A pharmacokinetic study of midazolam in dogs: nasal drop vs. atomizer administration.

PURPOSE: The purpose of this investigation was to compare the pharmacokinetics of midazolam following intravenous, intranasal drop, and nasal-atomizer administration in beagle dogs. METHODS: Six animals weighing 9-13 kg were used in a repeated-measure design, group assignment based on route of drug administration. Midazolam (1.5 mg/kg) was administered with the delivery route based on group assignment. Blood samples were obtained at baseline and at 1, 3, 5, 7, 10, 15, 20, 30, and 45 min after administration. Cerebrospinal fluid samples (CSF) were obtained at 5 and 10 min after administration. Plasma and CSF concentrations of midazolam were determined by electron-capture gas-liquid chromatography. RESULTS: Comparison between groups and over time demonstrated that both nasal routes resulted in significantly higher CSF concentrations relative to corresponding plasma levels, and that nasal-atomizer administration produced significantly higher CSF concentrations compared to the drop approach.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE: A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS: A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS: Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION: The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Prevention of group B Streptococcus infection in neonates.

OBJECTIVE: To review the epidemiology of group B Streptococcus (GBS) infection, risk factors for infection, and clinical manifestations of disease in the neonate, as well as the role of chemoprophylaxis and immunoprophylaxis in prevention of GBS disease and current recommendations for prevention. DATA SOURCES AND STUDY SELECTION: MEDLINE searchers (1976-1997) of the English-language literature. DATA SYNTHESIS: Despite clinical advances in health care in the past two decades, GBS remains a leading cause of serious neonatal infection. Most early-onset GBS infections can be prevented through the use of intrapartum antimicrobial chemoprophylaxis. Preventing GBS infection in neonates is more cost-effective than treating GBS infections, and implementing prevention programs can reduce morbidity and mortality resulting from GBS disease. Many proposals have been made regarding prevention strategies; however, they have not been implemented widely and consistently in the US. To coordinate both pediatric and obstetric supported strategies, the Centers for Disease Control and Prevention (CDC) recently published recommendations for prevention of neonatal GBS disease through two possible strategies. In the first strategy, intrapartum antibiotic chemoprophylaxis should be offered to all women identified by prenatal culture as colonized and those who develop premature membrane rupture or onset of labor at less than 37 weeks gestation. The second strategy involves administration of intrapartum antibiotics to all women who develop one or more risk factors at the time of membrane rupture or onset of labor. CONCLUSIONS: GBS is difficult to eradicate, causing many women to be colonized with the organism during pregnancy and labor, thereby infecting their infant. Prevention strategies have been published for more than 10 years without successful implementation. Although optimal prevention management has not been defined, following one of two strategies recommended by the CDC can prevent the majority of GBS infections in neonates.

Constructing reproductive histories by linking vital records.

Certificates of 1,449,287 live births and fetal deaths filed in Georgia from 1980 through 1992 were linked to create chronologies that, excluding induced abortions and ectopic pregnancies, constituted the reproductive experience of individual women. The authors initially used a deterministic method (whereby linking rules were not based on probability theory) to link as many records as possible, knowing that some of the linkages would be incorrect. They subsequently used a probabilistic method (whereby evaluation of linkages was developed from probability theory) to evaluate each linkage, and they broke those that were judged to be incorrect. Of the 1.4 million records, 38% did not link to another record. From the remaining records, 369,686 chains of two or more events were constructed. The longest chain included 12 events. Of the chains, 69% included two events; 22% included three events. Longer chains tended to have lower scores for probable validity. The probability-based evaluation of chains affected 3.0% of the records that had been in chains at the end of the deterministic linkage. A greater percentage of records in longer chains were affected by the evaluation. Unfortunately, the small subset of records that were the most difficult to link tended to overrepresent groups with the greatest risk of adverse pregnancy outcomes. Researchers contemplating a similar linkage can anticipate that, for the majority of records, linkage can be accomplished with a relatively straightforward, deterministic approach.

Evaluation of reproductive histories constructed by linking vital records.

We used 1.4 million fetal death and birth certificates filed in Georgia between 1980 and 1992 to construct 369,686 chains of two or more reproductive events occurring to the same woman. We evaluated these chains using both information on the certificates and information independently collected in interviews with 1311 women. Overall, 86.6% of the chains had the expected number of events, based on the certificate's information about previous pregnancies. Seventy-nine per cent of the chains had the expected number of events based on the maternal interviews. Consistency between the observed number of events in the chain and the number expected, based either on data from the certificates or from the maternal interviews, was greatest for chains with two or three events. Mothers born in Georgia were more likely to have complete chains than mothers born elsewhere. Among the 551,391 non-linked certificates, 48.7% were the mother's first birth, 40.2% were second or higher-order births to women whose previous pregnancy occurred before 1980, and 11.1% were second or higher-order births to women whose previous pregnancy occurred after 1980. Fetal death and livebirth certificates can be linked to construct pregnancy histories with reasonably low levels of underlinkage and overlinkage.

Stability of ondansetron stored in polypropylene syringes.

OBJECTIVE: To evaluate the stability of ondansetron hydrochloride undiluted and mixed in dextrose 5% injection or NaCl 0.9% injection during storage in polypropylene syringes when frozen, refrigerated, or at room temperature. DESIGN: Batch quantities of ondansetron 0.25, 0.5, 1.0, and 2.0 mg/mL were prepared and individual doses of 10.5 mg were drawn into polypropylene syringes that were stored at -20 degrees C for up to 3 months, at 4 degrees C for up to two weeks, or at 22-25 degrees C for two days, and various combinations of these conditions. At defined sampling times aliquots were withdrawn from syringes, the solution visually inspected, pH measured, and ondansetron concentration determined by HPLC. Drug loss of > or = 10 percent of the original content of the solution was considered clinically significant. RESULTS: The ondansetron concentration in each solution, regardless of storage conditions, remained above 90 percent of the original concentration at each observation time (range 92-107 percent). No changes in color or clarity of any of the solutions were observed, and only slight fluctuations in pH (< or = 0.05) were noted. CONCLUSIONS: Ondansetron 2 mg/mL undiluted, or at concentrations of 0.25, 0.5, or 1 mg/mL, mixed in dextrose 5% injection or NaCl 0.9% injection was determined to be stable when stored in polypropylene syringes for each storage condition at all time points studied, including the maximum for each: three months at -20 degrees C, followed by 14 days at 4 degrees C, and by 48 hours at 22-25 degrees C.

Treatment of infantile spasms.

OBJECTIVE: To summarize and evaluate the literature regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms. DATA SOURCES: A literature search of articles from January 1966 to July 1993 using MEDLINE, EM-Base, and Current Concepts/Life Sciences, as well as bibliographies of relevant articles. STUDY SELECTION: All identified original and review publications regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms were reviewed. Emphasis was placed on original studies published since 1975. DATA EXTRACTION: Data from published research were extracted and evaluated according to study design, sample size, dosing regimen, outcome measures, and treatment efficacy and safety. DATA SYNTHESIS: Infantile spasms constitute a rare epileptic syndrome with a poor long-term prognosis for normal intellectual development. The spasms are characterized by a brief symmetric contraction of the muscles of the neck, trunk, and/or extremities, often occurring in a series of 2 to more than 100 spasms during a single episode. The disorder is age-specific, with the peak onset of symptoms occurring between 2 and 8 months of age. Spasms of no identifiable cause in infants with normal development prior to the onset of infantile spasms are classified as cryptogenic or idiopathic, whereas those with an identifiable cause are classified as symptomatic. Long-term prognosis is best in cryptogenic cases, with 30-70 percent attaining normal intellect compared with 5-19 percent in symptomatic cases. The etiology and pathophysiology are not well understood. Recent theory postulates that infantile spasms may be caused by an excess of corticotropin-releasing hormone activity during infancy. The suspected association between the whole-cell pertussis vaccine and infantile spasms is coincidental. Few well-designed, prospective, controlled clinical trials for the treatment of infantile spasms have been conducted. CONCLUSIONS: Standard anticonvulsants such as phenytoin, the barbiturates, carbamazepine, and the succinimides have been ineffective. Of the anticonvulsants, only the benzodiazepines, valproic acid, and vigabatrin have shown efficacy in reducing spasm frequency and severity. Hormonal therapy with adrenocorticotropic hormone (ACTH) and/or prednisone has been the most frequently studied treatment modality and appears to be the most effective. Hormonal therapy achieves complete spasm control in 50-75 percent of infants within four weeks of initiation. Opinions differ regarding the relative efficacy between ACTH and prednisone, the need for early initiation of hormonal treatment, and the benefits of high dosages of ACTH (> 40 units/d). No treatment has been shown conclusively to improve the long-term intellectual development of these infants. Neurosurgery may be the treatment of choice in select cases when a localized central nervous system abnormality can be demonstrated. Well-designed, blind, prospective clinical trials are needed to answer definitively many lingering questions regarding the treatment of infantile spasms.

Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight neonates. The Multicenter Group for the Study of Immune Globulin in Neonates.

BACKGROUND: Nosocomial infection is a major risk for premature infants with very low birth weights. One reason for their susceptibility to infection may be antibody deficiency, since there is little transfer of maternal IgG to the fetus before 32 weeks' gestation. METHODS: We conducted a multicenter, double-blind study of neonates weighing 500 to 1750 g at birth. A total of 588 neonates were randomly assigned, with stratification for birth weight, to receive periodic intravenous infusions of either immune globulin (500 mg per kilogram of body weight per day) or a placebo. Mortality, morbidity, and nosocomial infection during the next 56 days were assessed. RESULTS: The infusions were well tolerated; mild, reversible adverse reactions occurred in five infants in each group. There was a significant reduction in the risk of a first nosocomial infection in the recipients of immune globulin as compared with the placebo recipients (relative risk, 0.7; 95 percent confidence interval, 0.5 to 0.9). About 85 percent of the nosocomial infections were bacterial; the majority of these were caused by coagulase-negative staphylococci or Staphylococcus aureus. The neonates who received immune globulin had fewer mean days of hospitalization than the controls (62 vs. 68, P = 0.15); among the infants with infections, the difference in the mean length of the hospital stay was even greater (80 days vs. 101 days, P = 0.02). CONCLUSIONS: For premature infants weighing between 500 and 1750 g at birth, treatment with intravenous infusions of immune globulin is safe and reduces the risk of nosocomial infection.

Recent developments in vaccines and immunization practices.

Dramatic changes have been made in the recommended schedule for immunizations, and for a variety of reasons: greater understanding of risks associated with whole-cell pertussis vaccine; introduction of more immunogenic vaccines to prevent invasive disease caused by Haemophilus influenzae type B; a national epidemic of measles that affected many vaccinated individuals; and the failure of targeted use of vaccine in high-risk patients to reduce the occurrence of hepatitis B. Additional changes in recommended regimens can be anticipated as new products are introduced. However, for vaccines to have their greatest impact, improved adherence to recommended immunization practices is necessary.

Longitudinal evaluation of polymorphonuclear leukocyte chemiluminescence in premature infants.

A chemiluminescence (CL) microassay was used to evaluate polymorphonuclear leukocyte (PMN) function in premature newborn infants longitudinally during a 2-month period and in healthy adult control subjects. At postnatal ages of 12, 26, 40 and 54 days the infants' mean peak CL activity was significantly lower than that of the adults. Infants with one or more low CL responses were more severely ill than those with normal CL activity. The infants with low CL responses had longer hospital stays and a higher frequency of serious infections, as well as more days of level 3 care, antimicrobial therapy, supplemental oxygen, assisted ventilation, and total parenteral nutrition. The PMN CL activity before, during, and after episodes of serious infection did not differ. In addition, a high frequency of depressed CL activity was observed at the time of infection. Our findings are consistent with previous studies suggesting that defective PMN oxidative metabolic responses are more common in neonates undergoing stress. Our results further suggest that defective PMN function may persist for the first 2 months of life and during the course of serious infection. Enhancement of PMN host defense may be an important strategy in the management of neonatal sepsis.

Metabolic effects of aminophylline in weanling rats.

Methylxanthines are commonly used to treat asthma and apnea in infants and children. A physiological effect of these compounds is an elevation of the metabolic rate, but the mechanism of this increase is unclear. We have investigated the hypothesis that this elevation of metabolic rate in young animals is in part due to increased physical activity. Metabolic rate and spontaneous physical activity of weanling Fischer 344 rats were measured before and during 2 days of aminophylline administration. Our results show increased metabolic rate measured over 23 h, concomitant with increased activity during treatment. Resting metabolic rate was not elevated. The results suggest that increased physical activity plays a major role in increasing metabolic rate during aminophylline treatment. Metabolic rate returned to control levels on the 2nd day of treatment despite a smaller but still significant elevation in physical activity. This suggests development of tolerance to the effects of aminophylline on activity together with adaptation to the metabolic effects of this drug.

Lack of effect of short-term passive smoking on the metabolic disposition of theophylline.

To test the hypothesis that involuntary smoking can result in increased drug metabolism, five nonsmoking healthy male volunteers (21-36 y old) were enrolled in a study of single-dose theophylline pharmacokinetics before and after intense environmental tobacco smoke (ETS) exposure. Exposure was provided by spending 3 h/day for five consecutive days in a small room with a smoking apparatus that burned four cigarettes simultaneously, at a rate of 20 cigarettes/h. Measurement of urine continine concentration demonstrated that significant absorption from ETS occurred in all subjects. However, pre- and post-exposure pharmacokinetic parameters for theophylline did not differ significantly: Vz = 0.438 vs 0.440 l.kg-1; t1/2 = 9.19 vs 9.69 h; CL = 34.4 vs 32.6 (ml.kg-1.h-1), respectively. Similarly, 24-hr urinary excretion of theophylline and its metabolites was unchanged by ETS exposure. We conclude that intense short-term passive smoking does not affect theophylline disposition. The possibility of chronic ETS exposure causing alterations in drug metabolism cannot be excluded.

Metabolic effects of aminophylline in rats.

Whole body metabolic rate is elevated after administration of methylxanthines, but the mechanism by which this occurs is not clear. We have investigated the hypothesis that this increase in metabolic rate is in part due to increased physical activity. Metabolic rate and spontaneous cage activity of Fischer 344 rats were measured over a 24-h period before and during aminophylline treatment. Weight, food, and water consumption were also measured. Our results show an increase in metabolic rate with a simultaneous increase in spontaneous activity over the 24-h period. These results are consistent with the hypothesis that increased physical activity is in part responsible for the increase in cellular metabolism that follows administration of aminophylline.

Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models.

Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl); weight was inferior to age and did not statistically improve the model (p greater than 0.005) when combined with age. Total Cl increased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Cl values: for a given age, Cl was 34% higher for blacks than the reference population composed of the remaining patients, and Cl for males was 25% higher than that for females. The volume of distribution (Vd) for the population was estimated to be 0.62 L/kg. The interindividual variability in Cl and Vd expressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 micrograms/ml. The STCs that represented some degree of outpatient dosing were 21% lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.