Antipyrine disposition in milk and saliva of lactating women.

Widely used to study hepatic drug metabolism, antipyrine rapidly distributes in total body water. Antipyrine distribution was studied in seven lactating women. Duration of lactation ranged from 2 to 19 mo. In all subjects the drug was rapidly absorbed; in five women peak concentrations were attained in milk and saliva by 1 hr and in the other two women by 3 hr (first point at which collections were made). In two women in whom antipyrine was measured at 10-min intervals during the first hour, peak concentrations in both milk and saliva were attained by 10 min after antipyrine. The time course for antipyrine disappearance from milk paralleled that from saliva for each subject. Antipyrine half-life (t1/2) varied from 5.6 to 20.3 hr for saliva (mean +/- SD = 11.5 +/- 4.8) and from 5.7 to 21.7 hr for milk (mean +/- SD = 11.6 +/- 5.4). In the two women with the shortest salivary antipyrine t1/2 (5.6 and 7.5 hr), antipyrine was readministered many months later, after they had stopped lactating. The salivary antipyrine t1/2 rose from 5.6 to 13.3 hr in one subject and from 7.5 to 14.6 hr in the other. The corresponding decrease in antipyrine clearance was 0.93 to 0.55 and 1.41 to 0.60 ml/min/kg. This observation suggests that in some subjects lactation may influence drug metabolism. The amount of antipyrine available to each nursing infant was estimated by assuming the the infant nursed 3 ounces every 4 hr for 24 hr after maternal antipyrine administration. The amount of antipyrine available to the nursing infant was calculated to range from 3.0 to 11.1 mg (mean +/- SD = 6.4 +/- 2.9 mg) or from 0.25% to 1.07% (mean +/- SD = 0.59 +/- 0.29%) of the maternal dose.

Quinine-induced alterations in drug disposition.

In normal volunteers, chronic quinine administration shortened plasma antipyrine half-life and significantly increased the intraindividual correlation between the disposition of quinine and antipyrine. Decreased plasma antipyrine half-life appears to be due to a quinine-induced enhancement of antipyrine metabolism. A dose-dependent prolongation of plasma quinine half-life was observed and attributed primarily to an increased apparent volume of distribution of quinine, although our data did not permit separation of an effect on quinine metabolism from an effect on quinine distribution between the peripheral and central compartments. Plasma protein binding of quinine was similar at both the low and high doses of quinine. Studies in dogs given quinine intravenously revealed a biphasic plasma decay curve compatible with a 2-compartment open model for quinine disposition. Dose dependence of plasma quinine half-life in the dog after intravenous quinine eliminated altered gastrointestinal absorption of quinine as a cause for the dose dependence of plasma quinine half-life. These studies illustrate the importance of such conditions as dose and time of administration in determining the type and magnitude of interaction observed between drugs.

Disposition of dietary caffeine in milk, saliva, and plasma of lactating women.

Caffeine is present in many dietary substances; its appearance from these sources in human milk has not previously been studied in detail. Fifteen lactating women ingested a known amount of a caffeinated beverage (36 to 335 mg). Simultaneous milk and saliva samples were collected at intervals for the subsequent 12 hours and assayed for caffeine content. Eleven of 15 mothers excreted measurable caffeine in milk. Caffeine was detected by 15 minutes in saliva and milk; peak levels in milk (2.09 to 7.17 micrograms/mL) and saliva (1.24 to 9.22 micrograms/mL) were achieved within 1 hour. Elimination half-lives were 1.3 to 13.5 hours (mean 4.0 +/- 3.7 [SD] hours) for saliva and 1.5 to 14.5 hours (mean 6.1 +/- 4.4 [SD] hours) for milk. Assuming each infant would ingest 90 mL of milk every three hours for 24 hours after maternal ingestion of caffeine, it is possible to estimate potential exposure of the nursing infant to caffeine. The amount of caffeine available for infant absorption ranged from 0.01 to 1.64 mg or 0.06% to 1.5% of the maternal dose. Caffeine was not present in the infants' urine collected for five hours after the first nursing period. The maternal ingestion of a single cup of caffeinated beverage does not appear to present significant doses of caffeine to the nursing infant.

Infant exposure to chemicals in breast milk in the United States: what we need to learn from a breast milk monitoring program.

The presence of environmental chemicals in breast milk has gained increased attention from regulatory agencies and groups advocating women's and children's health. As the published literature on chemicals in breast milk has grown, there remains a paucity of data on parameters related to infant exposure via breast-feeding, particularly those with a time-dependent nature. This information is necessary for performing exposure assessments without heavy reliance on default assumptions. Although most experts agree that, except in unusual situations, breast-feeding is the preferred nutrition, a better understanding of an infant's level of exposure to environmental chemicals is essential, particularly in the United States where information is sparse. In this paper, we review extant data on two parameters needed to conduct realistic exposure assessments for breast-fed infants: a) levels of chemicals in human milk in the United States (and trends for dioxins/furans); and b) elimination kinetics (depuration) of chemicals from the mother during breast-feeding. The limitations of the existing data restrict our ability to predict infant body burdens of these chemicals from breast-feeding. Although the data indicate a decrease in breast milk dioxin toxic equivalents over time for several countries, the results for the United States are ambiguous. Whereas available information supports the inclusion of depuration when estimating exposures from breast-feeding, the data do not support selection of a specific rate of depuration. A program of breast milk monitoring would serve to provide the information needed to assess infant exposures during breast-feeding and develop scientifically sound information on benefits and risks of breast-feeding in the United States.

Pharmacologic considerations of drug use in the lactating mother.

The recent increase in the incidence of breast-feeding has given impetus to the study of the excretion of drugs and chemicals into human milk. It appears that the major route of drug appearance in milk is via diffusion from the maternal circulation. In general, maternal plasma levels of a drug dictate milk levels. Un-ionized drugs with high lipid solubility and minimal binding to maternal plasma protein diffuse best. The amount of a drug excreted in milk is usually not more than 1 to 2% of the maternal dose. Most studies have been done with single-dose or short-term drug administration. Very few data are available for the mother who receives continuous drug therapy. Environmental chemicals such as insecticides are also a cause for special concern. They are highly lipid soluble and may remain in body fat for very long periods. Indeed, lactation may be the only route of elimination. The effect of even small amounts of these agents on the growing infant is unknown. Further studies are needed to determine the amount of these agents secreted and the possible risk to the nursing infant.

Drugs and chemicals: exposure of the nursing mother.

Over half of newborn infants begin life breastfeeding. Nearly all drugs ingested by nursing mothers appear in their milk; amount is 1 to 2 per cent of the mother's dose. Drugs for most maternal conditions are safe for the nursing infant. Information is presented to permit nursing mothers who need medication to nurse safely.

Methodology for characterizing distributions of incremental body burdens of 2,3,7,8-TCDD and DDE from breast milk in North American nursing infants.

A clear picture of ranges of doses of breast-milk contaminants experienced by nursing infants in North America has not yet been described, resulting in a significant gap in our understanding of potential health risks to infants from those contaminants. While point estimates of incremental dose have appeared in the published literature, these do not account for the wide variability in exposures experienced by nursing infants. This research expands on the current state of understanding of breast-milk contaminant exposure by characterizing distributions, rather than point estimates, of dose. Distributions of milk intake by nursing infants were characterized to examine intake of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and dichlorodiphenyl dichloroethane (DDE). The results indicate that, despite the uncertainties inherent in modeling incremental body burdens of chemicals from nursing, estimating incremental infant body burdens of lipophilic chemicals from breastfeeding using point estimates may result in overly conservative estimates of the contribution of breastfeeding to long-term body burdens of those chemicals in children. To develop reliable estimates of incremental body burden from nursing, depuration via lactation and half-life in the infant should be considered. Further, incremental infant body burdens of lipophilic chemicals increase rapidly at the start of lactation, but decrease after approximately 5 to 6 mo; by 2 yr postpartum, incremental body burdens have decreased substantially. Given the benefits afforded to infants who breastfeed, and because breastfeeding does not necessarily lead to significantly increased long-term body burdens in infants, breastfeeding should be encouraged and promoted.

Neuropathology of oral-facial-digital syndromes.

A 3-month-old female infant with oral-facial-digital syndrome (OFD-I) was found to have extensive malformations of the brain and spinal cord. Our review of other case reports indicated that the most common central nervous system malformations found in OFD-I include cerebral epithelial (ependymal) cysts, agenesis of the corpus callosum, cerebral micropolygyria, and hypoplasia or dysplasia of the cerebellum, pons, and medulla. It is suggested that the individuals with OFD-I syndrome should be carefully studied clinically and pathologically for complex nervous system anomalies.

Effect of dietary aspartame on plasma concentrations of phenylalanine and tyrosine in normal and homozygous phenylketonuric patients.

Six normal subjects each ingested a single 12-oz can of a diet cola (Diet Coke) providing 184 mg aspartame (APM), of which 104 mg is phenylalanine (Phe), and, on another occasion, a single 12-oz can of regular cola (Coke Classic). Neither cola significantly affected plasma concentrations of Phe or tyrosine over the three-hour postingestion study period. Each of five homozygous phenylketonuric (PKU) subjects (ages 11, 16, 17, 21, and 23 years) ingested a single 12-oz can of the same diet cola. In these five subjects (three with classic PKU and two with hyperphenylalinemia), the increase in plasma Phe concentrations varied from 0.26 mg/dL to 1.77 mg/dL two or three hours after ingestion (baseline levels, 5.04 to 17.2 mg/dL). Tyrosine concentrations did not differ significantly from baseline levels. The data indicate that ingestion of dietary Phe, as supplied in a single can of diet cola, is readily handled in both normal and PKU subjects. The small increases in plasma Phe concentrations in the homozygous PKU patients are not considered clinically significant.

Hepatic granulomata. Presenting with prolonged fever. Resolution with anti-inflammatory treatment.

A patient is described who presented with a 1-month history of daily fever to 38.8 degrees C. There was no sign of joint pain or swelling and no skin rash. The patient had impressive hepatomegaly without splenomegaly. The only abnormal laboratory test was a sedimentation rate of 120 mm/hr. Ultrasound examination showed hypoechoic foci throughout the liver. These foci were confirmed by CT scan, which showed multiple well-marginated lesions of decreased attenuation and variable size throughout the right and left lobes of the liver. A liver biopsy specimen showed large nodules that were yellow and gritty in texture. Microscopic examination of biopsy specimens of these nodules showed extensive areas of necrotizing granulomatous inflammation with palisading histiocytes and occasional giant cells surrounded by necrotic foci. There was an associated fibroinflammatory infiltrate. The patient was treated with a nonsteroidal anti-inflammatory agent with prompt cessation of fever. A repeat CT examination of the liver after 14 months of treatment showed only mild hepatomegaly and a normal liver parenchyma. The focal lesions had disappeared. This is a case of hepatic granulomata in a child showing features of necrotizing inflammation.

Advances in pediatric pharmacology, therapeutics, and toxicology.

This chapter reviews published studies in the field of pediatric therapeutics between July 1998 and July 2000. The most important area discussed in the first part of the chapter concerns the significant advances made in the labeling of drugs for children in the United States. Dr Harry Shirkey coined the term "therapeutic orphan" in 1968 to describe the state of children who were not being considered in either drug development or in drug clinical trials. This explains why about 80% of drugs listed in each edition of the Physicians' Desk Reference do not have labeling for the pediatric age group, especially children younger than 12 years. The recent legislative, regulatory, and pharmaceutical company activities to change this situation are summarized. These changes are current and promise to make significant contributions to the availability of drugs with adequate pediatric indications to the practicing physician. Another important change in recent years has been the appreciation of the importance of placebo-controlled clinical trials for psychotropic medications in children. Trials with one of the selective serotonin reuptake inhibitors, as well as further studies involving the appropriate dosing and preparation of stimulant drugs for attention-deficit/hyperactivity disorder (ADHD), are also discussed. Several new areas that promise significant knowledge in therapeutics are in the treatment of osteoporosis (a neglected condition in pediatrics), arthritis (a condition for which drugs are used to treat the disease rather than the symptoms), and acquisition of data concerning transplacental transfer of human immunodeficiency virus (HIV) and use of multiple anti-HIV drugs for treatment of this virus in the pediatric population.