Bruce R. Parks

Toxicity with dextromethorphan-containing preparations: a literature review and report of two additional cases.

Dextromethorphan-containing cold/cough preparations are frequently prescribed and bought over the counter for use in children. Although generally considered safe, dextromethorphan has been shown to cause CNS side effects, including hyperexcitability, increased muscle tone, and ataxia. Two deaths have been reported with intentional dextromethorphan overdose. A literature review, brief review of pharmacology, and report of two cases of adverse reactions to dextromethorphan-containing preparations are presented.

Pediatric Patients With Undetectable Anticonvulsant Blood Levels: Comparison With Compliant Patients

Undetectable anticonvulsant blood levels indicate sustained noncompliance (several consecutive doses missed). We compared 91 consecutive outpatients with epilepsy and undetectable anticonvulsant blood levels to 100 patients seen during the same time period, verified as compliant by acceptable serum levels. We hypothesized that pay status, application for Supplemental Security Income, patient age, history of missed appointments, and functional status would differ between compliant and noncompliant patients. We were surprised to find large differences between clinic and insurance patients and between Caucasian and non-Caucasian patients. The 100 compliant patients included 44 Caucasian and 56 non-Caucasian patients, whereas only 9 of 91 noncompliant patients were Caucasian, and only 9 had insurance, compared to 32 compliant patients. Applications for Supplemental Security Income and history of missed appointments were significantly associated with noncompliance, but patient age, seizure type, and seizure control were not. Uninsured Caucasians were more often compliant than non-Caucasians were. Many noncompliant patients had mild epilepsy, which was reportedly doing well. Race and pay status were closely correlated. Several noncompliant females became pregnant, whereas no compliant patients did. Compliant patients were much more likely to be accompanied by a parent or caretaker on clinic visits than noncompliant patients. Noncompliant patients had at least one acceptable subsequent serum level, although 2 patients with intractable epilepsy had undetectable serum levels on three or more occasions. Noncompliance may respond to discussion and advice. We reviewed 124 episodes of undetectable drug levels in the 91 noncompliant patients. Eighteen of these resulted in hospitalization, but in 25 cases, we were told that there had been no seizures since the preceding visit. Many noncompliant patients have infrequent seizures, even if they take little or no medication. Socioeconomic status influences health, life expectancy, and educational success, but it has been claimed to be irrelevant to compliance and adherence issues in epilepsy. Our data and the experience of other centers with childhood diabetes suggest that socioeconomic, racial, and family factors influence compliance or adherence to treatment for many chronic conditions. Educational efforts and support for parents at the start of anticonvulsant treatment may improve compliance. Uninsured patients missed more appointments and were much more likely to be noncompliant than insured patients. Attention to the special problems of Medicaid and minority children is needed. ( J Child Neurol 2001;16:164-168).

The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients.

Study Objective. To evaluate the safety, tolerability, and pharmacokinetic profile of fosphenytoin, a water‐soluble phenytoin prodrug, after intramuscular and intravenous administration.

Metabolism and Disposition of Indomethacin in Preterm Infants

38 preterm infants with symptomatic patent ductus arteriosus received indomethacin intravenously. Plasma samples were collected at 2, 4, 6 or 8 and 12 h after each of 3 doses. Indomethacin, demethylindomethacin and p-chlorobenzoic acid were determined in plasma and urine along with acid-labile metabolites using HPLC. Fifty-eight percent of the infants demethylated indomethacin; half of the unchanged and demethylated drug was found as conjugates in urine; 14% deacylated the drug. Shorter elimination half-life, smaller area under the plasma concentration-time curves and increased plasma clearance were associated with demethylation. Postnatal age greater than 2 weeks correlated with both demethylation and failure of indomethacin to effect ductal closure.

Intraosseous administration of antibiotics: Same-dose comparison with intravenous administration in the weanling pig

STUDY OBJECTIVES To assess the reliability of the intraosseous route of administration for delivery of a loading dose of broad-spectrum antibiotics in a pediatric animal model. DESIGN Serum levels achieved within 90 minutes of equivalent intraosseous (IO) and IV bolus dosing of ceftriaxone, cefotaxime, and a combination of ampicillin and gentamicin were compared in the weanling pig. SUBJECTS Twelve female weanling pigs were studied in the Animal Facilities Laboratory at the University of Mississippi Medical Center. INTERVENTIONS Through a proximal tibial IO catheter, each anesthetized animal received one of the following: 50 mg/kg ceftriaxone, 50 mg/kg cefotaxime, or 300 mg/kg ampicillin followed immediately by 2.5 mg/kg gentamicin. Venous blood was obtained for antibiotic assay at 15, 30, 45, 60, and 90 minutes after IO injection. The animals were allowed to recover, and, after a one-week washout period, each received the same antibiotic and dose as before through a peripheral IV. Levels were assayed at the same intervals and IO versus IV were compared. MEASUREMENTS AND MAIN RESULTS Comparable serum levels of all four antibiotics were achieved by the two routes. Gentamicin levels were statistically indistinguishable IO versus IV at all assay intervals. Ampicillin and cefotaxime levels achieved by the two routes were equivalent within one hour of dosing. Serum levels of ceftriaxone after IO administration paralleled those after IV dosing but remained significantly lower at all time intervals. CONCLUSIONS In the weanling pig model, the IO route was used to deliver serum levels of broad-spectrum antibiotics comparable to those attained after IV administration. The data support the use of standard parenteral doses for IO administration. To overcome potential avid protein binding of ceftriaxone in the bone marrow, we recommend using ceftriaxone at its highest recommended IO loading dose. Consistent with many other medications that have been similarly tested, these data indicate that initial or empiric antibiotic coverage in hypodynamic and shock states in infants and young children need not await the establishment of traditional IV access.

Indomethacin and the preterm infant with a patent ductus arteriosus: relationship between plasma concentration and ductus closure.

The relationship of indomethacin pharmacokinetics to clinical and echocardiographic evidence of closure of the patient ductus arteriosus (PDA) is described in 9 preterm infants. PDA closures occurred in 4 infants when peak indomethacin plasma concentrations were 0.71-1.10 micrograms/ml, mean 0.93 +/- 0.16 microgram/ml. With partial or no PDA response to oral treatment, the peak concentrations were 0.20-0.69 microgram/ml, mean 0.57 +/- 0.08 microgram/ml, p less than 0.01. The left atrial size in the study infants correlated inversely with the indomethacin peak concentrations, r = 0.75. The plasma apparent terminal half-life correlated with postnatal age, r = 0.75. All patients with peak concentrations greater than 0.50 microgram/ml had transient oliguria. This study suggests that a minimum indomethacin concentration may be needed to promote PDA constriction.

Hematologic Monitoring in Children With Epilepsy Treated With Carbamazepine

One hundred seventy-six children treated with carbamazepine for epilepsy were monitored over a 12-month period to determine the effects of carbamazepine on the hematologic system. There were no significant changes within the total population in the mean hematocrit or platelet count. The white blood cell count and total neutrophil count showed declines at 1, 8, and 12 months, but the differences did not achieve statistical significance. There was no correlation between the hematologic parameters and carbamazepine blood level, age or sex, or the presence of other drugs. Pretreatment leukopenia and neutropenia were present in 2.8% and 4.0% of children, respectively. During carbamazepine therapy, 8.0% and 17.0% of the children developed leukopenia and neutropenia, respectively, and it was persistent in 1.7% and 2.8%, respectively. The changes in the white blood cell count could be attributed to the changes in the total neutrophil count. (J Child Neurol 1989;4:286-290).

IN-UTERO DEATH AS A POSSIBLE CONSEQUENCE OF PRENATAL ADMINISTRATION OF INDOMETHACIN

Indomethacin, a non-specific prostaglandin synthesis inhibitor, has been advocated for use in a variety of areas including obstetrics. It rapidly crosses the placenta and significant concentrations occur in fetal blood and amniotic fluid. The present study was designed to determine the effects of indomethacin on near-term fetuses of mongrel dogs. Fetuses removed by Caesarian section (following maternal administration of 1 mg/kg/day indomethacin for 7 days prior to anticipated delivery) were fully developed but nonviable. Some placental separation was found on Caesarian section, and this was the major gross abnormality observed. In-utero closure of the ductus arteriosus was considered a possible cause of death but autopsies of the animals failed to confirm this. The ducti of the fetuses were found to be either of the same caliber as the pulmonary artery or only partially constricted (to the extent that the lumen was approximately one-half that of the pulmonary artery). The lungs had the appearance of normal unborn lungs. Since signs of obvious maternal complications were absent, it is probable that fetal demise was the result of the administration of the indomethacin. Autopsy findings demonstrated that in-utero closure of the ductus arteriosus was likely not the responsible factor.

Aldosterone-Induced Hypertension: Effects of a Kininase Inhibitor

A synthetic orally active angiotensin I converting enzyme inhibitor Captopril (Squibb), (D-2-methyl-3-mercaptopropanoyl-L-Proline), was administered to three groups of hypertensive animals. The animals were made hypertensive by uninephrectomy, daily injections of 5 ug/100 g body weight d-aldosterone (Sigma) in wheat germ oil and substitution of 0.9% NaCl for the drinking water. Captopril was given to pregnant and nonpregnant animals during the developmental phase of hypertension and to nonpregnant animals with established (4 weeks of treatment) hypertension. The agent attenuated the hypertension in both the pregnant and nonpregnant animals when given while hypertension was developing. Captopril was effective in reducing established aldosterone-NaCl hypertension to normotensive levels.

ELEVATED SERUM IRON LEVELS FOLLOWING ADMINISTRATION OF CISPLATINUM

An increase in serum iron levels and a decrease in serum unsaturated iron binding capacity (uIBC) were noted following the administration of cisplatinum to 9 children with malignancies. The mean serum iron concentration increased from a pretreatment level of 75.7±30.5 ug/ml to a post treatment level of 162.1±65.3 ug/ml with the first cisplatinum treatment course(p<0.004). The uIBC concomittantly decreased from 181.9±33.7 ug/ml to 86.4 ± 44.6 ug/ml(p<0.0005). Cummulative effect was noted following subsequent courses. The levels returned to baseline values within 2-4 months following cessation of therapy in 6 children in whom follow up data was available. It is possible that this reversal of the iron/uIBC ratio is the result of cisplatinum competition for iron binding sites to proteins.