Population pharmacokinetics of fluconazole in young infants.

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Management of stress urinary incontinence.

Stress urinary incontinence (SUI) is a common disorder that does not require treatment unless bothersome to the patient. The evaluation includes a thorough history and physical in order to evaluate for other bladder and pelvic floor disorders. Multichannel urodynamics are not necessary for the diagnosis of SUI, but may be helpful when choosing among appropriate treatment options and for patient counseling. Behavioral and physical therapies are appropriate first-line treatments and should be discussed with all patients, even those desiring surgical treatment. Conservative treatments include the use of pessaries to improve urethral support. Multiple surgical options exist. While mid-urethral slings are commonly used today, there is a still a role for traditional pubovaginal slings and the Burch retropubic urethropexy.

Risk of nonsteroidal anti-inflammatory drug-associated renal dysfunction among neonates diagnosed with patent ductus arteriosus and treated with gentamicin.

OBJECTIVE: To evaluate the risk of nonsteroidal anti-inflammatory drug (NSAID) therapy-associated acute kidney injury (AKI) among neonates diagnosed with patent ductus arteriosus (PDA) who are treated with gentamicin. STUDY DESIGN: Multicenter retrospective observational study of patients ⩽44 postmenstrual weeks of age diagnosed with PDA who received gentamicin during hospitalization between January 2006 and December 2014. Patients with and without NSAID exposure were matched on covariates associated with AKI and NSAID therapy. The primary end point, AKI, was defined according to Kidney Disease Improving Global Outcomes neonatal criteria. RESULTS: The rate of AKI for the entire cohort (n=594) was 12% (n=71). Among neonates receiving NSAIDS, 14.8% (n=44) experienced an AKI as compared to 9.1% (n=27) for those who were not exposed (relative risk, 1.6; 95% confidence interval, 1.0 to 2.6). Therefore, the attributable risk of NSAID use was 5.7% (95% confidence interval, 0.5 to 11.0). CONCLUSION: Among neonates with PDA and receiving gentamicin, NSAID therapy increases the risk of AKI by about 6%.

Basic and translational research in neonatal pharmacology.

Pharmacologic study is needed in the extremely immature newborns who currently survive. Study is needed of both the drug treatment previously established in more mature neonates and of novel drug therapy. Carefully controlled studies are needed to identify accurately both beneficial and harmful drug therapy and the mechanisms of that toxicity. Careful pharmacologic study of drug disposition and its mechanisms might lead to dosing paradigms or patient selection that minimize toxicity and maximize efficacy. In vivo, translational models of neonatal diseases are limited, but can be used to identify novel treatments and study mechanisms of established, successful therapy. Findings from such studies can generate hypotheses for study in humans leading to a continuing scientific interchange from bedside to bench to bedside. Similarly, clinical observations can generate hypotheses for study in translational models where more invasive analyses are possible. Specific areas of drug treatment should focus on neonatal disorders with long-term, adverse outcomes, such as chronic lung disease, that is amenable to translational study with animal models. National data show a progressive decrease in the clinician-scientist pool entering biomedical research. The future of neonatal pharmacology studies requires an increase in training programs for the physician-scientist whose clinical education in neonatology can be complemented by rigorous basic-science training. Success as a clinician-scientist will require collaboration with full-time basic scientists who can continue studies during periods of clinical work and provide critical study methodology to the overall study design. Such a work environment must be supported by academic institutions and may require more flexibility in the promotion and tenure schedule and process, such as the nature of what it rewards. To complement this, the NIH could modify its grant reporting process to identify co-investigators in studies who may provide unique input to the study concepts and design, such as clinical correlations or clinical investigations.

Prognosis in carcinoma of the urinary bladder based upon tissue blood group abh and Thomsen-Friedenreich antigen status and karyotype of the initial tumor.

Several markers of initial bladder carcinomas described recently may be clinically significant predictors of biological behavior of future recurrences. Comparison of the marker systems and assessment of the value of using multiple markers have been difficult, because the various markers have been studied in different patients. In this study, we compared four markers [chromosome mode, marker chromosomes, and expression of the ABH "blood group" antigens and the Thomsen-Friedenreich antigen (using immunoperoxidase or lectin immunoperoxidase methods)] in 39 patients presenting initially with low-stage bladder carcinoma and followed 3 to 11 years or until deep muscle invasion occurred. Each of the markers was significantly related to subsequent recurrences with deep muscle invasion, and each marker system was able to identify those patients with a very low risk of subsequent invasion. For detection of a subpopulation of patients with Grade II carcinomas who were at high risk for development of subsequent invasion, combinations of markers, especially hyperdiploidy and abnormal expression of the Thomsen-Friedenreich antigen, were significantly more effective than any single marker system.

Developmental pharmacology and toxicology: principles of study design and problems of methodology.

Pharmacologic investigations in the fetus, neonate and child are difficult for the various reasons outlined above, ranging from ethical constraints to difficulties with microanalytic techniques. Attempts to circumvent these difficulties through animal studies, retrospective analyses, and prospective surveys have provided only partial answers. These studies have often helped to guide subsequent similar studies in humans. Results of developmental pharmacologic studies applied to the human must be conducted in humans. The alternatives to randomized, controlled trials presented above may help with these studies, but these innovative study designs must be applied carefully to avoid biasing the results. Although difficult, definitive studies in developmental pharmacology are possible with investigators willing to work within the ethical constraints outlined above, to sensitively consider the needs of perinatal and pediatric patients, and to adhere to the strictest standards of study design.

Assessment of antifungal therapy in an 800-gram infant with candidal arthritis and osteomyelitis.

A 720-g premature newborn developed disseminated candidiasis during treatment with systemic antibiotics and total parenteral nutrition through an umbilical arterial catheter. Clinical features were typical for candidal skeletal infection at this age and included warmth and fusiform swelling of the lower extremities together with radiographic evidence of osteolysis and cortical bone erosion. Candida albicans was cultured from blood, urine, joint fluid, and a bone aspirate. The infection was cured with a 44-day course of amphotericin B and flucytosine (5-fluorocytosine). Antifungal therapy was monitored closely with serum drug levels and laboratory tests for bone marrow toxicity and renal dysfunction. Serum levels of both drugs were comparable to those achieved in older patients treated with similar doses. Significant concentrations of amphotericin B were detected in serum four and 17 days after completion of therapy, indicating a slow rate of elimination similar to that which occurs in adults. There was no evidence of drug-induced toxicity other than transient elevation in the fractional urinary excretion of sodium. This suggests that antifungal therapy may be effectively and safely administered to infants in dose schedules similar to those used for older patients.

Oliguria and tolazoline pharmacokinetics in the newborn.

Tolazoline treatment of neonates has been reported since 1965. Dosages increased from pulse doses of 1 to 2 mg/kg to continuous infusions of 10 mg/kg X h before neonatal plasma tolazoline concentrations were measured. We developed a microassay for tolazoline and determined neonatal distribution volume, 1.61 +/- 0.21 L/kg, and disposition rate constant (beta), 0.0027 +/- 0.005 min-1 (mean +/- SEM). Half-life (gamma) ranged from 1.47 to 41.25 (median = 4.43) hours and correlated inversely with urine output (x); y (h) = -0.46 + 7.63/x (mL/kg X h), r = .61, P less than .05. The highest plasma tolazoline concentration in a neonate was 20.3 mg/L. Lethal tolazoline concentrations in lambs ranged from 21.8 to 56.8 mg/L. Initial tolazoline concentrations during infusions and after 1- to 2-mg/kg pulse doses ranged from 0.35 to 2.3 mg/L and PaO2 increased greater than or equal to 15 mm Hg in 64% of 14 treatments. The average neonatal pharmacokinetics predict that each 1 mg of tolazoline HCl per kilogram pulse dose will increase the plasma concentration of tolazoline base by 0.5 mg/L. The plasma concentration should remain constant with infusion dose increments of 0.16 mg of tolazoline HCl per kilogram per hour for every 1.0-mg/kg loading dose. Tolazoline dose requirements for specific patients will vary, especially with renal dysfunction. Reduced tolazoline doses were used to treat two patients, concentrations remained constant, and PaO2 was maintained. Tolazoline doses derived from neonatal kinetics are less than current infusion doses and may avoid high concentrations.

Acute response to inhaled nitric oxide in newborns with respiratory failure and pulmonary hypertension.

OBJECTIVE: Systemic oxygenation is improved by inhaled nitric oxide therapy in some newborns with respiratory failure and pulmonary hypertension. Our results with inhaled nitric oxide were reviewed to determine factors associated with an acute improvement in systemic oxygenation. METHODS: Newborns with oxygenation indices of 25 to 40 were prospectively randomized to receive conventional therapy with or without 20 ppm inhaled nitric oxide. All newborns with oxygenation indices greater than 40 were treated with inhaled nitric oxide. Hemodynamic, blood gas, and Doppler ultrasound measurements were performed before and after 30 to 60 minutes of observation or therapy. The severity of lung disease was classified by the chest radiograph as: (1) normal or focal disease; (2) moderate diffuse disease-diffuse lung disease with well-defined heart borders; or (3) severe diffuse disease-diffuse lung opacification with indistinct heart borders. RESULTS: Heart rate, blood pressure, and ductal diameters did not change. Blood gases and ductal shunting acutely improved only in patients treated with inhaled nitric oxide. Patients with normal lung fields or focal disease had the greatest degree of improvement in systemic oxygenation. Changes in oxygenation were not influenced by gestational age, baseline blood gases, the proportion of right-to-left ductal shunting, prior treatment with a surfactant, or the use of conventional or high-frequency jet ventilation. Collectively, blood gases and ductal shunting did not improve with inhaled nitric oxide in patients with lung hypoplasia or severe diffuse lung disease. Sustained improvement in oxygenation occurred in 87% of patients with oxygenation indices greater than 40 in whom oxygenation indices less than 40 acutely developed after exposure to nitric oxide, whereas 90% of patients in whom oxygenation indices less than 40 did not acutely develop were treated with extracorporeal membrane oxygenation or ultimately died. CONCLUSIONS: Inhaled nitric oxide acutely improves systemic oxygenation in many newborns with respiratory failure and pulmonary hypertension. The diagnosis and chest radiograph are helpful in identifying patients who will have favorable acute responses to therapy. In patients with severe hypoxemia, the need for invasive support with extracorporeal membrane oxygenation may be determined by an acute trial of inhaled nitric oxide.

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.

Stimulus features that determine the visual location of a bright bar.

A modification to the standard vernier target that has a detrimental effect on acuity is described. The addition of an extra bar alongside one of the test bars and directly underneath the other increases thresholds by an amount that is a monotonic function of its luminance. This allows for the hypothesis that the location of a bright bar is a function of some widespread description of the light distribution arising from such a bar on the retina, rather than some local feature of such a distribution. In particular, the data are not consistent with any simple notion of boundary extraction and support the conjecture that position of a bar is assigned to the mean or centroid of its light distribution.

Evaluation of a QRS scoring system for estimating myocardial infarct size. IV. Correlation with quantitative anatomic findings for posterolateral infarcts.

This study correlated the location and size of posterolateral myocardial infarcts (MIs) measured anatomically with that estimated by quantitative criteria derived from the standard 12-lead ECG. Twenty patients were studied who had autopsy-proved, single, posterolateral MIs and no confounding factors of ventricular hypertrophy or bundle branch block in their ECG. Left ventricular anatomic MI size ranged from 1 to 46%. No patient had a greater than or equal to 0.04-second Q wave in any electrocardiographic lead and only 55% had a 0.03-second Q wave. A 29-point, simplified QRS scoring system consisting of 37 weighted criteria was applied to the ECG. Points were scored by the ECG in 85% of the patients (range 1 to 8 points). MI was indicated by a wide variety of QRS criteria; 19 of the 37 criteria from 8 different electrocardiographic leads were met. The correlation coefficient between MI size measured anatomically and that estimated by the QRS score was 0.72. Each point represented approximately 4% MI of the left ventricular wall.

Diagnosis of pleural effusions by chromosome analysis.

Cytogenetic changes, namely numerical (aneuploidy) and morphologic chromosome abnormalities including markers, clearly indicate the presence of malignant cells. To compare the utility of chromosome and cytogenetic analysis, the idiopathic pleural effusions of 60 patients were subjected to a double-blind analysis. A fluid was considered "positive" for malignancy if there was a marker chromosome, or if 10 percent of metaphases were hyperdiploid. Of the 33 neoplastic effusion, 30 (91 percent) were diagnosed "positive" by chromosome analysis whereas only 21 (64 percent) were classified "positive" or "suggestive positive" by cytology. All 27 benign effusions were correctly diagnosed by cytology; however, two were labelled "positive" by chromosome analysis. Combining the results of cytologic and chromosome analysis did not increase the number of "positive" diagnoses.

Drug therapy of the fetus.

The fetus has become an intended object of drug therapy administered through the mother with the successful prevention of hyaline membrane disease with glucocorticoids. Maternal drug treatment has now been undertaken for a variety of fetal problems, including arrhythmias, congestive heart failure, infections, and inborn errors of adrenal metabolism. Interestingly, this planned maternal drug exposure during pregnancy coincided with increasing concerns during the last two decades about inadvertent transplacental exposure of the fetus to licit and illicit drugs. Efforts to direct drug therapy to the fetus have pointed out important gaps in knowledge of the pharmacology of the maternal-placental-fetal-unit (MPFU), whereas other observations illustrated recognized principles of the pharmacology of the MPFU. Many of these principles fit the basic framework of pharmacokinetics: absorption, distribution, metabolism and excretion. Rapid changes in maternal-placental physiology and fetal development during gestation, however, lead to dramatic variations in these processes throughout pregnancy.

Ten guiding principles for teaching children and adolescents about medicines. US Pharmacopeia.

In 1996, an open conference sponsored by the US Pharmacopeia (USP) and attended by more than 100 health care professionals established the need and rationale for teaching children and adolescents about medicines. After the conference, a public, iterative, consensus-development process including participation by 35 health-professional organizations was undertaken. This process resulted in a USP position statement, "Ten Guiding Principles for Teaching Children and Adolescents About Medicines," which supports the right of children and adolescents to receive developmentally appropriate information and direct communications about medicines that are consistent with their health status, capabilities, and culture. The position statement is intended to stimulate activities that will help children become active participants in the process of appropriate use of medicines and prepare them for the day they begin to use medicines independently.

Difficulties in the study of adverse fetal and neonatal effects of drug therapy during pregnancy.

This article reviews the difficulties in studying adverse effects of drugs during pregnancy on the fetus and newborn. A study design should strive for prospective recording of drug intake during pregnancy, comparison to appropriate control groups adjusted for inherited traits, and single drug exposures for evaluation of specific syndromic causation, such as the Fetal Hydantoin Syndrome. Animal models are best used in mechanistic study of adverse drug effects on the fetus rather than for screening for adverse effects. Careful conclusions about causation of drug-induced adverse effects are needed to avoid false associations while providing appropriate safeguards to the fetus and newborn.

Metabolic effects of methylxanthines.

As predicted, methylxanthines influence several metabolic processes and increase the serum concentrations of glucose, FFAs, and catecholamines in adults. Although these increases are significant statistically, they may not be clinically important. Based upon a small number of studies, methylxanthines seem to affect infants in a more complex fashion. In infants, methylxanthines increase metabolic rate, do not increase catecholamine release, and produce variable effects on carbohydrate balance. The serum glucose concentration after methylxanthines likely represents a complex interplay of glycogen stores, types of nutrient administered, rate of nutrient administration, and degree of increased metabolic rate. Carefully controlled prospective studies are needed to determine the possible effects of methylxanthines on growth, carbohydrate balance, FFA release, and salt and water excretion at high and low serum concentrations. In addition, it is necessary to assess the effect on these variables of chronic pre- and postnatal exposure to methylxanthines.

The detection of deviation from straightness in lines.

A wide range of differently shaped perturbations were introduced into long thin straight lines, and threshold amplitude for their detection was measured. This amplitude threshold varies over a 20-fold range, depending on the shape of the cue, but can be economically expressed as just one numerical value, irrespective of the cue shape. This quantity is the area of the largest bump in the target around a least squares regression line axis, and its value is 0.3 arc min2. This value can be related to a fundamental spatial error of 3 arc sec (standard deviation) which is the limiting constraint on shape sensitivity.

Motion displacement thresholds for compound stimuli predicted by the displacement of centroids.

Minimum displacement thresholds were measured using a compound motion stimulus, in which a single bar split into oppositely moving components, having different luminances and absolute displacements. The results fit a simple model in which observers detect the movement of the centroid of the combined luminance pattern of the two components. This was so even when the two components were separated by more than the static spatial resolution limit of 30 sec arc.

The use of different cues in vernier acuity.

The roles of the various cues in the traditional vernier target are examined. We conclude that there are at least two mechanisms by which vernier acuities of the order of 5 sec arc may be obtained. The two cues are the overall slope of the target, and the relative positional differences. By using vernier targets that are degraded in two different ways, we can demonstrate each mechanism.