Intranasal Naloxone During Recurrent Exercise in Individuals with Type-1 Diabetes Mellitus: Evaluation of the Clinical Predictors of Pharmacokinetics and Exposure-Response.

Impaired awareness of hypoglycemia (IAH) impacts 25%-30% of individuals with type 1 diabetes mellitus (T1D), potentially leading to severe outcomes due to reduced symptom perception. Naloxone, a mu-opioid receptor antagonist, shows promise as a preventive measure against IAH. This study explored intranasal (IN) naloxone as a potential therapy to preserve counterregulatory and symptom responses to hypoglycemia following exercise in T1D patients.

Efficacy and tolerability of celastrol and edaravone in the multiple-hit rat model of infantile spasms.

Objective: To test whether anti-inflammatory and antioxidant drugs that inhibit the nuclear factor kappa light chain enhancer of activated B cells (NF-kB), celastrol and edaravone, suppress spasms and improve developmental outcomes in the multiple-hit rat model of refractory infantile spasms (IS) due to structural lesions.

Methods: Postnatal day 3 (PN3) Sprague-Dawley rats were treated according to the multiple-hit IS model protocol. Using a randomized, blinded, vehicle-controlled, dose- and time-response study design, we tested the effects of single celastrol [1, 2, or 4 mg/kg intraperitoneally (i.

Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.

Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia.

Levetiracetam Pharmacokinetics and Brain Uptake in a Lateral Fluid Percussion Injury Rat Model.

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.

Intravenous and Intramuscular Allopregnanolone for Early Treatment of Status Epilepticus: Pharmacokinetics, Pharmacodynamics, and Safety in Dogs.

Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABA 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.

Characterizing Baclofen Withdrawal: A National Survey of Physician Experience.

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.

Population Pharmacokinetic Analysis of N-Acetylcysteine in Pediatric Patients With Inherited Metabolic Disorders Undergoing Hematopoietic Stem Cell Transplant.

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.

Early Neurologic Recovery, Practice Pattern Variation, and the Risk of Endotracheal Intubation Following Established Status Epilepticus.

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.

A pharmacokinetic simulation study to assess the performance of a sparse blood sampling approach to quantify early drug exposure.

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).

Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial.

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.

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High-Dose Intravenous Administration in Young Children With Benzodiazepine-Refractory Status Epilepticus.

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.

Infusion of N-acetyl cysteine during hypoglycaemia in humans does not preserve the counterregulatory response to subsequent hypoglycaemia.

Aim: Administration of N-acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans.

Methods: This was a randomized double-blind cross over study where humans were given either a 60-minute infusion of NAC (150 mg/kg) followed by a 4-hour infusion of NAC (50 mg/kg) or saline starting 30 minutes before the initiation of a 2-hour hypoglycaemic (HG) clamp at 8 am. After rest at euglycaemia for ~2 hours, subjects were exposed to a 2nd HG clamp at 2 pm and discharged home in euglycaemia.

The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus.

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.

Pharmacokinetics, Safety, and Tolerability of Orally Administered Ursodeoxycholic Acid in Patients With Parkinson's Disease-A Pilot Study.

Mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease. Preliminary data have shown lower brain adenosine triphosphate (ATP) levels in Parkinson's disease versus age-matched healthy controls. Ursodeoxycholic acid (UDCA) may improve impaired mitochondrial function.

Lessons from the Established Status Epilepticus Treatment Trial.

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.

Intranasal Coadministration of a Diazepam Prodrug with a Converting Enzyme Results in Rapid Absorption of Diazepam in Rats.

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.

Rescue therapies for seizure emergencies: New modes of administration.

A subgroup of patients with drug-resistant epilepsy have seizure clusters, which are a part of the continuum of seizure emergencies that includes prolonged episodes and status epilepticus. When the patient or caregiver can identify the beginning of a cluster, the condition is amenable to certain treatments, an approach known as rescue therapy. Intravenous drug administration offers the fastest onset of action, but this route is usually not an option because most seizure clusters occur outside of a medical facility.

Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress.

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).

Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy.

Rationale: Barriers to developing treatments for human status epilepticus include the inadequacy of experimental animal models. In contrast, naturally occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics of an intravenous (IV) dose of topiramate (TPM) in dogs with epilepsy and evaluate its effect on intracranial electroencephalographic (iEEG) features.

A Randomized Dose Escalation Study of Intravenous Baclofen in Healthy Volunteers: Clinical Tolerance and Pharmacokinetics.

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.

Intravenous Administration of Stable-Labeled N-Acetylcysteine Demonstrates an Indirect Mechanism for Boosting Glutathione and Improving Redox Status.

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.

Canine status epilepticus treated with fosphenytoin: A proof of principle study.

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.