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Abstract: Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease‐modifying effect. Intravenous administration of a high dose of N‐acetylcysteine (NAC), a well‐known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4‐week open‐label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using 1H‐MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4‐hydroxynonenal (4‐HNE) concentrations and the reduced‐to‐oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration–time profiles were described by a first‐order absorption, 1‐compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4‐HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage. [ABSTRACT FROM AUTHOR]

Water-soluble prodrugs can be rapidly converted by enzymes to hydrophobic drugs, whose aqueous thermodynamic solubilities are low, but are maintained in aqueous solution at supersaturated concentrations due to slow precipitation kinetics. Recently, we investigated avizafone (AVF) in combination with Aspergillus oryzae protease as a prodrug/enzyme system intended to produce supersaturated diazepam (DZP). Several fold enhancement of permeation of supersaturated DZP across Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers was observed, compared to saturated DZP solutions. However, prodrug conversion was incomplete, putatively due to partial racemization of AVF and stereoselectivity of A oryzae protease. Here we report synthesis of chirally pure AVF, and demonstrate complete conversion to supersaturated DZP followed by complete DZP permeation at enhanced rates across MDCKII-wt cell monolayers. We also synthesized, for the first time, a chirally pure prodrug of midazolam (MDZ-pro) and carried out the same sequence of studies. A oryzae protease was identified as a benign and efficient activating enzyme for MDZ-pro. The MDZ-pro/ A oryzae protease system showed greater than 25-fold increase in absorption rate of MDZ across MDCKII-wt monolayers, compared to saturated MDZ. Such chirally pure prodrug/enzyme systems are promising candidates for efficient intranasal delivery of benzodiazepine drugs used in the treatment of seizure emergencies. [ABSTRACT FROM AUTHOR]

A sequential pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol-Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19-55 years of age), using both oral and a novel stable-labeled intravenous (IV) formulation of topiramate, an inhibitory Emax model was found to characterize the topiramate concentration-SDMT score relationship well. At the EC50 of 2.85 μg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings. [ABSTRACT FROM AUTHOR]

Intravenous and intramuscular antiseizure drugs (ASDs) are essential in the treatment of clinical seizure emergencies as well as in replacement therapy when oral administration is not possible. The parenteral formulations provide rapid delivery and complete (intravenous) or nearly complete (intramuscular) bioavailability. Controlled administration of the ASD is feasible with intravenous but not intramuscular formulations. This article reviews the literature and discusses the chemistry, pharmacology, pharmacokinetics, and clinical use of currently available intravenous and intramuscular ASD formulations as well as the development of new formulations and agents. Intravenous or intramuscular formulations of lorazepam, diazepam, midazolam, and clonazepam are typically used as the initial treatment agents in seizure emergencies. Recent studies also support the use of intramuscular midazolam as easier than the intravenous delivery of lorazepam in the pre-hospital setting. However, benzodiazepines may be associated with hypotension and respiratory depression. Although loading with intravenous phenytoin was an early approach to treatment, it is associated with cardiac arrhythmias, hypotension, and tissue injury at the injection site. This has made it less favored than fosphenytoin, a water-soluble, phosphorylated phenytoin molecule. Other drugs being used for acute seizure emergencies are intravenous formulations of valproic acid, levetiracetam, and lacosamide. However, the comparative effectiveness of these for status epilepticus (SE) has not been evaluated adequately. Consequently, guidelines for the medical management of SE continue to recommend lorazepam followed by fosphenytoin, or phenytoin if fosphenytoin is not available. Intravenous solutions for carbamazepine, lamotrigine, and topiramate have been developed but remain investigational. The current ASDs were not developed for use in emergency situations, but were adapted from ASDs approved for chronic oral use. New approaches for bringing drugs from experimental models to treatment of human SE are needed. [ABSTRACT FROM AUTHOR]

There is an increasing interest in using N-acetylcysteine ( NAC) as a treatment for neurodegenerative disorders to increase glutathione ( GSH) levels and its redox status. The purpose of this study was to characterize the biosynthesis of NAC to GSH using a novel stable isotope-labeled technique, and investigate the pharmacodynamics of NAC in vivo. Female wild-type mice were given a single intravenous bolus dose of 150 mg kg−1 stable-labeled NAC. Plasma, red blood cells ( RBC), and brain tissues were collected at predesignated time points. Stable-labeled NAC and its metabolite GSH (both labeled and unlabeled forms) were quantified in blood and brain samples. Molar ratios of the reduced and oxidized forms of GSH ( GSH divided by glutathione disulfide, redox ratio) were also determined. The elimination phase half-life of NAC was approximately 34 min. Both labeled and unlabeled GSH in RBC were found to increase; however, the area under the curve above baseline ( AUCb0-280) of labeled GSH was only 1% of the unlabeled form. These data indicate that NAC is not a direct precursor of GSH. In addition, NAC has prolonged effects in brain even when the drug has been eliminated from systemic circulation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2619-2626, 2015 [ABSTRACT FROM AUTHOR]

Benzodiazepines (BZDs), including diazepam (DZP) and midazolam (MDZ), are drugs of choice for rapid treatment of seizure emergencies. Current approved use of these drugs involves administration via either intravenous or rectal routes. The former requires trained medical personnel, while the latter is socially unacceptable for many patients and caregivers. In recent years, efforts have been made to formulate BZDs for nasal administration. Because of the low solubility of these molecules, organic vehicles have been used to solubilize the drugs in the nasal products under development. However, organic solvents are irritating, potentially resulting in injury to nasal tissue. Here we report preliminary studies supporting a strategy in which water-soluble BZD prodrugs and a suitable converting enzyme are coadministered in an aqueous vehicle. Diazepam and midazolam prodrugs were synthesized and were readily converted to their active forms by a protease from Aspergillus oryzae . Using a permeation assay based on monolayers of Madin–Darby canine kidney II-wild type cells, we found that enzymatically produced BZDs could be maintained at high degrees of supersaturation, enabling faster transport across the membrane than can be achieved using saturated solutions. This strategy not only obviates the need for organic solvents, but it also suggests more rapid absorption and earlier peak concentrations than can be otherwise achieved. This article is part of a Special Issue entitled “Status Epilepticus”. [ABSTRACT FROM AUTHOR]

Objective Canine status epilepticus ( CSE) has potential as a translational platform to evaluate the safety and efficacy of novel compounds and inform human status epilepticus trials. The aim of this study was to determine the intravenous dose of fosphenytoin ( FOS) needed for dogs in a CSE clinical trial to attain phenytoin ( PHT) concentrations similar to those used for human status epilepticus and monitor PHT concentrations. Methods Four healthy dogs were used to characterize PHT pharmacokinetics. Each received either 15 mg/kg or 25 mg/kg of PHT equivalent intravenously. Blood samples were collected and FOS (total) and derived PHT (total and unbound) plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Noncompartmental pharmacokinetics ( PK) parameter values were determined and compartmental PK modeling and simulations were used to select the dose for the clinical trial with a target goal of 1-2 μg/ml unbound PHT at 30-60 min postinfusion. Predicted total and unbound PHT concentrations were compared with concentrations in blood collected from dogs treated for CSE in the clinical trial. Results Initial estimates suggested that a loading dose of 25 mg/kg would attain unbound concentrations of 1-2 μg/ml; however, this dose produced concentrations above 3-6 μg/ml, which resulted in clinically significant toxicity. A two-compartment model best fit the PHT concentration data with alpha-phase half-life of 2-5 min and elimination half-life of ~5 h. Based on the simulations, a dose of 15 mg/kg was selected and used in the clinical trial and 15 of 16 dogs randomized to the treatment arm had PHT plasma concentrations within the goal range. Significance This study demonstrates that characterization of pharmacokinetics in a small number of dogs is useful in determining dosage regimens designed to attain targeted concentrations in clinical trials. Using this approach, we were able to determine a safe and effective dose of FOS for a clinical trial of CSE. [ABSTRACT FROM AUTHOR]

Objectives There are a limited number of marketed intravenous antiepileptic drugs (AEDs) available to treat status epilepticus (SE). All were first developed for chronic therapy of epilepsy, not specifically for SE. Epilepsy and canine SE (CSE) occur naturally in dogs, with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. The objective of this study was to determine if CSE treated with fosphenytoin (FOS) results in a similar responder rate as for people. Methods A randomized clinical trial was performed for dogs with CSE. Dogs who presented during a seizure or who had additional seizures after enrolling received intravenous (i.v.) benzodiazepine (BZD) followed immediately by intravenous infusion of 15 mg/kg phenytoin equivalent (PE) of fosphenytoin (FOS) or saline placebo (PBO). If seizures continued, additional AEDs were administered per the standard of care for veterinary patients. Total and unbound plasma phenytoin (PHT) concentrations were measured. Results Consent was obtained for 50 dogs with CSE. Thirty-one had additional motor seizures and were randomized to the study intervention (22 FOS and 9 PBO). There was a statistically significant difference in the 12 h responder rate, with 63% in the FOS group versus 22% in the placebo group (p = 0.043) having no further seizures. The unbound PHT concentrations at 30 and 60 min were within the therapeutic concentrations for people (1-2 μg/ml) with the exception of one dog. There was mild vomiting in 36% of the FOS group (7/22) within 20 min of FOS administration and none of the placebo group (0/9) (p = 0.064). Significance This proof of concept study provides the first evidence that FOS is tolerated and effective in canine SE at PHT concentrations clinically relevant for human SE. Furthermore, naturally occurring CSE can be utilized as a translational platform for future studies of novel SE compounds. [ABSTRACT FROM AUTHOR]

Aims The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association ( COWA) test in healthy volunteers after administration of an oral and a novel intravenous ( IV) formulation of topiramate ( TPM). Methods Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic-pharmacodynamic ( PK- PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions. Results Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ∼100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l−1 increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions. Conclusions This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK- PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population. [ABSTRACT FROM AUTHOR]

Objective Evaluate the pharmacokinetics ( PK), safety, and tolerability of single doses of once-daily USL255, Qudexy XR (topiramate) extended-release capsules, over a wide dosing range. Methods Two single-dose, phase I studies in healthy adults were used to evaluate the PK profile and maximum tolerated dose ( MTD) of USL255 from 25-1,400 mg. Standard PK parameters assessed included area under the plasma concentration-time curve ( AUC) and maximum plasma concentration (Cmax). Dose proportionality, linearity, and intersubject and intrasubject variability (coefficient of variation [% CV]) of AUC and Cmax were evaluated. Investigator-reported adverse events ( AEs) were obtained throughout the studies. Results After the initial increase in plasma concentration levels immediately following administration of USL255 25-1,400 mg, plasma topiramate concentration-time profiles were flat up to 24 h after dosing. AUC was dose proportional from 25-1,400 mg, and Cmax was dose proportional from 50-1,400 mg; both AUC and Cmax were linear across the entire dose range. Low intersubject and intrasubject % CV values were observed for AUC0−t, AUC0−∞, and Cmax (intersubject % CV: 20.2, 19.6, and 22.4%, respectively; intrasubject % CV of dose-normalized mean values: 10.8, 8.2, and 13.2%, respectively). USL255 was generally safe and well tolerated with MTD established at 1,200 mg. Significance These results demonstrate that USL255 provides consistent plasma topiramate exposure across an extended-dosing interval and predictable plasma topiramate concentrations over a wide dosing range. Overall, the favorable safety profile and consistency of exposure suggest once-daily USL255 can be a useful treatment option for patients with epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Abrupt discontinuation of baclofen therapy is associated with a clinically serious withdrawal syndrome. Current treatment modalities are often ineffective. Intravenous ( IV) baclofen is a potential method for preventing or treating baclofen withdrawal syndrome. Objectives To complete a preliminary study of IV baclofen in dogs. Methods Single bolus IV doses (0.5, 2 and 3 mg/kg) as well as multiple dose regimens were evaluated. Sedation and clinical tolerability was assessed by modified Glasgow Coma Scale and Discomfort and Behaviour Scale. Key findings Baclofen concentration-time profiles following single IV boluses were best fit by a two-compartment model which was used to predict plasma concentrations for the multiple dose regimens. The mean distribution and elimination half-lives were 11 min and 222 min, respectively. Maximum clinical effect did not occur until approximately 120 min. The discomfort score increased proportionately with increased single IV bolus doses. Multiple dose regimens resulted in greater than proportionate discomfort scores based on total dose and were generally not as well tolerated. Conclusions If projected for human use, our data suggests that initial IV baclofen doses will need to be reduced by approximately one-third of the usual oral dose, and clinicians should observe patients for several hours before administering subsequent doses. [ABSTRACT FROM AUTHOR]

Highlights: [•] We compared the bioavailability of two nasal diazepam formulations. [•] Bioavailability of an intranasal solution & suspension were 97% and 67% respectively. [•] Both intranasal diazepam formulations were well tolerated. [•] A well tolerated intranasal diazepam therapy with high bioavailability is feasible. [Copyright &y& Elsevier]

Purpose Although oral topiramate ( TPM) products are widely prescribed for migraines and epilepsy, injectable TPM is not available for human use. We have developed a solubilized TPM formulation using a cyclodextrin matrix, Captisol with the long-term goal of evaluating its safety and efficacy in neonatal seizures. This study in healthy adult volunteers was performed as required by the U.S. Food and Drug Administration ( FDA) to demonstrate the pharmacokinetics and safety prior to initiation of studies involving children. This study allowed investigation of absolute bioavailability, absolute clearance, and distribution volume of TPM, information that could not be obtained without using an intravenous TPM formulation. Methods This study was an open-label, two-way crossover of oral and intravenous TPM in 12 healthy adult volunteers. Initially two subjects received 50 mg, intravenously and orally. Following evidence of safety in the first two subjects, 10 individuals received 100 mg doses of intravenous and oral TPM randomly sequenced 2 weeks apart. Blood samples were taken just prior to drug administration and at intervals up to 120 h afterwards. TPM was measured using a validated liquid chromatography-mass spectrometry method. Concentration-time data were analyzed using a noncompartmental approach with Win Nonlin 5.2. Key Findings All subjects completed the study. The mean (±standard deviation) absolute oral bioavailability was 109% (±10.8%). For intravenous and oral TPM the mean distribution volumes were 1.06 L/kg (±0.29) and 0.94 L/kg (±0.24). Clearances were 1.33 L/h (±0.26) and 1.22 L/h (±0.26). The half-life values were 42.3 h (±6.2) and 41.2 h (±7.5). No changes in heart rate, blood pressure, electrocardiography, or infusion site reactions were observed. Mild central nervous system cognitive adverse events and ataxia occurred between dosing and 2 h post dose with both intravenous and oral administration. With intravenous TPM, these adverse effects occurred as early as during the 15-min intravenous infusion. Significance In healthy adults, oral TPM is bioequivalent to intravenous TPM, and infusion of 50-100 mg over 15 min is safe. Neurologic effects occurred during the infusion, demonstrating that TPM rapidly diffuses into the brain, which supports its evaluation for neonatal seizures. Results from this pilot study will inform the design of subsequent studies in children and newborns, including controlled clinical trials intended to assess the efficacy and safety of intravenous TPM for neonatal seizures. In addition, our results provide support for the further development of intravenous TPM as bridge therapy for older children and adults in whom oral TPM therapy is interrupted. [ABSTRACT FROM AUTHOR]

Purpose Although topiramate is widely prescribed for epilepsy and migraine, there is no intravenous product. We have developed an injectable topiramate formulation in which the drug is solubilized in a cyclodextrin matrix, Captisol® (Ligand Pharmaceuticals, Inc., La Jolla, CA). Our long-term goal is to evaluate intravenous topiramate for the treatment of neonatal seizures. Prior to studies in newborns, we carried out an investigation of injectable topiramate's safety and pharmacokinetics in adult patients. Methods Twenty adult volunteers with epilepsy or migraine on stable, on maintenance topiramate therapy were given 25 mg of a stable-labeled intravenous topiramate over 10 min, followed by their usual oral doses. Vital signs were taken, electrocardiography studies ( ECGs) were recorded, and the infusion sites were periodically examined prior to and up to 24 h after dosing. Blood samples were collected prior to administration and serially for 96 h thereafter. Plasma concentrations of both stable-labeled and regular topiramate were measured using liquid chromatography-mass spectrometry (LC-MS). Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, U.S.A.). Key Findings Seven patients experienced one or more of the following minor adverse events including nausea and vomiting (1), tingling around the lips (1), paresthesia in the arms and legs (1), and a mild vasovagal response with intravenous catheter placement (1). Included in the adverse events were four patients with epilepsy who had seizures consistent with their histories. There were no changes in heart rate, blood pressure, or ECG results, and there were no infusion site reactions. Pharmacokinetic parameters (mean ± standard deviation [ SD]) determined following the intravenous dose included absolute bioavailability: 110 ± 16%, distribution volume: 0.79 ± 0.22 L/kg, clearance: 2.03 ± 1.07 L/h, and elimination half-life: 27.6 ± 9.7 h. Distribution volume, half-life, and clearance were significantly altered by enzyme-inducing drugs. Significance A single 25-mg dose of intravenous topiramate caused minimal infusion site or systemic adverse effects in patients taking oral topiramate. Pharmacokinetic results show that oral topiramate is completely absorbed and that its steady-state elimination half-life is longer than previously assumed, which permits once or twice daily dosing even in the presence of enzyme-inducing drugs. The information from this study can inform the design of subsequent studies in adults, older children, and newborns, including controlled clinical trials intended to determine the efficacy and safety of intravenous topiramate for neonatal seizures. [ABSTRACT FROM AUTHOR]

The objective of the study was to investigate the pharmacokinetics (PK) of unbound and total plasma carbamazepine (CBZ) concentrations following simultaneous administration of intravenous and oral formulations. We tested the hypothesis that age-related alterations in physiology and patient characteristics influence CBZ disposition and protein binding. Patients (n = 113) on maintenance therapy received a 100 mg dose of a novel, intravenous, stable-labeled (SL) CBZ formulation as partial replacement of their morning CBZ dose. A two-compartment model described unbound and total SL-CBZ data. The stable-labeled intravenous dosing methodology enabled the estimation of the CBZ clearance (CL) and volumes of distribution. The CL of CBZ was dependent on race through the model equation unbound CL (L/hour) = 11.2 × (1.30)Race; where Race = 1 for Caucasian, 0 for African American. Total body weight explained 57% and 70% of the interindividual variability in the central and peripheral volumes of distribution, respectively. Age, sex, smoking, plasma albumin, and alpha 1-acid glycoprotein concentrations had no effect on CL, binding or volumes of distribution. The model was evaluated via bootstrap and predictive check. Results may support race specific dosing for CBZ where an average African-American individual would receive 70% of the standard dose prescribed for the Caucasian person. [ABSTRACT FROM AUTHOR]

N-acetyl- l-cysteine (NAC), a well-known antioxidant, has been successfully used as adjuvant therapy for late-stage childhood cerebral adrenoleukodystrophy (c-ALD); however, the mechanisms of NAC action are poorly understood. Previous research indicates that NAC serves as a precursor to l-cysteine (Cys), the rate-limiting substrate in the biosynthesis of glutathione (GSH), a potent, endogenous antioxidant. We hypothesized that NAC acts by liberating protein-bound Cys in plasma in an NAC concentration-dependent manner, which increases unbound Cys available for GSH biosynthesis. Human plasma was incubated for 1 h with varying, clinically relevant concentrations of NAC (0-1000 µg/mL). The effect of this interaction over time was evaluated by incubating plasma for 5-90 min with 100 µg/mL NAC. Unbound and bound Cys and NAC were separated by ultrafiltration, and concentrations were measured using high-performance liquid chromatography-mass spectrometry. Significant increases in unbound Cys were observed with increasing NAC concentrations. Also, Cys plasma protein binding decreased from 85% (10 µg/mL NAC) to approximately 0% (1000 µg/mL). Total endogenous Cys was 66% unbound at 5 min after incubation. These results demonstrate that NAC liberates endogenous, protein-bound Cys in human plasma at clinically relevant NAC concentrations. A greater understanding of NAC actions will aid in the optimization of NAC therapy including its use in c-ALD. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4653-4659, 2012 [ABSTRACT FROM AUTHOR]

Summary Current treatment of human status epilepticus (SE) relies on drugs developed for chronic treatment of epilepsy. Many potent compounds have been discovered in animal models of SE. But they may never be useful for chronic treatment of epilepsy and thus not available for human use. Naturally occurring canine SE may become a translational platform for evaluating these compounds for eventual use in human trials. A pilot study of levetiracetam in canine SE demonstrated a 56% response rate compared to 10% for placebo. Based on these results we have obtained an NIH R-21 to further evaluate canine SE as a translational platform for developing new approaches for treating human SE. [ABSTRACT FROM AUTHOR]

Summary: Intranasal therapy has been proposed as an alternative for the management of seizure emergencies. The bioavailability, dose proportionality and tolerability of a supersaturated intranasal formulation of diazepam (DZP) solubilized in a glycofurol–water cosolvent system was investigated. Eight healthy volunteers were randomized into a single-blind, three-way crossover study to compare 5 and 10mg intranasal DZP doses of the investigational formulation with a 5mg dose of a DZP solution (DZP injectable, 5mg/mL) administered intravenously. Treatments were separated by a two-week washout period. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 48h post-dose and assayed by HPLC. Visual analog scales (VAS) were used to assess tolerability (1-tolerable; 10-extremely intolerable) and pain (1-no pain; 4-extreme pain) at predefined time points. Following the 5 and 10mg doses, the median t max were 20 and 30min and the mean C max were 134.3±62 and 247.6±61ng/mL. Estimated bioavailability was 75% for both doses. Pain scores of 2 and 2.3 were observed following the 5 and 10mg doses; tolerability scores were 4.4 and 4.7. Pain and tolerability scores returned to baseline within 10h. Our formulation provided reasonable bioavailability, but was not well tolerated. [Copyright &y& Elsevier]

Objectives: To compare the bioavailability of divalproex extended release (divalproex–ER) given once daily relative to the conventional divalproex formulation given once every 8 hours, using various divalproex–ER doses that are 8–20% greater than the corresponding divalproex total daily doses. Design and subjects: This multiple-dose, fasting, randomised, two-period, crossover design study in 76 subjects with epilepsy taking a concomitant enzyme inducing antiepileptic drug compared the bioavailability of divalproex once every-8-hours regimens with 8–20% higher daily dose divalproex–ER once-daily regimens. Results: The 8–20% higher divalproex–ER once-daily-dose regimens were equivalent, with respect to exposure (area under the concentration-time curve; 1551 vs 1539 mg · h/L), to the corresponding total daily divalproex dose regimens. The divalproex–ER maximum concentration central value was significantly lower (83.3 vs 92.6 mg/L), and the minimum concentration mean was not significantly different (45.8 vs 44.8 mg/L) from the corresponding values for the divalproex regimen. The peak-to-trough fluctuation in plasma concentrations was significantly lower for once-daily divalproex–ER (64%) compared with once-every-8-hours divalproex (79%). The size of the divalproex dose and the presence of a concomitant enzyme-inducing antiepileptic drug did not have a statistically significant effect on divalproex–ER/divalproex relative bioavailability. No adverse event occurred in more than 5% of subjects on either treatment; all were mild or moderate in severity with none resulting in discontinuation. Both tested formulations were well tolerated by the subjects. Conclusion: This study demonstrated that patients with epilepsy taking divalproex may switch to 8–20% higher doses of divalproex–ER and have equivalent valproic acid exposure, lower fluctuation in valproic acid concentrations, and similar tolerability. [ABSTRACT FROM AUTHOR]

Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures" • Careful design from the outset is essential for successful delivery of emergency medicine trials • Bayesian adaptive randomization and analysis an ethical need to optimise study efficiency/safety in emergency trials • Key practical design features included step-forward randomization, "use next" study kits and a protocol assist device • Formulating drugs to maintain blinding can lead to suboptimal dosing in some cases, and has a significant cost implications • Expert independent review of source documents may be essential where diagnosis/classification needs specialists espertise [ABSTRACT FROM AUTHOR]

Post-traumatic epilepsy (PTE) is a life-long complication of traumatic brain injury (TBI). The development of PTE is associated with neurological morbidity and increases the risk of mortality. An aim of EpiBioS4Rx (Epilepsy Bioinformatics Study for Antiepileptogenic Therapy) was to test potential therapies to prevent the development of PTE in the lateral fluid percussion injury (LFPI) rat model of TBI, in which rats were subjected to injury at the left parietal cortex. Sodium selenate has been reported to be antiepileptogenic post-TBI in rodent models by activating protein phosphatase 2A and reducing phosphorylated tau (p-tau) protein. We aimed to characterize the pharmacokinetics (PK) and brain uptake of sodium selenate using naïve control and LFPI rats. Rats received either a single bolus dose or a single bolus dose followed by a 7-day subcutaneous minipump infusion of sodium selenate. Sodium selenate and selenium concentrations in plasma and brain were analyzed and used for PK estimation and brain exposure assessment. Selenium concentrations rapidly increased after sodium selenate administration, demonstrating biotransformation from sodium selenate to selenium. Sodium selenate and selenium PK parameters were estimated using non-compartmental analysis. Sodium selenate clearance (CL/F) and volume of distribution (V d /F) varied by dose and route of administration, suggesting differences in bioavailability and nonlinear pharmacokinetics at the doses tested. Brain-to-plasma partition coefficients (AUC brain /AUC plasma ) for sodium selenate and selenium were found to be 0.7-1.3 and 0.1-0.3 following single-dose injection, respectively, indicating active transport of sodium selenate across the blood-brain barrier (BBB)., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser 202 /Thr 205 -immunoreactivity (AT8-ir) and pTAU-Ser 199/202 -ir at 2 days, and pTAU-Thr 231 -ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.

Post-traumatic epilepsy (PTE) occurs in some patients after moderate/severe traumatic brain injury (TBI). Although there are no approved therapies to prevent epileptogenesis, levetiracetam (LEV) is commonly given for seizure prophylaxis due to its good safety profile. This led us to study LEV as part of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Project. The objective of this work is to characterize the pharmacokinetics (PK) and brain uptake of LEV in naïve control rats and in the lateral fluid percussion injury (LFPI) rat model of TBI after either single intraperitoneal doses or a loading dose followed by a 7-day subcutaneous infusion. Sprague-Dawley rats were used as controls and for the LFPI model induced at the left parietal region using injury parameters optimized for moderate/severe TBI. Naïve and LFPI rats received either a bolus injection (intraperitoneal) or a bolus injection followed by subcutaneous infusion over 7 days. Blood and parietal cortical samples were collected at specified time points throughout the study. LEV concentrations in plasma and brain were measured using validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods. Noncompartmental analysis and a naive-pooled compartmental PK modeling approach were used. Brain-to-plasma ratios ranged from 0.54 to 1.4 to 1. LEV concentrations were well fit by one-compartment, first-order absorption PK models with a clearance of 112 ml/h per kg and volume of distribution of 293 ml/kg. The single-dose pharmacokinetic data were used to guide dose selection for the longer-term studies, and target drug exposures were confirmed. Obtaining LEV PK information early in the screening phase allowed us to guide optimal treatment protocols in EpiBioS4Rx. SIGNIFICANCE STATEMENT: The characterization of levetiracetam pharmacokinetics and brain uptake in an animal model of post-traumatic epilepsy is essential to identify target concentrations and guide optimal treatment for future studies., (Copyright © 2023 by The Author(s).)

The lack of reliable biomarkers is a significant challenge impeding progress in orphan drug development. For appropriate interpretation of intervention-based results or for evaluating candidate biomarkers, other things being equal, lower variability in biomarker measurement would be helpful. However, variability in rare disease biomarkers is often poorly understood. Type 1 Gaucher disease (GD1) is one such rare lysosomal storage disorder. Oxidative stress and inflammation have been linked to the pathophysiology of GD1 and validated measures of these processes can provide predictive value for treatment success or disease progression. This study was undertaken to investigate and compare the extent of longitudinal biological variation over a three-month period for various blood-based oxidative stress and inflammation markers in participants with GD1 on stable standard-of-care therapy (N = 13), treatment-naïve participants with GD1 (N = 5), and in age- and gender-matched healthy volunteers (N = 18). We utilized Bland-Altman plots for visual comparison of the biological variability among the three measurements. We also report group-wise means and the percentage of coefficient of variation (%CV) for 15 biomarkers. Qualitatively, we show specific markers (IL-1Ra, IL-8, and MIP-1b) to be consistently altered in GD1, irrespective of therapy status, highlighting the need for adjunctive therapies that can target and modulate these biomarkers. This information can help guide the selection of candidate biomarkers for future intervention-based studies in GD1 patients.

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate drug development. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early-stage clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases., (© 2021 British Pharmacological Society.)

Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABA A receptors. We hypothesize that ALLO may be useful as first-line treatment of status epilepticus (SE). Our objectives were to (1) characterize ALLO pharmacokinetics-pharmacodynamics PK-PD after intravenous (IV) and intramuscular (IM) administration and (2) compare IV and IM ALLO safety and tolerability. Three healthy dogs and two with a history of epilepsy were used. Single ALLO IV doses ranging from 1-6 mg/kg were infused over 5 minutes or injected IM. Blood samples, vital signs, and sedation assessment were collected up to 8 hours postdose. Intracranial EEG (iEEG) was continuously recorded in one dog. IV ALLO exhibited dose-proportional increases in exposure, which were associated with an increase in absolute power spectral density in all iEEG frequency bands. This relationship was best described by an indirect link PK-PD model where concentration-response was described by a sigmoidal maximum response (E max ) equation. Adverse events included site injection pain with higher IM volumes and ataxia and sedation associated with higher doses. IM administration exhibited incomplete absorption and volume-dependent bioavailability. Robust iEEG changes after IM administration were not observed. Based on PK-PD simulations, a 2 mg/kg dose infused over 5 minutes is predicted to achieve plasma concentrations above the EC 50 , but below those associated with heavy sedation. This study demonstrates that ALLO is safe and well tolerated when administered at 1-4 mg/kg IV and up to 2 mg/kg IM. The rapid onset of effect after IV infusion suggests that ALLO may be useful in the early treatment of SE. SIGNIFICANCE STATEMENT: The characterization of the pharmacokinetics and pharmacodynamics of allopregnanolone is essential in order to design clinical studies evaluating its effectiveness as an early treatment for status epilepticus in dogs and people. This study has proposed a target dose/therapeutic range for a clinical trial in canine status epilepticus., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C22:0) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether N -acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C26:0, 1-100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C26:0 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C26:0 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C26:0-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.

N-acetylcysteine (NAC) has been used in patients with cerebral adrenoleukodystrophy as an antioxidant agent in association with hematopoietic stem cell transplant (HSCT). However, an understanding of the pharmacokinetic characteristics of intravenous NAC dosing in these patients is limited. If and how NAC pharmacokinetics change following the transplant is unknown. Toward that end, a total of 260 blood samples obtained from 18 pediatric patients with inherited metabolic disorders who underwent HSCT were included in a population pharmacokinetic analysis using nonlinear mixed-effects modeling. NAC clearance (CL) and volume of distribution (V) were explored on 3 occasions: -7, +7, and +21 days relative to transplant. Additionally, the effect of transplant procedure on NAC disposition was explored by accounting for between-occasion variability. The covariate OCC was modeled as a fixed-effect parameter on CL and/or V1. A 2-compartment model adequately described the pharmacokinetics of total NAC. Weight-based allometric scaling on pharmacokinetic parameters was assumed using standard coefficients. Estimates for CL, central (V1), and peripheral volume (V2), and intercompartment clearance were 14.7 L/h, 23.2 L, 17.1 L, 3.99 L/h, respectively, for a 70-kg person. The data only supported between-subject variability in CL (12%) and V1 (41%). Residual variability was estimated to be 16%. HSCT did not change CL and V1 significantly, and analysis across occasions did not reveal any trends. Pharmacokinetic parameter estimates were in general comparable to those reported previously in different populations. These results suggest that dosing of NAC does not need to be altered following HSCT., (© 2021, The American College of Clinical Pharmacology.)

Objective: We studied physicians' opinions and experiences concerning clinical concerns, perceived severity, occurrence, and management of baclofen withdrawal due to abrupt discontinuation., Methods: A nationwide 26-question electronic survey was distributed via e-mail to physicians (N = 952) representing varying specialties who manage spasticity with baclofen. A total of 110 physicians provided responses to the survey (response rate = 11.6%). Results were evaluated using descriptive statistics., Results: Withdrawal from both oral and intrathecal (IT) baclofen was recognized as a significant concern and was observed by most respondents. However, approximately 75% and 35% of respondents or their clinic sites lack established management protocols for managing anticipated interruption of oral or IT baclofen, respectively., Conclusions: These findings highlight the need for further research on and the development of guidelines for the prevention and treatment of baclofen withdrawal. The results of this survey, along with a systematic literature review and multidisciplinary stakeholder input, may be helpful in establishing guidelines for the treatment and prevention of baclofen withdrawal., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Estimating early exposure of drugs used for the treatment of emergent conditions is challenging because blood sampling to measure concentrations is difficult. The objective of this work was to evaluate predictive performance of two early concentrations and prior pharmacokinetic (PK) information for estimating early exposure. The performance of a modeling approach was compared with a noncompartmental analysis (NCA). A simulation study was performed using literature-based models for phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA). These models were used to simulate rich concentration-time profiles from 0 to 2 h. Profiles without residual unexplained variability (RUV) were used to obtain the true partial area under the curve (pAUC) until 2 h after the start of drug infusion. From the profiles with the RUV, two concentrations per patient were randomly selected. These concentrations were analyzed under a population model to obtain individual population PK (PopPK) pAUCs. The NCA pAUCs were calculated using a linear trapezoidal rule. Percent prediction errors (PPEs) for the PopPK pAUCs and NCA pAUCs were calculated. A PPE within ±20% of the true value was considered a success and the number of successes was obtained for 100 simulated datasets. For PHT, LEV, and VPA, respectively, the median value of the success statistics obtained using the PopPK approach of 81%, 92%, and 88% were significantly higher than the 72%, 80%, and 67% using the NCA approach (p < 0.05; Mann-Whitney U test). This study provides a means by which early exposure can be estimated with good precision from two concentrations and a PopPK approach. It can be applied to other settings in which early exposures are of interest., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition., (© 2020, The American College of Clinical Pharmacology.)

Objective: To quantify the association between early neurologic recovery, practice pattern variation, and endotracheal intubation during established status epilepticus, we performed a secondary analysis within the cohort of patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT)., Methods: We evaluated factors associated with the endpoint of endotracheal intubation occurring within 120 minutes of ESETT study drug initiation. We defined a blocked, stepwise multivariate regression, examining 4 phases during status epilepticus management: (1) baseline characteristics, (2) acute treatment, (3) 20-minute neurologic recovery, and (4) 60-minute recovery, including seizure cessation and improving responsiveness., Results: Of 478 patients, 117 (24.5%) were intubated within 120 minutes. Among high-enrolling sites, intubation rates ranged from 4% to 32% at pediatric sites and 19% to 39% at adult sites. Baseline characteristics, including seizure precipitant, benzodiazepine dosing, and admission vital signs, provided limited discrimination for predicting intubation (area under the curve [AUC] 0.63). However, treatment at sites with an intubation rate in the highest (vs lowest) quartile strongly predicted endotracheal intubation independently of other treatment variables (adjusted odds ratio [aOR] 8.12, 95% confidence interval [CI] 3.08-21.4, model AUC 0.70). Site-specific variation was the factor most strongly associated with endotracheal intubation after adjustment for 20-minute (aOR 23.4, 95% CI 6.99-78.3, model AUC 0.88) and 60-minute (aOR 14.7, 95% CI 3.20-67.5, model AUC 0.98) neurologic recovery., Conclusions: Endotracheal intubation after established status epilepticus is strongly associated with site-specific practice pattern variation, independently of baseline characteristics, and early neurologic recovery and should not alone serve as a clinical trial endpoint in established status epilepticus., Trial Registration Information: ClinicalTrials.gov Identifier: NCT01960075., (© 2021 American Academy of Neurology.)

Objective: This study was undertaken to describe patterns of benzodiazepine use as first-line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second-line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT)., Methods: Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second-line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline-recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second-line agent., Results: Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second-line medications in these benzodiazepine-refractory seizures., Significance: Benzodiazepines as first-line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.)., (© 2021 International League Against Epilepsy.)

The prevalence of non-suicidal self-injury (NSSI) is high in adolescents and young adults. However, there is a paucity of evidence-based treatments to address this clinical problem. An open-label, pilot study in the target population showed that treatment with oral N-acetylcysteine (NAC), a widely available dietary supplement, was associated with reduction in NSSI frequency. In preparation for a biologically informed design of an efficacy trial, a critical preliminary step is to clarify NAC's biological signatures, or measures of the mechanisms underlying its clinical effects. Toward that end, we propose a 2-stage project to investigate NAC's biological signatures (changes in glutathione (GSH) and/or glutamate (Glu)) in women with NSSI. The first stage; a double-blind randomized placebo-controlled study will focus on identifying the optimal dose to achieve meaningful change in GSH and Glu during short-term (4 weeks) NAC treatment in 36 women aged 16-24 years with NSSI. Go/No-go criteria to determine if the study will progress to the second stage include pre-specified changes in brain and blood measures of GSH. Changes in the brain GSH are measured through magnetic resonance spectroscopy (MRS). The dose for the stage 2 will be selected based on the biological changes and the tolerability observed in the stage 1. The stage 2 will seek to replicate the biological signature findings in an 8-week trial in a new patient cohort, and examine the relationships among biological signatures, NAC pharmacokinetics and clinical response. This 2-stage project is unique as it unifies clinical psychiatric measurements, quantitative MRS and pharmacological approaches in the first placebo-controlled clinical trial of NAC in young women with NSSI., Trial Registration: The stage 1 trial protocol has been registered on https://clinicaltrials.gov/ with ClinicalTrials.gov ID "NCT04005053" (Registered on 02 July 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT04005053)., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests.

Gaucher disease is an autosomal recessive metabolic disorder caused by mutations in GBA1 , which encodes for the lysosomal hydrolase enzyme, β-glucocerebrosidase. The resulting misfolded protein can trigger endoplasmic reticulum stress and an unfolded protein response within the affected cells. The enzyme deficiency leads to accumulation of its substrates, glucosylceramide and glucosylsphingosine, within macrophage lysosomes and with prominent disease manifestations in macrophage rich tissues. Resultant lysosomal pathology and impaired autophagy leads to redox imbalance, mitochondrial dysfunction and intracellular oxidative stress. Here we have systematically examined a role for oxidative stress in individuals affected by Gaucher disease. We compared multiple oxidative stress biomarkers in plasma and red blood cell samples from patients who are currently untreated, with those who are stable on standard-of-care therapy, and with healthy controls. We found significant differences in key oxidative stress biomarkers in untreated patients compared to healthy control. In treated patients, results generally fell between the controls and the untreated patients. Interestingly, even asymptomatic and minimally symptomatic untreated patients had evidence of significant systemic oxidative stress. We conclude that underlying oxidative stress may contribute to Gaucher disease pathophysiology including long-term adverse outcomes such as Parkinsonism and malignancies. Therapies targeting oxidative stress may prove useful as adjuvant treatments for Gaucher disease and other lysosomal storage disorders., Competing Interests: RVK and JCC has received grants from NIH, Sanofi-Genzyme, Pfizer Inc.; NJW has received grants from Sanofi-Genzyme and Takeda-Shire, personal fees from Sanofi-Genzyme, Takeda-Shire and Pfizer Inc., and non-financial support from Sanofi-Genzyme; MRT, RB, AT, KR and JRJ declare no conflict of interest., (© 2020 The Authors.)

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings., (© 2020 International League Against Epilepsy.)

The discovery that patients with Gaucher Disease (GD), a rare lysosomal storage disorder, were developing symptoms similar to Parkinson's disease (PD) led to investigation of the relationship between the two seemingly unrelated pathologies. GD, an autosomal recessive disorder, is the result of a biallelic mutation in the gene GBA1, which encodes for the enzyme glucocerebrosidase (GCase). Since the observation of its relation to PD, GBA1 mutations have become recognized as the most common genetic risk factor for development of synucleinopathies such as PD and dementia with Lewy bodies. Although the exact mechanism by which GBA1 mutations promote PD is unknown, current understanding suggests that impaired GCase inhibits lysosomal activity and decreases the overall ability of the cell to degrade proteins, specifically the neuronal protein α-synuclein. Decreased elimination of α-synuclein can lead to its abnormal accumulation and aggregation, an important component of PD development. Further understanding of how decreased GCase activity increases risk for α-synuclein pathology can assist with the development of clinical biomarkers for early detection of synucleinopathies, as well as promote novel treatments tailored for people with a GBA1 mutation. Historically, α-synuclein has not been a reliable biomarker for PD. However, recent research on α-synuclein content within exosomes, which are small vesicles released by cells that carry specific cellular cargo, has yielded encouraging results. Moreover, decreased GCase activity has been shown to influence exosomal contents. Exosomes have emerged as a promising new avenue for the identification of novel biomarkers and therapeutic targets aimed at improving neuronal GCase function and limiting the development of synucleinopathies., Competing Interests: Declaration of competing interest PJ declare no conflict of interest. RVK have received grants from NIH, Pfizer Inc. and Sanofi-Genzyme outside of this work. JCC have received grants from NIH, Pfizer Inc. and Sanofi-Genzyme outside of this work. PJT has received grants from NIH, Parkinson Study Group, Northwestern University, Biogen Inc., and Bristol-Myers Squibb. NJW has received grants from Sanofi-Genzyme and Takeda-Shire, personal fees from Sanofi-Genzyme, Takeda-Shire and Pfizer Inc., and non-financial support from Sanofi-Genzyme., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Intranasal administration is an attractive route for systemic delivery of small, lipophilic drugs because they are rapidly absorbed through the nasal mucosa into systemic circulation. However, the low solubility of lipophilic drugs often precludes aqueous nasal spray formulations. A unique approach to circumvent solubility issues involves coadministration of a hydrophilic prodrug with an exogenous converting enzyme. This strategy not only addresses poor solubility but also leads to an increase in the chemical activity gradient driving drug absorption. Herein, we report plasma and brain concentrations in rats following coadministration of a hydrophilic diazepam prodrug, avizafone, with the converting enzyme human aminopeptidase B Single doses of avizafone equivalent to diazepam at 0.500, 1.00, and 1.50 mg/kg were administered intranasally, resulting in 77.8% ± 6.0%, 112% ± 10%, and 114% ± 7% bioavailability; maximum plasma concentrations 71.5 ± 9.3, 388 ± 31, and 355 ± 187 ng/ml; and times to peak plasma concentration 5, 8, and 5 minutes for each dose level, respectively. Both diazepam and a transient intermediate were absorbed. Enzyme kinetics incorporated into a physiologically based pharmacokinetic model enabled estimation of the first-order absorption rate constants: 0.0689 ± 0.0080 minutes -1 for diazepam and 0.122 ± 0.022 minutes -1 for the intermediate. Our results demonstrate that diazepam, which is practically insoluble, can be delivered intranasally with rapid and complete absorption by coadministering avizafone with aminopeptidase B. Furthermore, even faster rates of absorption might be attained simply by increasing the enzyme concentration, potentially supplanting intravenous diazepam or lorazepam or intramuscular midazolam in the treatment of seizure emergencies., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

The low aqueous solubility of diazepam (DZP) presents a challenge in formulating nasal sprays without the use of organic solvents. One approach to overcome this challenge involves co-administration of a soluble prodrug, avizafone (AVF), with a converting enzyme to produce supersaturated DZP at the site of administration. In addition to overcoming solubility issues, the supersaturated state of DZP provides an increased driving force for enhanced permeation across nasal mucosa. However, supersaturated solutions are metastable, and there is a limit to the degree of supersaturation (S) that can be reached without causing spontaneous phase separation of the solute. The aim of this article was to determine how formulation parameters affect the rate of DZP supersaturation, maximum degree of supersaturation, and phase separation kinetics. A model enzyme, Aspergillus oryzae protease (AOP), was used to convert AVF to DZP, via an open ring intermediate (ORI). A second derivative UV spectroscopic method was developed to simultaneously monitor DZP solution concentration and the time course of DZP phase separation. Fitting a kinetic model, with prior knowledge of the enzyme kinetic parameters, the rate constant for conversion of ORI to DZP was found to be 0.470 ± 0.012 min -1 . Kinetics and supersaturated solution stability were studied as a function of formulation parameters, including temperature, pH, buffering agent, AVF concentration, and enzyme concentration. The maximum aqueous solution concentration for DZP at 32 °C was determined to be 1.22 ± 0.03 mM DZP (S = 9.38) and was insensitive to changes in formulation parameters, excepting temperature. Supersaturated solutions of DZP could be maintained at the maximum concentration for >24 h, even in the presence of phase separated DZP. Polarized light microscopy, PXRD, and DSC analysis indicated that the phase separated DZP was amorphous upon formation and remained so for >24 h. Our findings suggest that co-administration of AVF with a suitable human converting enzyme will provide a viable mechanism for IN delivery of DZP and result in very rapid and complete absorption to quickly terminate seizure emergencies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Abrupt discontinuation of baclofen can result in a potentially severe withdrawal syndrome. The current treatment for baclofen withdrawal is inadequate, resulting in a critical need to develop an alternative method to prevent or treat this withdrawal syndrome., Objective: To evaluate the safety profile and pharmacokinetics of oral (PO) and investigational intravenous (IV) baclofen formulations at clinically relevant doses., Design: Randomized, open-label, dose-escalation, crossover study., Setting: Contract Research Organization (CRO)., Methods: Three cohorts of 12 healthy adults received single doses of PO baclofen (10 mg, 15 mg or 20 mg) and 10-minute infusions of IV baclofen (7.5 mg, 11.5 mg, or 15 mg) with a minimum 48-hour wash-out period. The third cohort also received a 60-minute infusion of 15 mg IV baclofen after an additional 48-hour wash-out period., Main Outcome Measures: Subjects were observed in a CRO for 24 hours after each dose of baclofen, and were assessed for nystagmus, ataxia, and sedation. Blood samples were collected from 0 to 24 hours and analyzed for baclofen concentration using high-performance liquid chromatography-mass spectroscopy. Noncompartmental pharmacokinetic analyses were performed. Dose linearity and proportionality was assessed using 2-way repeated-measures analysis of variance and a power model analysis., Results: None of the PO or IV doses resulted in significant sedation compared to baseline. All subjects could perform tandem gait after each baclofen dose. The most common side effect, transient mild nystagmus, was noted in 4 of 36 and in 13 of 36 subjects after PO and IV administration, respectively. This was likely related to increased maximum concentrations (C max ). After the 20 mg PO and 15 mg IV doses, mean C max levels were 255 and 722 ng/mL and half-lives were 5.24 and 5.79 hours for PO and IV baclofen, respectively. The mean oral bioavailability for the 20-mg PO dose was approximately 80%., Conclusions: All PO and IV doses of baclofen were well tolerated clinically. The 80% bioavailability suggests that a 20% reduction in IV dose will produce comparable total drug exposures to that of the PO dose. When PO therapy is interrupted, bridging with IV baclofen may be feasible., Level of Evidence: II., (Copyright © 2017 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Epileptic seizure emergencies are life-threatening conditions, which in their most severe form, status epilepticus, have a high mortality rate if not quickly terminated. Treatment requires rapid delivery of anti-epileptics such as benzodiazepines to the brain. The nasal route is attractive due to its non-invasiveness, potential for direct nose to brain delivery, high vascularity, relatively large absorptive surface area, and avoidance of intestinal/liver metabolism. However, the limited volume of the nasal cavity and poor water solubility of anti-epileptics restrict absorption, leading to insufficient therapeutic brain levels. This review covers various formulation approaches adopted to improve nasal delivery of drugs, especially benzodiazepines, used to treat seizure emergencies. Other general topics such as nasal anatomy, challenges to nasal delivery, and drug/formulation considerations for nose to brain delivery are also discussed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background and Objective: Carbamazepine is a potent inducer of drug metabolizing enzymes, which results in a number of clinically significant drug-drug interactions. Deinduction occurs when long-term carbamazepine therapy is discontinued. The goal of this study was to develop a population pharmacokinetic model to describe the time course of carbamazepine deinduction., Patients and Methods: Stable-labelled carbamazepine was administered intravenously on three occasions during the deinduction period to 15 patients with epilepsy for whom carbamazepine therapy was being discontinued. Data were analysed using a nonlinear mixed-effects model (NONMEM). An enzyme turnover model consisting of a one-compartment model linked with a hypothetical enzyme compartment was applied to characterize the time course of carbamazepine deinduction. Model evaluation was performed using the bootstrap approach and a visual predictive check., Results: In the final model, the deinduction process was accomplished by decreasing the rate of enzyme synthesis, resulting in a decrease in the relative amount of enzymes. The estimated rate constant for enzyme degradation was 0.00805 h-1, corresponding to a half-life of the combined enzymes of 86.1 hours (3.6 days)., Conclusion: An enzyme turnover model adequately characterized the experimental data. Based on the predicted enzyme half-life from the final model, the deinduction process should be completed within 2 weeks after carbamazepine therapy is terminated.

Because aging is associated with changes in physiological processes, it is widely believed that antiepileptic drug pharmacodynamics and pharmacokinetics in elderly patients differ from those in younger adults. In order to better characterize these differences, this chapter reports on preliminary results from an investigation of the effect of age on steady-state phenytoin (PHT) and carbamazepine (CBZ) pharmacokinetics. Parenteral formulations of stable-labeled PHT, fosphenytoin (FOS), and CBZ were administered to elderly (> or =65 years of age) and adult (18-64 years of age) patients on maintenance regimens of PHT or CBZ; a labeled 100-mg dose was infused over 10 min, then the remainder of the patient's AED dose was administered as unlabeled drug. Blood samples were collected just before administration of the labeled drug and for up to 192 h afterward. Samples were then assayed for the concentrations of labeled and unlabeled drug. Preliminary results from 60 patients on PHT therapy (41 elderly, mean age 76 years; 19 younger adults, mean age 41 years) indicate that PHT bioavailability did not differ between the two age groups; however, absorption and elimination half-lives were more variable in the elderly patients. The elimination half-life for the entire patient population was approximately twofold longer than the value reported in the product labeling (40-50 h vs 22 h). Preliminary results from 67 patients on CBZ therapy (14 elderly, mean age 70 years; 53 younger adults, mean age 41 years) showed no apparent difference between elderly and adult patients in any parameter; however, the mean CBZ elimination half-life for the combined groups (21 h) was longer than previous estimates. These results indicate that the effect of age on CBZ and PHT absorption may result in greater variability in plasma concentrations in elderly patients, whereas the effect on half-life is modest.

Background and Objective: Maintenance of effective drug concentrations is essential for adequate treatment of epilepsy. Some antiepileptic drugs can be successfully administered rectally when the oral route of administration is temporarily unavailable. Oxcarbazepine is a newer antiepileptic drug that is rapidly converted to a monohydroxy derivative, the active compound. This study aimed to characterise the bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension using a randomised, crossover design in ten healthy volunteers., Methods: Two subjects received 300 mg doses of oxcarbazepine suspension via rectal and oral routes and eight received 450 mg doses. A washout period of at least 2 weeks elapsed between doses. The rectal dose was diluted 1:1 with water. Blood samples and urine were collected for 72 hours post-dose. Adverse effects were assessed at each blood collection time-point using a self-administered questionnaire. Plasma was assayed for oxcarbazepine and monohydroxy derivative; urine was assayed for monohydroxy derivative and monohydroxy derivative-glucuronide. Maximum plasma concentration (C(max)) and time to reach C(max) (t(max)) were obtained directly from the plasma concentration-time curves. The areas under the concentration-time curve (AUCs) were determined via non-compartmental analysis. Relative bioavailability was calculated and the C(max) and AUCs were compared using Wilcoxon signed-rank tests., Results: Mean relative bioavailability calculated from plasma AUCs was 8.3% (SD 5.5%) for the monohydroxy derivative and 10.8% (SD 7.3%) for oxcarbazepine. Oxcarbazepine and monohydroxy derivative C(max) and AUC values were significantly lower following rectal administration (p < 0.01). The total amount of monohydroxy derivative excreted in the urine following rectal administration was 10 +/- 5% of the amount excreted following oral administration. Oral absorption was consistent with previous studies. The most common adverse effects were headache and fatigue with no discernible differences between routes., Conclusions: Monohydroxy derivative bioavailability following rectal administration of oxcarbazepine suspension is significantly lower than following oral administration, most likely because of poor oxcarbazepine water solubility. It is unlikely that adequate monohydroxy derivative concentrations can be achieved with rectal administration of diluted oxcarbazepine suspension.