MATERIALS AND METHODS: This was a single-center, prospective study. Pregnant women with epilepsy on levetiracetam were enrolled after getting written informed consent from them. Serum trough levels of levetiracetam were estimated at all trimesters by high-performance liquid chromatography (HPLC). RESULTS: The study included 16 participants with mean ± standard deviation (SD) age of 27.75 ± 4 years. There were nine (56.2%) participants with generalized seizure disorder and seven (43.8%) participants of focal seizure disorder. Among 16 patients, 10 (62.5%) participants were on levetiracetam alone and six (37.5%) participants were on levetiracetam combined with other antiepileptic drugs. In a total of 48 trough samples, 45 sample concentrations were below the therapeutic range of 12-46 mg/l and three sample concentrations were within the therapeutic range. There was a statistically significant difference in the concentration-dose ratio (CDR) of levetiracetam between the third and first trimesters (P-value 0.018). CONCLUSION: There was a statistically significant difference in serum levetiracetam concentration between the third and first trimesters. A well-conducted, intensive pharmacokinetic sampling study in PWWE with a control group is needed in future to evaluate the whole pharmacokinetic profile of levetiracetam and to correlate the clinical outcome.

Effect of Nonadherence on Levetiracetam Pharmacokinetics and Remedial Dose Recommendations Using Monte Carlo Simulations.

BACKGROUND AND OBJECTIVE: Nonadherence to levetiracetam (LEV) use can result in subtherapeutic concentrations and increase the risk of the occurrence of seizures. The impact of missing LEV doses on its pharmacokinetics and evidence of the appropriate remedial dose is lacking. This study has determined the influence of missed LEV doses on its pharmacokinetics and has explored the appropriate remedial dosage regimens. METHODS: Monte Carlo simulation was used to assess the impacts of different remedial dosage regimens on LEV concentrations. Simulated LEV concentrations outside the individual therapeutic range were calculated for the compliance scenario and for each of the remedial dosage regimens. The percentage of deviation from the full compliance scenario was also calculated. The regimen with the lowest percentage of deviation was considered the most appropriate. RESULTS: The suitable LEV remedial dose varied across the delay times. For one missed dose, a remedial regimen with a regular dose followed by the usual dose was suitable for a delay time of less than 6 h, while a replacement with a regular dose followed by a partial dose appeared to be appropriate for a delay time of 6 h and longer. This was justified based on the concerns of LEV toxicity when the remedial dose is close to the next scheduled dose. For two consecutive missed doses, a remedial dose with one and a half of the regular dose was suitable if the gap between that and the next dose was greater than 6 h. CONCLUSIONS: The appropriate remedial dosage regimen for one and two consecutive missed doses of LEV have been proposed. These remedial regimens, however, should be applied with clinicians' judgment based on the clinical status of the patients.

Neuroprotective and anti-inflammatory activity of DAT inhibitor R-phenylpiracetam in experimental models of inflammation in male mice.

R-phenylpiracetam (R-PhP, (4R)-2-(4-phenyl-2-oxopyrrolidin-1-yl)acetamide) is an optical isomer of phenotropil, a clinically-used nootropic drug that improves physical condition and cognition. Recently, R-PhP was shown to bind to the dopamine transporter (DAT). Since growing evidence suggests that dysfunction of the dopaminergic system is associated with persistent neuroinflammation, the aim of this study was to determine whether R-PhP, an inhibitor of DAT, has neuroprotective and anti-inflammatory effects in male mice. The pharmacokinetic profiles of R-PhP in mouse plasma and its bioavailability in brain tissue were assessed. To study possible molecular mechanisms involved in the anti-inflammatory activity of R-PhP, target profiling was performed using radioligand binding and enzymatic activity assays. To clarify the neuroprotective and anti-inflammatory effects of R-PhP, we used a lipopolysaccharide (LPS)-induced endotoxaemia model characterized by reduced body temperature and overexpression of inflammatory genes in the brain. In addition, the antinociceptive and anti-inflammatory effects of R-PhP were tested using carrageenan-induced paw oedema and formalin-induced paw-licking tests. R-PhP (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (ip) and peroral (po) injections. The maximal concentration of R-PhP in the brain tissues was 28 µg/g and 18 µg/g tissue after ip and po administration, respectively. In radioligand binding assays, DAT was the only significant molecular target found for R-PhP. A single ip injection of R-PhP significantly attenuated the LPS-induced body temperature reduction and the overexpression of inflammatory genes, such as tumour necrosis factor-α (TNF-α), interleukin 1 beta (IL-1ß) and inducible nitric oxide synthase (iNOS). Seven-day po pretreatment with R-PhP dose-dependently reduced paw oedema and the antinociceptive response, as shown by the carrageenan-induced paw oedema test. In addition, R-PhP decreased the nociceptive response during the inflammatory phase in the formalin-induced paw-licking test. Our study showed that R-PhP possesses neuroprotective and anti-inflammatory effects, demonstrating the potential of DAT inhibitors as effective therapeutics.

Pharmacokinetics of rectal levetiracetam as add-on treatment in dogs affected by cluster seizures or status epilepticus.

BACKGROUND: Levetiracetam can be used for seizure control alone or in combination with other antiepileptic medications. A previous study achieved the minimum targeted serum drug concentration after rectal administration of levetiracetam in healthy dogs. The purpose of the present study was to determine the pharmacokinetics of rectal LEV in dogs presented for cluster seizures or status epilepticus and potentially in treatment with other anti-epileptic drugs. Furthermore, preliminary information on response to this treatment as add-on to the standard treatment protocol is reported. RESULTS: Eight client-owned dogs were enrolled. Plasma levetiracetam concentrations (measured at 0, 30, 60, 90, 120, 180, 240, 360, 720, and 1440 min after drug administration) reached the minimum target concentration (5 µg/ml) at 30 min in all but one patient. At T1 (30 min) the mean concentration was 28.2 ± 15.5 µg/ml. Plasma concentrations remained above the targeted minimum concentration in all patients until 240 min and in 7/8 until 360 min. Six out of eight patients experienced no seizures in the 24-h period after hospitalization and were classified as "responders". CONCLUSIONS: Minimum plasma levetiracetam concentration can be reached after rectal administration of 40 mg/kg in dogs affected by cluster seizures and status epilepticus and concurrently receiving other antiepileptic drugs. These preliminary results may encourage the evaluation of rectal levetiracetam as an additional treatment option for cluster seizures and status epilepticus in a larger number of dogs.

Serum levetiracetam concentrations and adverse events after multiple dose extended release levetiracetam administration to healthy cats.

BACKGROUND: Multiple dose administration of antiepileptic drugs to cats presents a challenge for owners. Extended release levetiracetam (XRL) has once daily recommended dosing interval, but multiple dose administration of XRL has not been evaluated in cats. OBJECTIVE: Evaluate serum levetiracetam concentrations and adverse clinical effects after 11 days of once daily XRL administration to healthy cats. ANIMALS: Nine healthy privately owned cats, body weight ≥ 5 kg METHODS: Extended release levetiracetam (500 mg/cat) was administered PO q24h for 10 days. On day 11, blood was collected at trough, 4, 6, and 8 hours after tablet administration. Owners maintained records of adverse effects throughout study. Levetiracetam was quantitated in serum using immunoassay validated in cats. RESULTS: Median dose 94.3 mg/kg q24h. Median (range) trough, 4, 6, and 8 hour serum levetiracetam concentrations were 7.0 (2.3-14.1), 82.6 (7.8-125.3), 92.3 (13.3-97.3), and 72 (22.8-96.4) µg/mL, respectively. Peak was not observed in 4 cats because of missed samples (n = 2) and failure to reach maximal concentration (Cmax ) by 8 hours (n = 2). Median time of maximal concentration (Tmax ) for the remaining 5 cats 5.2 (range 4-6) hours. Adverse effects were minimal and included ataxia (n = 1), sedation (n = 1), and vomiting or regurgitation (n = 1). All signs resolved without dose adjustment or additional treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Mean trough serum levetiracetam concentrations were ≥5 µg/mL and adverse effects were minimal throughout dosing period, indicating that the drug was well tolerated. Once daily XRL (500 mg/cat) administration may provide an easier alternative to 3 times daily dosing of intermediate-release levetiracetam for epileptic cats.

Development and validation of a HPLC-UV assay for quantification of levetiracetam concentrations in critically ill patients undergoing continuous renal replacement therapy.

Limited clinical data exists on the effects of continuous renal replacement therapy (CRRT) on drug pharmacokinetics. A high-performance liquid chromatography with ultraviolet detection method was developed and validated to determine levetiracetam concentrations in human plasma and CRRT effluent samples. Five hundred microliters of human plasma and 250 µL effluent samples were used to quantify levetiracetam. Plasma samples were purified by protein precipitation, evaporated under nitrogen gas at room temperature and reconstituted in 50 mm potassium dihydrogen phosphate buffer (pH of 4.5). Reverse-phase chromatographic separation was achieved within 20 min using a mobile phase eluting gradient of 50 mm potassium dihydrogen phosphate and acetonitrile. UV detection was set at 195 nm. The calibration curve was found to be linear over the range of 2-80µg/mL. Inter- and intra-day precisions were < 8% for both plasma and effluent samples. The accuracy was determined to be within -12-10% of nominal concentrations. The method was selective and sensitive with a lower limit of quantification of 2 µg/mL. Overall recovery of levetiracetam from plasma was ~100%. The validated assay was successfully applied in a pharmacokinetic study to determine potential dose adjustments in patients undergoing CRRT and receiving levetiracetam.

Determination of plasma Levetiracetam level by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS-MS) and its application in pharmacokinetics studies in neonates.

BACKGROUND: Levetiracetam (LEV) is an antiepileptic drug which has good safety and efficacy in neonatal seizure (NS), a common incident in neonates with weight <1500 g. The pharmacokinetics for LEV in neonatal populations is yet to be clearly understood. In this study, we developed and validated a method for determination of LEV in plasma by liquid chromatography tandem mass spectrometry for the purpose of pharmacokinetic study. METHODS: Plasma LEV was spiked with Lamivudine as internal standard before extraction by C18 solid-phase extraction (SPE) cartridge. Chromatography was performed using isocratic elution with mobile phase A: B (10: 90) for 2.0 min with flow rate 0.4 mL/min. The mobile phase was composed of 0.1% formic acid in 10.0 mM ammonium acetate (A) and 100% methanol (B). The injection volume was 1.0 µL and the total run time was 2.0 min. Multiple reaction monitoring (MRM) with electro spray in positive mode was used. The mass transition for LEV was 171.2/126.0 and 230.0/112.0 for IS with retention time of 0.73 and 0.72 min, respectively. RESULTS: A calibration curve range from 0.50-80.0 µg/mL was obtained with a correlation coefficient >0.99 in the quadratic model. Precision and accuracy was within the acceptable range and the intra- and inter-day %CV for three concentrations of QCs were <10%. CONCLUSION: This method was reliable, accurate and applicable for LEV pharmacokinetic study in neonates with seizure.

Pharmacokinetics and Safety of Levetiracetam Extended-Release Tablets and Relative Bioavailability Compared with Immediate-Release Tablets in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: Levetiracetam is a second-generation antiepileptic drug and distributed ubiquitously in the central nervous system. The extended-release formulation of levetiracetam was developed to provide patients with the convenience of once-daily dosing, to improve drug compliance and tolerability. The objective of this study was to evaluate the pharmacokinetics and safety of levetiracetam extended-release (ER) tablets in healthy Chinese subjects following single and multiple doses. METHODS: Two panels of 34 healthy subjects were enrolled. Trial 1 was a two-way crossover between levetiracetam ER tablets and immediate-release (IR) tablets under fasting conditions. Trial 2 was a four-way crossover single-dose study between levetiracetam ER fasted and ER with food. RESULTS: Intake of single and multiple levetiracetam ER tablets resulted in a 42.3% lower maximum plasma concentration (Cmax) and a 33.6% lower minimum steady-state plasma concentration (Css min) than IR tablet intake, while the median time to Cmax (tmax) was significantly delayed. The 90% CI of the ER/IR ratios for area under the curve (AUC) from zero to last measurable sample (AUC0-t), AUC from zero to infinity (AUC0-∞), AUC at steady state (AUCss, τ = 24 h), Cmax at steady state (Css max) and average concentration at steady state (Css av) were contained within the 80-125% range of bioequivalence. The Cmax and AUC were dose proportional across the dose cohorts. Following a high-fat meal, levetiracetam ER tablets resulted in a 14.4% higher Cmax. The 90% confidence interval (CIs) of the fed/fasted ratios for Cmax and AUC were entirely contained within the 80-125% range of bioequivalence acceptance, except the tmax was delayed (P < 0.05). The most frequent treatment-emergent adverse events were somnolence, dizziness and thirst. CONCLUSIONS: After single and multiple doses, the absorption of levetiracetam ER was equal to IR, the tmax was significantly delayed, and the Cmax and Css min were significantly decreased. Food did not affect the absorption of the levetiracetam ER tablet, but the Cmax increased and the tmax was delayed. The levetiracetam ER tablet was well tolerated and found to be dose proportional from 500 to 2000 mg in healthy Chinese subjects.

Population pharmacokinetic model of levetiracetam in Korean neonates with seizures
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OBJECTIVE: This study was conducted to develop a population pharmacokinetic (PK) model of levetiracetam in Korean neonates with seizures. MATERIALS AND METHODS: Data were obtained from a retrospective study of 18 neonates with seizures admitted to the Neonatal Intensive Care Unit (NICU) of Severance Children's Hospital for the period of from 2013 to 2015. Sampling and dosing times were recorded by clinical research coordinators on case report forms. Demographic factors and laboratory results were tested as potential covariates for PK parameters. Model development was performed within a mixed-effect modeling framework using NONMEM. RESULTS: With a one-compartment model with first-order elimination chosen as a basic PK model based on theory-based allometric relationships, postmenstrual age and serum creatinine were found to have significant influences on clearance (CL). Typical parameter estimates of the final PK model obtained, evaluated at covariate medians, were 1.08 L/kg for volume of distribution (V) and 0.073 L/h/kg (= 1.23 mL/min/kg) for CL, illustrating that V in Korean neonates is a little larger than in Western population while CL is similar. CONCLUSION: A population PK model of levetiracetam for Korean neonates with seizures was developed in this study. The result of this study can be used as a basis to develop an optimal dosage regimen in Korean neonates with seizures.
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Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats.

BACKGROUND AND OBJECTIVE: Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. METHODS: Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion. After 24 h of middle cerebral artery occlusion or 22 h of reperfusion, piracetam was administered for pharmacokinetic, brain penetration, and pharmacological experiments. In pharmacokinetic study, blood samples were collected at different time points after 200-mg/kg (oral) and 75-mg/kg (intravenous) administration of piracetam through right external jugular vein cannulation. In brain penetration study, the cerebrospinal fluid, systemic blood, portal blood, and brain samples were collected at pre-designated time points after 200-mg/kg oral administration of piracetam. In a separate experiment, the pharmacological effect of the single oral dose of piracetam in middle cerebral artery occlusion was assessed at a dose of 200 mg/kg. RESULTS: All the pharmacokinetic parameters of piracetam including area under curve (AUC0-24), maximum plasma concentration (C max), time to reach the maximum plasma concentration (t max), elimination half-life (t 1/2), volume of distribution (V z), total body clearance, mean residence time, and bioavailability were found to be similar in ischemic stroke condition except for brain penetration. Piracetam exposure (AUC0-2) in brain and CSF were found to be 2.4- and 3.1-fold higher, respectively, in ischemic stroke compared to control rats. Piracetam significantly reduced infarct volume by 35.77% caused by middle cerebral artery occlusion. CONCLUSIONS: There was no change in the pharmacokinetic parameters of piracetam in the ischemic stroke model except for brain penetration. This indicates that variables influencing brain penetration may not be limiting factors for use of piracetam in ischemic stroke.

Disposition of levetiracetam in healthy adult horses.

Nine horses received 20 mg/kg of intravenous (LEVIV ); 30 mg/kg of intragastric, crushed immediate release (LEVCIR ); and 30 mg/kg of intragastric, crushed extended release (LEVCER ) levetiracetam, in a three-way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEVCIR and LEVCER were 50.72 ± 10.60 and 53.58 ± 15.94 µg/ml, respectively. The y-intercept for IV administration was 64.54 ± 24.99 µg/ml. The terminal half-life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEVCIR , LEVCER, and LEVIV , respectively. Volume of distribution at steady-state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg-1  hr-1 . Bioavailability was 96 ± 10, and 98 ± 13% for LEVCIR and LEVCER , respectively. A single dose of Levetiracetam (LEV) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.

Population pharmacokinetics of levetiracetam in neonates with seizures.

WHAT IS KNOWN AND OBJECTIVE: This study developed a population pharmacokinetic (PK) model of levetiracetam (LEV) for treating neonatal seizures (NS) and determined the influence of clinically relevant covariates to explain the interindividual variability and residual error. METHODS: Twenty newborns admitted to the Neonatal Intensive Care Unit at the Hospital Central "Dr. Ignacio Morones Prieto" were included. LEV doses were administered by intermittent infusion. Blood samples were drawn 3 times post-infusion. Levetiracetam was quantified by a chromatographic technique. NONMEM software was used to determine the population PK model of LEV in neonates and the influence of clinical covariates on drug disposition. RESULTS AND DISCUSSION: The LEV PK in neonates is described by a one-compartment open model with first-order elimination. The influence of creatinine clearance (CRCL) and body weight (BW) on clearance (CL[L/h] = 0.47*CRCL), as well as the volume of the distribution (Vd[L] = 0.65*BW) of LEV, were confirmed, considering interindividual variabilities of 36% and 22%, respectively, and a residual error of 13%. WHAT IS NEW AND CONCLUSION: Based on the PK of LEV in neonates and the influence of the final PK model, a priori dosing guidelines are proposed considering CRCL, BW and LEV plasma concentrations between 6 and 20 mg/L for NS treatment.

Influence of Comedication on Levetiracetam Pharmacokinetics.

BACKGROUND: To evaluate the effect of concomitant antiepileptic therapy on levetiracetam (LEV) pharmacokinetics. METHODS: A 6-year retrospective observational study. Patients were grouped according to the antiepileptic drug used as concomitant medication: group A, LEV in monotherapy; group B, LEV + enzyme-inducing antiepileptic drugs (EIAEDs); and group C, LEV + non-enzyme-inducing antiepileptic drugs (NEIAEDs). Apparent oral levetiracetam clearance (LEV CL/F) and basal serum levetiracetam concentrations (LEV C0) were compared among the different groups by analysis of variance. RESULTS: A total of 330 LEV C0 corresponding to 205 patients (56% men) were identified. The mean (±SD) of LEV CL/F in group A (n = 180), B (n = 92), and C (n = 58) was 4.41 ± 2.06 L/h, 7.23 ± 3.72 L/h, and 4.87 ± 1.65 L/h, respectively. EIAEDs increased LEV CL/F (L/h) by 64% compared with the monotherapy group and by 48% compared with the NEIAEDs group. The greatest induction in LEV CL/F, compared with the LEV monotherapy group, was observed with carbamazepine, followed by oxcarbazepine and phenobarbital, and was increased by 81%, 64%, and 44%, respectively. LEV C0 values were significantly lower in the EIAEDs group than in the monotherapy group (17.30 ± 7.77 versus 20.08 ± 9.69 mcg/mL; P = 0.038) or indeed the NEIAEDs group (17.30 ± 7.77 versus 20.49 ± 9.46 mcg/mL; P = 0.027). CONCLUSIONS: Comedication with EIAEDs increased LEV CL/F by more than 40%, whereas carbamazepine had the greatest inducing potency with LEV CL/F being 81% higher than that of the monotherapy group. These data suggest that monitoring LEV serum concentration during polytherapy with EIAEDs is indicated.

Pharmacokinetics of the anticonvulsant levetiracetam in neonatal foals.

BACKGROUND: Seizures are a common manifestation of neurological disease in the neonatal foal and are an important cause of morbidity and mortality in this population. Current antiepileptic options are effective, but often have undesirable adverse effects, short duration of action and high cost. Levetiracetam has an ideal safety and pharmacokinetic profile in multiple species, including the adult horse, and may be a safe and cost-effective alternative anticonvulsant in neonatal foals. Due to differences in drug disposition and clearance dosages in neonates, dosing recommendations in other species or adult horses cannot be extrapolated to foals. OBJECTIVE: To establish the pharmacokinetic profile of single-dose i.v. and intragastric administration of levetiracetam in healthy neonatal foals. STUDY DESIGN: Randomised crossover experimental study. METHODS: Levetiracetam was administered as a single dose to six healthy foals (ages 1-10 days) at a dose of 32 mg/kg bwt i.v. or intragastrically. Plasma levetiracetam concentrations were measured using a validated HPLC protocol. RESULTS: After i.v. administration to healthy foals, levetiracetam had a mean (±s.d.) elimination half-life of 7.76 ± 0.51 h, a mean systemic clearance of 61.67 ± 10.96 (mL/h/kg) and a mean apparent volume of distribution at steady state of 0.670 ± 0.124 (L/kg). Following intragastric administration, levetiracetam had a peak concentration of 38.34 ± 7.42 mg/L and time to achieve peak concentration was 0.875 (0.5-1.5) h. Mean bioavailability for IG administration was excellent (103.04 ± 14.51%). No significant differences in pharmacokinetic variables between routes and order of administration were observed. MAIN LIMITATIONS: Small sample size and single-dose administration. CONCLUSIONS: Levetiracetam has excellent intragastric bioavailability in foals and is predicted to maintain plasma concentrations at or above the proposed target concentration with twice daily i.v. or oral administration. Once-daily administration may be possible in some foals based on the therapeutic range recommended in other species.

Pharmacokinetics of Single Oral Dose Extended-Release Levetiracetam in Healthy Cats.

BACKGROUND: Repeated PO dosing of anti-epileptic drugs may contribute to poor compliance in treated cats. Intermediate-release levetiracetam has been used safely in cats, but must be given q8h to maintain serum concentrations in the therapeutic interval for humans (5-45 µg/mL). Approved extended-release levetiracetam (XRL) for human use may require less frequent dosing, but the large dosing unit has limited its use in cats. HYPOTHESES: In healthy cats, serum levetiracetam concentration will remain above 5 µg/mL for at least 24 hours after administration of a single dose of XRL PO and will be well tolerated. ANIMALS: 7 healthy cats. METHODS: Extended-release levetiracetam (500 mg) was administered PO. Blood was collected and neurologic examination findings recorded at scheduled times over 30 hours. Serum levetiracetam concentration was quantitated by an immunoassay validated in cats. Data were subjected to noncompartmental analysis. Descriptive statistics were reported. RESULTS: The median dosage of 86.2 mg/kg, (range, 80-94.3) achieved a mean maximum concentration (Cmax ) of 89.8 ± 25.8 µg/mL at 4.9 ±1.57 hours. Serum levetiracetam was >5 µg/mL in all cats by 90 minutes. Mean concentrations were 43.7 ± 18.4 and 4.9 ± 3.4 µg/mL at 12 and 24 hours, respectively. The half-life was 4.1 ± 1.0 hours. The drug was well tolerated. CONCLUSIONS AND CLINICAL IMPORTANCE: A single 500 mg PO dose of XRL safely maintained serum levetiracetam concentration ≥5 µg/mL in healthy cats for at least 21 hours. Clinical efficacy studies in epileptic cats receiving XRL are indicated; however, monitoring should be implemented for individual cats.

Intervenciones farmacológicas que mejoren la cognición y el funcionamiento adaptativo en el síndrome de Down: Progresos hasta la fecha / No disponible

Pese al creciente número de ensayos clínicos desarrollados para evaluar la cognición en el síndrome de Down, sus resultados para identificar intervenciones eficaces han sido muy limitados hasta la fecha. Las intervenciones en los modelos animales, con frecuencia muy favorables, no se han visto reflejadas en los ensayos clínicos. Esta revisión describe los resultados de los principales ensayos realizados. Ofrece consideraciones a los investigadores y describe estrategias a la industria farmacéutica para que se implique crecientemente en el descubrimiento de fármacos en el síndrome de Down

Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre-clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome

The preclinical discovery and development of brivaracetam for the treatment of focal epilepsy.

INTRODUCTION: Brivaracetam (BRV) is a new AED currently licensed for the adjunctive treatment of adult patients with focal epilepsies. It is a ligand of the ubiquitous synaptic vesicle glycoprotein 2A (SV2A). Areas covered: This paper covers the preclinical and subsequent clinical development of BRV focusing on the discovery of the SV2A protein as the main target for levetiracetam (LEV) and the main similarities and differences between LEV and BRV in terms of pharmacodynamic and pharmacokinetic properties. Phase II and Phase III studies are also presented and data from post-marketing phase IV studies are discussed. Expert opinion: The preclinical development of BRV is quite unique and has raised several doubts on current methodologies adopted for AED development, reinforcing the need for new approaches. The preclinical and clinical profile suggest that BRV is potentially an ideal compound in the emergency setting given the rapid onset of action associated with being water soluble and, therefore, available in intravenous formulation. In addition, data from Phase III studies have already suggested that BRV may be effective not only in focal epilepsies but also in generalised syndromes. Further data from special populations such as children and women of child bearing age are urgently needed.

A Review on Pharmacokinetics of Levetiracetam in Neonates.

BACKGROUND: Neonatal seizures are the most common clinical manifestation of Central Nervous System (CNS) dysfunction and are associated with various neurological sequelae. There are currently no evidence-based guidelines for the management of neonatal seizures and currently used drugs such as phenobarbital, and phenytoin have limited efficacy and potential toxicities. Newer second line anticonvulsant, levetiracetam, has been used in refractory neonatal seizures despite limited data and off-label use. OBJECTIVE: In this review, we will discuss various pharmacological properties of levetiracetam when used in neonatal population. METHODS: A PubMed search for MEDLINE was undertaken to look for studies using the terms "Levetiracetam", AND "Neonates" as key words from year 1995 to January 2017. Relevant articles were selected and information was extracted about pharmacokinetics, pharmacodynamics and clinical uses of levetiracetam in neonates. RESULTS: Levetiracetam is an active, water-soluble S-enantiomer of racemic pyrrolidine acetamide which exerts its antiepileptic action by binding to the synaptic vesicle protein within the brain. Metabolism of levetiracetam does not include the CYP P450 system and it is mainly eliminated through kidneys after rapid absorption. Also, no significant interactions with other drugs have been identified. Unlike other commonly used antiepileptic drugs, levetiracetam is not bound to plasma proteins, thereby, reducing the chances of toxicity and severe, life threatening side effects have not been reported. In fact, it has been shown to prevent neuro-degeneration after hypoxia/ischemia in rodent models of epilepsy. CONCLUSION: Levetiracetam has been emerging as a potential therapeutic option for refractory neonatal convulsions owing to its non-hepatic elimination, linear pharmacokinetics, low protein binding and better safety profile.

Heroin-piracetam mixture: Suggested mechanisms of action and risks of misinterpretation for drug users.

Piracetam is a positive allosteric modulator of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor that has been frequently used in the treatment of cognitive disorders. Press and internet reports indicate that the use of piracetam, as a heroin adulterant, has spread rapidly in some countries, especially in Asia and Europe. Its use, as adulterant, is believed to produce more profound desirable effects, while decreasing hangover. Recent surveys demonstrated that piracetam protects neurons from heroin-induced apoptosis. The protective role of this adulterating substance may be related to restoration of beta-endorphin levels and to its neuroprotective effects. The aim of this paper is to review the relevant literature and suggest the main hypothetical mechanisms that justify its use as a heroin adulterant, try to understand if its use could help people who want to come off heroin by reducing withdrawal symptoms and, finally, give useful information that permit us to understand why drug trafficking organisations started to use piracetam as heroin adulterant.

Levetiracetam Pharmacokinetics in a Patient with Intracranial Hemorrhage Undergoing Continuous Veno-Venous Hemofiltration.

BACKGROUND Levetiracetam is an antiepileptic drug frequently used in critically ill patients. Levetiracetam is primarily eliminated as a parent compound via glomerular filtration and requires dose adjustment in renal insufficiency, but the literature on patients receiving continuous veno-venous hemofiltration (CVVH) is scant. CASE REPORT We report the levetiracetam pharmacokinetic profile of a patient being treated with levetiracetam 1000 mg intravenously every 12 h who required continuous veno-venous hemofiltration (CVVH). The patient underwent CVVH utilizing a high-flux polyethersulfone membrane filter. The blood flow rate was 250 ml/min, and the predilution replacement therapy fluid flow rate was 2000 ml/h. After achieving presumed steady-state on levetiracetam 1000 mg q12h, serial plasma samples (pre- and post-filter) and effluent samples were drawn at 2, 4, 6, 8, and 10 h. Levetiracetam concentrations were determined utilizing LC-MS/MS. The levetiracetam maximum concentration (Cmax), minimum concentration (Cmin), half-life, area under the concentration-time curve (AUC0-12), clearance (CL), and volume of distribution (Vd) were 30.7 µg/ml, 16.1 µg/ml, 12.9 h, 272 mg·hr/L, 3.68 L/h, and 0.73 L/kg, respectively. The sieving coefficient was 1.03±0.08. CVVH represented 61.3% of the total levetiracetam clearance. The patient was maintained on CVVH for 24 consecutive days and then transitioned to intermittent hemodialysis and remained seizure-free. CONCLUSIONS CVVH is highly effective in removing levetiracetam from circulating plasma. Due to the effective removal, standard doses of levetiracetam are required to maintain adequate plasma concentrations. Dose reductions utilizing HD or estimated creatinine clearance recommendations will likely lead to subtherapeutic levels, especially if higher CVVH flow rates are used.