Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteers.

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 C(max) and T(max) 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.

Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance.

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.

Neuroanatomical and electroencephalographic correlations in Sanfilippo syndrome, type A.

Waking and all-night-sleeping electroencephalographic recordings were obtained on a boy with Sanfilippo disease, type A. The most striking abnormalities were noted during sleep and included (1) lack of progression through normal sleep stages, (2) absence of vertex waves and normal sleep spindles, (3) inability to stage sleep by the usual criteria, and (4) an unusual alteration of low-amplitude (12 to 15 Hz) activity with generalized delta frequencies. Subsequently, neuropathological examination was performed. The electrophysiological phenomena may be correlated with severe cortical involvement.

Absorption of valproic acid suppositories in human volunteers.

The absorption of valproic acid administered by rectal suppository was studied in six male volunteers. Valproic acid was incorporated into a synthetic lipid base in our pharmacy. Each subject received 500 mg of valproic acid by rectal suppository and 500 mg of oral valproate sodium syrup one week apart; 13 blood samples were drawn to determine serum concentrations over 48 hours after administration of each formulation. Significant differences were evident in the amount absorbed, maximum serum concentration, and time to achieve maximum serum concentration between the oral and rectal formulations. Mean absorption after rectal suppository was 80%. Maximum serum concentration was 43.4 mg/L after oral administration and 29.2 mg/L after rectal suppository. The time to achieve maximum serum concentration was 1.0 hour after oral syrup and 3.1 hours after rectal suppository. Absorption of the rectal suppository was consistent and complete within 3 hours. The use of valproate sodium in rectal suppository form can be a more convenient and satisfactory method of administering valproic acid when the oral route is impossible. Dosage increases may be necessary, and serum concentrations should be monitored.

Bioavailability of rectally administered valproic acid syrup.

The bioavailability of commercially available valproic acid (VPA) syrup was studied following rectal administration in both dogs and children. Six dogs were studied following both oral (PO) and rectal (PR) administration of a dilute VPA syrup given in a dose of 40 mg per kilogram. There was no significant difference (p greater than 0.1) in the area under the serum concentration-time curve (AUC) between the oral (201.1 mg L-1hr) and rectal 219.6mg L-1hr) routes of administration. Four children were given VPA syrup by the rectal route. In three patients on maintenance VPA therapy, absorption following rectal administration was similar to that following oral administration. In a fourth child, VPA serum levels following an initial rectal dose of 20 mg per kilogram reached a maximum of 42 mg per liter 2 hours after the drug was given. These results indicate that the bioavailability of a diluted VPA syrup given rectally is comparable to that following oral administration. Rectal administration of VPA syrup appears to be a satisfactory alternative when the oral route is unavailable.

Phenobarbital dosage for control of neonatal seizures.

The relationship of the initial phenobarbital dose to weight, gestational age, blood level, and seizure control was studied in 39 neonates. The blood proportional to the dosage per kilogram, and was not related to weight or gestational age. Seizures remitted only at blood phenobarbital concentrations above 16.9 micrograms per milliliter. Therapeutic levels can be achieved by the intravenous or intramuscular administration of 16 to 23 mg per kilogram of phenobarbital.

Valproic acid pharmacokinetics in children. II. Discontinuation of concomitant antiepileptic drug therapy.

We studied the pharmacokinetics of valproic acid (VPA) in 11 children before and after discontinuance of enzyme-inducing antiepileptic drugs (AEDs). Valproic acid elimination half-life increased from 7.1 to 11.8 hours. Total and intrinsic VPA clearance decreased by approximately 40%. Valproic acid serum protein binding varied among patients from 7 to 23.8%, but was not altered by AEDs. Seizure control was maintained and mental status improved once all other AEDs were withdrawn. After discontinuation of enzyme-inducing AEDs, serum VPA concentrations can be maintained with a lower VPA dosage given less frequently.

Altered phenytoin clearance with febrile illness.

A prospective study was performed of antiepileptic drug levels in 14 boys resident in a pediatric chronic care facility. Blood samples and 24-hour urine collections were obtained monthly. During febrile illness (temperature greater than 101 degrees F for more than 24 hours), six additional blood samples and two urine collections were obtained for each child. During 8 of 10 febrile illnesses, phenytoin (PHT) decreased more than 40% from pre-illness baseline. Mean PHT level before illness was 16.7 (+/- 4.5 micrograms/ml) and during illness, 8.2 (+/- 3.6 micrograms/ml), significantly lower (p less than 0.001). Neither PHT binding nor absorption was altered by illness, so the most probable cause of the drop in PHT levels was induction of the hepatic oxidative enzyme system.

Phenobarbital maintenance dose requirements in treating neonatal seizures.

We studied the pharmacokinetics of phenobarbital in 15 neonates after a single intramuscular dose. The mean apparent distribution volume, half-life, and apparent total body clearance were 0.81 liter per kilogram, 103.4 hours, and 6.4 ml per hour per kilogram, respectively. Substantial interpatient variation was observed in the half-life and apparent total body clearance. Maintenance doses of 3.1 and 3.8 mg per kilogram per day were projected from the mean apparent total body clearance to produce plasma concentrations of 20 and 25 micrograms per milliliter, respectively. These recommendations provide initial maintenance dosage guidelines, which should be adjusted according to plasma concentrations and clinical effects.

Pharmacokinetics of valproic acid in children: I. Multiple antiepileptic drug therapy.

We studied the pharmacokinetics of valproic acid (VPA) in 37 children who were taking other antiepileptic drugs. Thirteen children were studied both after initial and while on maintenance valproic acid therapy. Significant differences occurred between initial and maintenance therapy in the mean apparent volume of distribution and in apparent VPA clearance, whereas VPA half-life remained relatively constant. Analysis of data in the 13 children studied on two occasions demonstrated wide intrapatient variability of VPA pharmacokinetics. Children taking VPA together with other antiepileptic medications generally require higher doses of VPA given more frequently.

Treating repetitive seizures with a rectal diazepam formulation: a randomized study. The North American Diastat Study Group.

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 i.v. 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 < 0.007). The most common adverse event was somnolence. 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.

Pediatric head injury resulting from all-terrain vehicle accidents.

In our experience, accidents involving all-terrain vehicles are an increasingly frequent cause of brain injury in children. The risk associated with operation of these vehicles is not fully appreciated and should be better publicized. We believe that it is possible to delineate several steps that could significantly reduce the risk to the pediatric population without curtailing the recreation altogether. Although construction design has promised to produce safer vehicles, our experience has shown that extreme injury is still possible with the newer four-wheel machine.

Automatic garage door openers: hazard for children.

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.

Relative bioavailability of lamotrigine chewable dispersible tablets administered rectally.

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 = AUC(rectal)/AUC(oral)) 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.

Rectal administration of antiepileptic drugs in children.

This article reviews the current literature describing the use of rectally administered antiepileptic drugs. Individual antiepileptic drugs are discussed in regard to efficacy, toxicity, and rate of absorption. Absorption occurs through passive diffusion; therefore, solutions are absorbed most quickly. Paraldehyde, diazepam, secobarbital, and valproic acid are used when rapid effect for termination of prolonged or serial seizures is desired. Valproic acid, lorazepam, carbamazepine, and phenytoin all can be used for maintenance therapy.

Fosphenytoin in infants of extremely low birth weight.

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.

Baclofen for chronic hiccups.

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.

Outcome of children with prolonged unconsciousness and vegetative states.

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.

Movement disorders after status epilepticus and other brain injuries.

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.

Closed head injury: comparison of children younger and older than 6 years of age.

The outcomes of 97 children with severe closed head injuries referred to a regional rehabilitation center were studied. Patients were divided according to referral source and age (less than 6 and greater than or equal to 6 years). Patients referred from more distant sources had worse outcomes in terms of cognition, motor ability, and brain atrophy for both age groups. Children 6 years of age and older had better cognitive, motor, and brain atrophy outcomes than younger patients for each referral origin. These results do not support the hypothesis that the youngest children have the best recovery after profound closed head injury. All abused children were younger than 6 years of age; compared to other age-matched, closed head injury patients, these children had significantly worse cognitive and motor abilities.