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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.

Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different ( P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures.

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.

Diazepam rectal gel (Diastat(®)) is the only FDA-approved product indicated for acute repetitive seizures. Despite its proven efficacy, most older children and adults object to this route of administration. As a result, many patients do not realize the benefit of a therapy that can improve outcomes and decrease healthcare costs. Intranasal administration of benzodiazepines offers a potential alternative. The primary objective of this study was to compare the bioavailability and pharmacokinetics of two novel intranasal (IN) diazepam (DZP) formulations versus intravenous (IV) administration in healthy volunteers. Twenty-four healthy volunteers were randomized into an open-label, three-way crossover study. 10mg doses of two investigational intranasal DZP formulations (solution, suspension) and a 5mg IV dose of commercially available DZP injectable, USP were given. A two-week washout period separated treatments. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 240 h post-dose. DZP concentration-time data were analyzed using a non-compartmental pharmacokinetics approach. Exposure following administration of DZP IN solution (absolute bioavailability - 97%) was greater than the IN suspension (absolute bioavailability - 67%). Mean Cmaxvalues for the suspension and solution formulations were 221 ng/mL and 272 ng/mL, respectively. Median time to maximum concentration (Tmax) was 1h and 1.5h for suspension and solution formulation, respectively. Both investigational intranasal formulations were well tolerated. The results of this pilot study indicate that development of an intranasal diazepam formulation with high bioavailability, reasonable variability, and good tolerability is feasible.

Summary 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 WinNonlin 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.

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

OBJECTIVE Assess safety and tolerance of intravenous (IV) baclofen using a dog model. DESIGN Prospective pharmacokinetic study involving 6 adult dogs. Two dogs received baclofen 10 mg oral and IV bolus doses. Subsequent 4 dogs were given IV boluses of 0.5, 1.0 and 1.5 mg/kg followed by constant infusion of baclofen (rates of 0.1, 0.2 and 0.4 mg/kg/hour). Also, dogs were given single IV 2 and 3 mg /kg bolus doses. Outcome measures included clinical observation scales and baclofen levels. RESULTS Oral bioavailability was 0.66 and 0.69 in 2 dogs. Following IV baclofen, terminal phase half-lives were 3.3 and 3.6 hours. Single bolus doses of 2 and 3 mg/kg caused mild to moderate clinical changes which were delayed at least 2 hours after peak blood levels. Boluses of 0.5 and 1.0 mg/kg with constant infusion between boluses were tolerated, however within 30 minutes of beginning constant infusion of 0.2 mg/kg/hr after the second bolus (1.0 mg/kg), dogs showed progressive sedation and ataxia. Clinical improvement occurred within 7 hours of stopping baclofen. Dogs appeared normal by the next morning. CONCLUSIONS IV baclofen bolus doses of 0.5 to 3 mg/kg were well tolerated. Maximum clinical effect was delayed for at least 2 hours after peak plasma levels.

Aim To determine whether intrathecal baclofen (ITB) changes mortality risk in persons with cerebral palsy (CP). Method Records were reviewed for all persons with CP who were managed with ITB for hypertonicity at a specialty hospital in Minnesota between May 1993 and August 2007. A comparison cohort was randomly selected from clients of the California Department of Developmental Services who were initially evaluated between 1987 and 1990 and were matched to those with ITB for age, sex, Gross Motor Function Classification System (GMFCS) level, presence or absence of epilepsy, and feeding-tube use. Survival probabilities were estimated using the Kaplan–Meier method, and differences were tested via log-rank. Results Three hundred and fifty-nine persons with CP (202 males, 157 females) receiving ITB for hypertonicity (mean age 12y 8mo, SD 7y 9mo, range 3y 1mo to 39y 9mo) were matched to 349 persons without ITB pumps (195 males, 154 females; mean age 12y 7mo, SD 8y 4mo, range 2y 7mo to 40y). The proportion of patients at different GMFCS levels in the ITB and in the non-ITB cohorts, respectively, was as follows: level II 3% and 3%, level III 16% and 16%, level IV 38% and 37%, and level V 43% and 44%. Survival at 8 years of follow-up was 92% (SD 1.9%) in the ITB cohort and 82% (SD 2.4%) in the non-ITB cohort (p

The objective of the present study was to understand the clinical reasons for changes from simple continuous to complex (flex) dosing for tone reduction in individuals receiving intrathecal baclofen. Methodology was a retrospective chart review study of 164 individuals (95 male, 69 female) at a multi-specialty children's hospital who were followed for at least 1 year for intrathecal baclofen management. Eighty-two persons were in the simple continuous only group and 82 also were on complex schedules at least once during the follow-up period. Mean age at most recent follow-up was 18 years and 0 months (median, 15 years and 8 months; standard deviation, 8 years and 0 months; range, 6-45). The top three clinical reasons for switching dosing method were to (1) optimize intrathecal baclofen effect, (2) treat predictable daily tone variation, and (3) manage signs and symptoms of intrathecal baclofen withdrawal or underdelivery. In both groups, 90% of individuals had cerebral palsy, and mean baseline leg Ashworth scores were the same in both groups (mean, 3.7; standard deviation, 0.7). Mean total daily dose at chart review was higher in complex dosing (429.3 vs 211.9 microg/day), as was mean follow-up time (4.8 vs 3.9 years). Case examples are presented.

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 300mg doses of oxcarbazepine suspension via rectal and oral routes and eight received 450mg 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 (Cmax) and time to reach Cmax (tmax) 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 Cmax 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 Cmax 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.

The purpose of this study was to assess whether there is an improvement in motor function in persons with cerebral palsy (CP) who have had a reduction of muscle tone by continuous intrathecal baclofen infusion. This was a prospective, open label, non-blinded case series without a control group, conducted at multiple centres. There were 31 subjects, aged 4-29 years. All had a pre-treatment mean lower extremity Ashworth scores ofor= 3 and a significant reduction in tone after a bolus injection of intrathecal baclofen (ITB) and received an implanted pump for continuous delivery of ITB. Motor function was assessed by the Gross Motor Function Measure (GMFM) prior to and 1 year following pump implantation. Significant improvement (p0.05) in mean GMFM scores was seen in subjects8 years (mean change 4.1) and in those from 8-18 years (mean change 3.7) and in subjects with CP Classes 2 and 5 (mean changes 6.2 and 2.9). There was a statistically significant decrease (p0.05) in Ashworth scores in CP classes 2-5. Subjects or their caregivers that completed a survey about perceived changes stated that motor control, positioning and endurance improved.

Summary: Purpose: To assess safety of diazepam rectal gel (DZPRG) for control of acute seizures in epilepsy patients and to evaluate tolerance with repeated use of DZPRG at intervals of ≤5 days. Methods: Subjects were persons with epilepsy, age 2 years or older, with seizure clusters or prolonged seizures. Onset of a treatable episode was defined; caregivers were trained to administer DZPRG and to monitor respiration, seizures, and adverse effects (AEs). DZPRG was dispensed in a single-use, prefilled syringe; dosage was determined by age and weight. Maximal use was ≤5-day intervals, ≥5 times/month. After use, caregivers returned data booklets and syringe. Caregivers and physicians completed global ratings yearly. Results: In 149 subjects treated, 77% of 1,578 administrations resulted in seizure freedom for the next 12 h. One hundred twenty-five received two or more treatments (two to 78; median, 8), 0.03–4.3/month (median, 0.4). To evaluate tolerance, subjects with two or more episodes were divided into low (two to seven episodes) and high use (eight to 78 episodes treated). There was no difference in proportion seizure free 12 h after the first administration versus last administration, for either infrequent or frequent administration. Sedation occurred in 17%, attributed to DZPRG in 9%. No respiratory depression was attributable to DZPRG. Three subjects withdrew because of AEs attributable to (agitation) or possibly attributable to DZPRG (chest pain, rash). Five subjects withdrew because of AEs unrelated to DZPRG. Caregiver and physician global ratings were highly positive at both 12 and 24 months. Conclusions: DZPRG is safe and effective in children and adults with epilepsy with breakthrough seizures. Neither tolerance nor significant medication-related AEs were seen with repeated DZPRG administration at intervals ≤5 days.

The purpose of these investigations was to determine from combined data the response to rectal diazepam (DZP) gel (Diastat [Athena Neurosciences, South San Francisco, CA]) in home treatment of children with episodes of acute repetitive seizures (ARS). A subset of patients aged 2-17 years were selected from two prospective placebo-controlled studies of children and adults. In both studies a prospective, double-blind, placebo-controlled design was used. The treatment groups (68 DZP; 65 placebo) did not differ significantly in age, race, seizure type or etiology, or in the median number of ARS episodes per month before study entry. DZP-treated children demonstrated a significant reduction in median seizure frequency compared with the placebo group (0.00 vs 0.25 seizures per hour, P = 0.001). Significantly more DZP-treated children remained seizure free during the observation period (40 vs 20, P = 0.001). Somnolence was the only adverse effect present significantly more often in the DZP-treated children (25.0% vs 7.7%, P = 0.0095). There were no instances of serious respiratory depression. Rectal DZP was demonstrated to be an effective and safe treatment to abort an episode of ARS in a child and, additionally, lessened the likelihood of seizure recurrence within the next 12 hours.

Objective: To evaluate the effectiveness and safety of a single-dose treatment for acute repetitive seizure (ARS) episodes (e.g., clusters) administered in a nonmedical setting by caregivers. Background: Patients with epilepsy may experience ARS episodes despite optimal anticonvulsant treatment. Such episodes require rapid treatment as medical emergencies. Typically, the patient is treated in an emergency medical setting with IV medication by trained medical personnel. Methods: The authors undertook a multicenter, randomized, parallel, double-blind study of a single administration of Diastat (diazepam rectal gel) for treating episodes of ARS. ARS episodes and treatment criteria were defined for each patient at the start of the study. Caregivers were taught to determine ARS episode onset, administer a predetermined dose of study medication, monitor outcome, count respirations, and record seizures and adverse events. Results: A total of 29 centers enrolled 158 patients, of whom 114 patients had a treated ARS episode (Diastat, n = 56; placebo, n = 58). Diastat treatment reduced median seizure frequency ( p = 0.029). More Diastat patients were seizure free post-treatment (Diastat, 55%; placebo, 34%; p = 0.031). Kaplan-Meier analysis of the time to the next seizure favored Diastat treatment ( p Conclusion: Administration of a single rectal dose of Diastat was significantly more effective than placebo in reducing the number of seizures following an episode of ARS. Caregivers could administer treatment safely and effectively in a nonmedical setting.

This study describes the characteristics of children who had central autonomic dys function (CAD) after acquired brain injury. CAD was defined as an unexplained increase in body temperature, blood ...

Objectives. Despite significant advances in automatic garage door opener design, automatic garage door openers continue to severely injure or kill children. In this investigation, we sought to determine the frequency and circumstances of accidents that have caused severe injury or death to children. We also tried to develop a means by which homeowners can evaluate their door openers. Methods. We present the histories of three children severely injured or killed by automatic garage door openers. We reviewed national data of similar accidents primarily published by the US Product Safety Commission and Underwriters Laboratories. Also, we evaluated 50 automatic door openers for safety of operation. The reversing mechanisms of door openers were tested using a cardiopulmonary resuscitation mannequin, a roll of paper towels, and a block of wood. Results. In the United States, at least 85 children have had permanent brain injury or have died since 1974 as a result of accidents involving automatic door openers. A review of circumstances of the accidents illustrates that accidents are caused both by use of the openers by children and by faults in design. Most accidents have occurred when children have found access to the activation devices and have been entrapped under closing doors that failed to reverse. However, in one case, an adult activated the opener and left the premises before the door completely closed. Our evaluation of 50 garage door openers showed that although 88% percent reversed when encountering a block of wood, 40% failed to reverse when coming down on a supine, child-sized cardiopulmonary resuscitation mannequin. Conclusions. Automatic garage door openers pose a serious risk of severe injury or death to children. It is probable that many doors would not reverse if they came down on a young child. Therefore, we have devised a way for homeowners to test their door openers that closely mimics our evaluations using the mannequin by using a large roll of paper towels. If the door fails to reverse using this test, we suggest that homeowners disconnect their openers and operate the doors manually until the openers are serviced or replace their automatic openers with one that meets the latest Underwriters Laboratory standards. We also have other recommendations regarding the safe operation of the doors, including improving the safety standards for openers in apartment complexes. Compliance with these recommendations should reduce the number of injuries to children caused by garage door openers.

The purpose of this investigation was to determine the effect of the use of valproate (VPA) on bleeding and requirement for replacement blood products in patients undergoing major surgical procedures. One hundred thirty-nine patients had posterior spinal fusion performed by 1 of 3 surgeons at our institution from 1987 to 1993. The clinical status of the patient, pre- and postoperative laboratory values, type and extent of instrumentation, surgeon performing the procedure, and medications (including VPA) were variables considered. The outcome measures were intra- and postoperative blood loss and number of blood products used. Intraoperative blood loss was correlated with the method of instrumentation, platelet count, and the surgeon performing the procedure. Postoperative blood loss was correlated with the diagnosis of cerebral palsy. By hierarchical stepwise regression analysis, the only outcome measure correlated with VPA was the number of blood products used.

Summary 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.

The regaining of language skills in thirty children unconscious for ninety days or more following acquired brain injury is reported. Although language skills were limited in twenty-six children, four children with closed head injuries were sufficiently function al to be placed in mainstream classes. The recovery of language was correlated with cause of injury—children with closed head injuries were much more likely to regain lan guage. Ten children acquired language more than one year after injury, two at nearly four years after injury. In the four children who were most functional, initial language attempts were observed within 96 to 133 days after injury. Only children with closed head injuries regained higher language skills.

There remains an unmet medical need in the out-of-hospital management of seizure emergencies because older children and adults often refuse treatment with diazepam rectal gel due to social objections. We have previously reported that intranasal diazepam (DZP) administration is feasible, with maximum plasma concentrations (C(max)) and time to maximum concentration (T(max)) that are comparable to rectal DZP; but tolerability was poor. In the present study, the tolerability and pharmacokinetics of two investigational nasal formulations were compared with DZP rectal gel. Twelve healthy volunteers were enrolled into an active-control, double-blind, four-period, crossover pharmacokinetic and tolerability study. Three intranasal treatments (Nas-A 10mg, Nas-B 10mg and Nas-B 13.4 mg) were compared to a 10mg dose of the rectal gel. A single dose of each formulation was administered followed by at least a 14 day washout period. Blood samples for plasma DZP concentration-time characterization were collected pre-dose and at regular intervals to 240 h post-dose. Tolerability and sedation were assessed using visual analog scales. Mean DZP C(max) (±SD) was 181.8 ± 84.16, 151.3 ± 108.1 and 180.7 ± 82.1 ng/mL for Nas-A 10mg, Nas-B 10 and Nas-B 13.4 mg respectively; in comparison the C(max) for the rectal gel was 160.9 ± 109.4 ng/mL. Median T(max) was 0.75 h for all treatments. Both intranasal formulations were well tolerated and exhibited relatively rapid, but variable, absorption with bioavailability of 70-90% relative to DZP rectal gel. This study shows that the development of a well-tolerated nasal formulation is possible and that the rate and extent of absorption approximates that of DZP rectal gel. We conclude that intranasal DZP offers a viable alternative to rectal administration, but enhancement of formulations is needed to improve the extent and consistency of absorption.

The outcome of 25 children who had anoxic or ischemic brain injuries at 2 months to 14 years of age is reported. Follow-up was from 1 to 14 years after injury; causes were near-drowning, 11; suffocation, 7; cardiac arrest, 3; electrocution with cardiac arrest, 2; strangulation, 1; aborted sudden infant death syndrome, 1. All patients were unconscious for at least 24 hours. Of 11 remaining in vegetative states, 5 died. Seven children regained some language skills and are in special education or self-contained classrooms. Seven are profoundly impaired and show only a social smile. Cognitive and motor outcomes were correlated with the severity of injury as indicated by the duration of unconsciousness. All children who regained language skills or the ability to walk were unconscious less than 60 days. Dystonic rigidity was observed in all children who were nonambulatory. Outcome was also correlated with the cause of injury; mortality, cognitive outcome, feeding outcome, and duration of unconsciousness were all worse in children with near-drowning.

The outcomes of 60 children unconscious for 90 days or longer following acquired brain injury are reported. Eight children who died had remained in persistent vegetative states. As expected, most neurologic improvement occurred within the first year after injury, although some delayed improvements were observed. Outcomes were strongly correlated with causes of brain injury. Better cognitive and motor function was observed with nonanoxic injuries. No child in this report with anoxic brain injury regained functional cognitive or motor skills, although 3 became socially responsive. The remarkable contrast with adults following acquired brain injury is the significantly longer survival of children. The only children who died had remained in persistent vegetative states.

Fosphenytoin, a phosphorylated prodrug of phenytoin, is useful for acute seizures, is given by parenteral administration, and has few cardiac and local irritation adverse effects. There is limited experience in the administration of this new agent to newborns, and concern has been raised regarding the conversion of the prodrug to phenytoin. In two low–birth-weight infants, it was observed that fosphenytoin was converted adequately with varying effects on seizure control.

A retrospective medical record review was conducted of 173 consecutive children hospitalized for acquired brain injuries on a specialized pediatric rehabilitation service. The chart review identified children who developed movement disorders with acquired brain injuries: 8 with status epilepticus, 2 with trauma, and 1 with anoxia. Movement disorders were observed more frequently following status epilepticus (8 of 12) than following other causes of acquired brain injury (3 of 161; P = .0001). Four additional children had severe neurologic deficits following status epilepticus but did not develop movement disorders. The 11 patients who developed movement disorders had choreiform movements predominantly. Even though status epilepticus is a clinical phenomenon resulting from a variety of etiologies, the features of movement disorders in these children were strikingly similar. The pathophysiology of this complication is unknown.

To determine whether intrathecal baclofen (ITB) changes mortality risk in persons with cerebral palsy (CP).Records were reviewed for all persons with CP who were managed with ITB for hypertonicity at a specialty hospital in Minnesota between May 1993 and August 2007. A comparison cohort was randomly selected from clients of the California Department of Developmental Services who were initially evaluated between 1987 and 1990 and were matched to those with ITB for age, sex, Gross Motor Function Classification System (GMFCS) level, presence or absence of epilepsy, and feeding-tube use. Survival probabilities were estimated using the Kaplan-Meier method, and differences were tested via log-rank.Three hundred and fifty-nine persons with CP (202 males, 157 females) receiving ITB for hypertonicity (mean age 12y 8mo, SD 7y 9mo, range 3y 1mo to 39y 9mo) were matched to 349 persons without ITB pumps (195 males, 154 females; mean age 12y 7mo, SD 8y 4mo, range 2y 7mo to 40y). The proportion of patients at different GMFCS levels in the ITB and in the non-ITB cohorts, respectively, was as follows: level II 3% and 3%, level III 16% and 16%, level IV 38% and 37%, and level V 43% and 44%. Survival at 8 years of follow-up was 92% (SD 1.9%) in the ITB cohort and 82% (SD 2.4%) in the non-ITB cohort (p0.001). After adjustment to account for recent trends in improved survival in CP, 8-year survival in the non-ITB cohort was 88%, which was not significantly different from the ITB cohort (p=0.073).ITB therapy does not increase mortality in individuals with CP and may suggest an increase in life expectancy.

Sixty elementary schools in Minneapolis were asked to participate in a study to evaluate the most effective education method to increase booster seat knowledge and use in kindergarten-age children. School personnel selected one of the following interventions: (1) written information, (2) parent education class and a free booster seat, or (3) student education and a free booster seat. Twenty schools participated, with 132 parents completing the telephone interview 3 to 6 months post-survey. Providing instructions to parent groups and teaching children in the classroom, along with providing an incentive booster seat, was shown to increase booster seat use. Providing information only was found to be ineffective. Pediatric and school nurses should focus their injury prevention efforts beyond written materials. Results indicate that presentations for children and their parents, along with incentives, can result in changes in behavior.

Objective – The purpose of this pilot study was to determine the pharmacokinetics and tolerability of an investigational diazepam (DZP) formulation and a parenteral midazolam (MDZ) formulation following intranasal (i.n.) administration for the efficient treatment of seizure emergencies. Methods – Each subject received 5 mg of DZP and MDZ via both i.n. and intravenous routes in a four-way, randomized crossover trial. Blood samples were collected over 48 h. DZP and MDZ concentrations were measured using HPLC. Using analog scales, subjects rated tolerability (0 = no change from normal; 10 = maximum intolerability) and pain (0 = no pain; 4 = extreme pain) prior to and 0, 5, 15, 60 min, and 8 h after administration. Results – The Cmax and Tmax values for i.n. DZP and MDZ were 179.2 ng/ml and 28.8 min vs 62.8 ng/ml and 21.6 min, respectively. Immediately following i.n. administration, subjects reported tolerability scores of 6.75 and 6.0, and identical pain scores, 3.2, for DZP and MDZ, respectively. Conclusion – Both formulations were rapidly absorbed following i.n. administration with transient discomfort. DZP had a longer half-life, which may result in an extended duration of action. Further studies in large patient populations to evaluate the safety after long term use, efficacy and pharmacokinetics of i.n. DZP are warranted.

From 1982 through 1987, 128 families, who were instructed in the use of rectally administered diazepam (R-DZP) for the treatment of severe epileptic seizures, were surveyed. Sixty-seven families returned questionnaires and met inclusion/exclusion criteria; the results were used to analyze the medical, psychosocial, and economic impact of this program during the first year following instruction. Twenty-six families did not use R-DZP, primarily because of patient improvement. Among families using R-DZP, a total of 428 doses were administered to 41 children. R-DZP was effective in controlling seizures in 85% of patients. Adverse reactions usually were mild, consisting of drowsiness and/or behavioral changes. Compared to the year prior to instruction, emergency room visits decreased in both R-DZP-treated and -nontreated children; however, cost-savings were greater for the R-DZP group ($1,039.00 vs $420.00 per patient per year). Improvements in quality of life associated with the availability of R-DZP were observed by 58% of users and 27% of nonusers which included improved management of their children's seizures, increased flexibility in family activities, and greater peace of mind. R-DZP appears to be a practical method in the effective treatment of severe seizures at home.

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.

discharge patient was having 5.7% BWS at a speed of 3.0mph and a 2% grade incline. Patient was able to ambulate 150 ft independently indoors and 300ft independently outdoors on uneven surfaces and inclines. Patient was ASIA D at discharge. Discussion: Surfer’s myelopathy is a rare non-traumatic cause of spinal cord injury. The literature has very few reported cases but all presents with very similar onset. Patients have sudden onset lower back pain, lower leg weakness and paralysis within 10-60 minutes. Patients with higher grade ASIA grades on admissions appeared to have worse prognosis. The patient mentioned in this case report had a relatively low ASIA grade at C and made excellent progress to his goals of ambulating independently particularly with the use of BWS

Emigration of talented professionals from resource poor to resource rich countries is a serious and increasing problem. We think that the internet could be used to address some of the root causes of this emigration, substituting collaboration between countries for competition. Our ideas arose from a detailed review of Cuba's disappointing history of research collaboration with other countries, especially the United States. While Cuba modelled its educational, scientific, and technological systems on those of the United States and embarked on research programmes of US relevance, since 1959 contact between Cuban and US professionals and students has been limited, owing to travel restrictions and limited funds. Despite these handicaps, Cuban professionals still assimilated overseas knowledge. Cuba has developed a substantial biomedical network …

Objective: To determine the relative bioavailability and tolerability of a topiramate (TPM) suspension after rectal administration. Design/method: Seven healthy men and five healthy non-pregnant women were enrolled. A 100 or 200 mg tablet of TPM was given orally and a 200 mg dose was given rectally in a randomized, open-label, crossover study with at least a 2-week washout period between doses. Plasma samples were collected prior to dosing and the following times after each dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 h. Relative bioavailability was determined by calculating the ratio of the dose-normalized area under the curve (AUC/D) for the rectal and oral doses. Results: Ten subjects completed the study. Two of the first seven subjects who received a 200 mg initial oral dose, withdrew because of side effects. The remaining subjects received a 100 mg oral dose. Three subjects received a 200 mg dose orally and rectally, and seven subjects received 100 mg orally and 200 mg rectally. The average AUC/D was 0.72±0.18 h/l for the rectal dose and 0.76±0.20 h/l for the oral dose. The relative bioavailability (n=10) for TPM administered rectally was 0.95±0.17 with a range of 0.68–1.2. There were no statistically significant differences between the oral or rectal pharmacokinetic parameters. Conclusions: In healthy adults, rectally administered TPM is absorbed to a similar extent as the oral dosage form. Rectal administration is an acceptable route of administration for TPM, when the oral route is temporarily unavailable.

An extended-release formulation of carbamazepine (Carbatrol) might be suited for administration through feeding tubes because the capsules can be pulled apart to release the small granules. However, after encouraging several parents to use the new formulation, we were informed that the drug occluded some tubes. The purpose of this study was to determine if a protocol could be developed to administer Carbatrol without occlusion of the tubes. We administered the granules through feeding tubes to six children. Ten milliliters of water was used to flush the tube before administration. One capsule of Carbatrol was added to the 15 mL of liquid followed by an additional 10 mL water flush. For four children, 152 of 154 doses were administered without difficulty; however, two children were withdrawn from the study because of frequent tube occlusions. No adverse experiences occurred other than tube occlusion. The two children with frequent tube occlusions had long-standing problems with constipation or rigidity, which may have increased intra-abdominal pressure and slowed the rate of administration. We conclude that the use of Carbatrol granules for children with feeding tubes can be useful. However, some children are prone to frequent occlusion.

Study Objective. To determine the relative bioavailability of lamotrigine (LTG) chewable dispersible tablets after rectal administration. Design. Two-period, crossover study with a 2-week washout between dosing periods. Setting. Clinical research center. Patients. Twelve healthy adult volunteers. Intervention. One hundred milligrams of a LTG chewable dispersible tablet was administered by oral and rectal routes. Measurements and Main Results. Plasma samples were collected before and up to 120 hours after drug administration. The samples were analyzed for LTG by high-performance liquid chromatography, and the relative bioavailability was determined. Drug concentrations were lower after rectal than after oral administration. The relative bioavailability (F = AUCrectal/AUCoral) was 0.52 ± 0.23 (SD). Conclusion. Drug prepared from LTG chewable dispersible tablets is absorbed rectally, although not to the same extent as when given orally. Rectal administration of suspension of these tablets can be an acceptable route of administration.

Summary: Purpose: Interruption of oral drug administration poses a significant clinical problem for antiepileptic drugs that have no parenteral formulation. If a drug is absorbed rectally, rectal administration can be a useful alternative when the oral route of administration is not possible. The purpose of this study was to compare the single-dose pharmacokinetics of la-motrigine (LTG) compressed tablets after rectal and oral administration in healthy volunteers. Methods: A single LTG compressed tablet (100 mg) was administered orally and rectally to 12 volunteers in this single-dose, two-period, crossover study with a 2-week washout between doses. For rectal administration, tablets were crushed and suspended in 10 mL of water. Plasma samples were collected from 0 to 120 hr after each dose and analyzed for LTG by an HPLC method developed for this investigation. Results: LTG plasma concentrations were lower after rectal administration versus oral administration. The average area under the curve was 28.90 ± 9.5 μg/mL/hr after rectal administration and 51.71 ± 19.2 μg/mL/hr after oral administration. The average maximum LTG concentration was 0.53 ± 0.14 μg/mL after rectal administration and 1.45 ± 0.35 μg/mL after oral administration. The relative bioavailability for LTG compressed tablets was 0.63 ± 0.33 for rectal administration. There were no drug-related rashes or serious side effects. Conclusions: LTG suspension prepared from LTG compressed tablets is absorbed rectally, although not to the same extent or rate as when given orally.

Summary: Purpose: We wished to determine the extent of absorption of gabapentin (GBP) after rectal administration to children on maintenance therapy. Methods: Two children scheduled for extensive surgery received GBP rectally and orally. A pharmacokinetic profile was derived after each route of administration. Results: Serum GBP levels after rectal administration decreased at a rate similar to their rate of decrease after oral administration. However, GBP concentrations were much lower after rectal administration; therefore, we concluded that the aqueous solution was poorly absorbed rectally. The GBP half-life (t?h) for the 2 children after oral doses were 4.2 and 4.8 h. Conclusions: Rectal administration of GBP is not satisfactory when oral administration is interrupted. When oral GBP therapy is temporarily discontinued, clinicians should consider administration of alternative antiepileptic drugs (AEDs) that can be administered parenterally or rectally. Key Words: Gabapentin-Rectal-Bioavailability . Gabapentin (GBP) is a new antiepileptic drug (AED) that has been approved for adjunctive treatment of partial and secondarily generalized seizures in patients aged a12 years. Several reports describe the use and adverse effects of GBP in children (1-4) although systematic pharmacokinetic studies either are still in progress or have not been published. Although GBP is soluble in water, neither oral liquid nor parenteral formulations are available. The drug is absorbed by an active transport process and is eliminated unchanged by the kidney (5). In numerous circumstances, oral administration of medication is impossible, particularly in children. Examples of these include gastrointestinal infections with vomiting, intestinal dysfunction after abdominal surgery, fasting states prior to administration of anesthesia, and times of severe impairment of consciousness. During such episodes, physicians caring for children often administer medications rectally if parenteral formulations are unavailable (6). Because use of GBP in children is increasing, clinicians will undoubtedly encounter situations in which oral therapy will be interrupted. There

The purpose of this investigation was to describe the late improvements in functional mobility in children who have sustained severe acquired anoxic or traumatic brain injuries. Ninety-eight children from a consecutive series of 199 with acquired brain injuries met inclusion criteria. As expected, children with traumatic injuries had better mobility at time of discharge from rehabilitation than did children with anoxic injury. In addition, children with traumatic injuries improved more in mobility status during the first 2 years after injury than did children with anoxic injury. The children who continued to improve in mobility after discharge were unconscious for a shorter time. Children who became community ambulators during the first year after discharge had higher mobility ratings at discharge. Although children who eventually achieved more functional mobility were admitted to rehabilitation service sooner after injury, discriminant analysis revealed that the duration of unconsciousness, and therefore severity of injury, was more closely correlated with the final mobility status.

Chronic hiccups is a rare occurrence but can be debilitating for the patient. Successful intervention is seldom reported. The present case is a young adult who had severe almost continuous hiccups for 3 years after placement of a feeding gastrostomy and Nissen fundoplication. Within weeks of initiation of baclofen treatment, the hiccups ceased. Recurrences of hiccups have responded to increases in baclofen dosage.

A 12-year-old girl developed Kluver-Bucy syndrome (KBS) following heat stroke. She demonstrated the features typical of human KBS, including visual agnosia, hypermetamorphosis, hypersexuality, language disorder with aphasia, hyperorality, placidity, flat affect, and memory dysfunction. Magnetic resonance imaging 11 1/2 months after onset disclosed mild, diffuse atrophy. Fourteen months after onset, she did not consistently respond to language or communicate verbally, and was dependent on others. A comparison is made with previously reported KBS cases in children.

Pharmacokinetic data from 48 children who were taking valproic acid were analyzed by multiple stepwise linear regression. Children who were receiving enzyme-inducing antiepileptic drugs (n = 27) had greater (p < 0.01) clearances, elimination rates, and dosage requirements and greater (p < 0.05) variability in pharmacokinetic values than patients receiving monotherapy. Age and polytherapy explained most of the interpatient variability in total (r2 = 0.80; p < 0.001) and intrinsic (r2 = 0.77; p < 0.001) clearances and the elimination rate (r2 = 0.61; p < 0.002). Free fraction variability was related to valproate concentration and phenobarbital (r2 = 0.47; p < 0.001). Distribution volume variance was associated with free fraction (r2 = 0.48; p < 0.001). The effect of age and polytherapy on valproate clearance is primarily attributable to changes in metabolism rather than in protein binding. Valproic acid dosage requirements are greater and more variable for children who are receiving other enzyme-inducing antiepileptic drugs.

We reviewed the incidence of external leakage from feeding gastrostomies in 8 patients who received valproate sprinkle (VPA-S). We also identified a control group of 31 children with feeding gastrostomies who were also cared for in our clinic, but who did not receive VPA-S. All patients in both groups have had their feeding gastrostomy greater than or equal to 6 months. Four of 8 children who received VPA-S through feeding gastrostomies developed problems with recurrent external leakage. The incidence of external leakage in our control group of children who had not received VPA-S was 2 in 31 (6.4%). We hypothesize that the external leakage is caused by adherence of the undissolved VPA-S particles to the exterior of the tube, preventing close approximation of the tube to the gastrostomy stoma. In most cases, VPA-S could continue to be administered and the problem of leakage reduced if the tubes were more frequently changed and/or a larger size were used. Complications with either leakage or occlusion were noted in all patients with the button feeding tube who had received VPA-S. Because of the especially high complication rate associated with administration of VPA-S in children with the "button" feeding tubes, we discourage VPA-S administration to children with that device.

We compared a new coated-particle formulation of valproate (Depakote Sprinkle) capsules with valproic acid (Depakene) syrup for bioavailability, side effects, and patient and parent preference. Twelve children with epilepsy, aged 5 to 16 years, participated in this randomized, two-period, crossover study. They were assigned to a 7-day regimen with one formulation and then crossed over to the other; the drug was given every 12 hours. On day 7, blood samples collected during a 12-hour period were analyzed for the presence of valproate. At the study's end, parents and children were asked structured questions regarding formulation preference and adverse events. The extent of absorption from sprinkle equaled that from syrup (relative bioavailability = 1.02), but absorption was slower (time to maximum concentration = 4.2 vs 0.9 hour; p less than 0.01). Fluctuations in serum concentrations were less with sprinkle (34.8% vs 62.3%; p less than 0.01). Sprinkle was preferred by 9 of the 12 parents because of east of administration, and by nine of the children because of improved palatability. We conclude that sprinkle may be substituted for syrup without changing the daily dose. Furthermore, sprinkle, because of its prolonged absorption, may be given every 12 hours to children receiving monotherapy. Compliance may be enhanced because of the more convenient dosing schedules and the high degree of patient and parent acceptance.