Endotypes of difficult-to-control asthma in inner-city African American children.

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

Using ultrasonic fetal size measurements to estimate gestational age in Brisbane, Australia.

The purpose of this paper was to construct population-specific charts of gestational age (GA) from antenatal ultrasound biometry assessment using a large sample of normal Australian pregnancies when examination was carried out to a standard protocol by experienced operators. All consenting eligible women attending a large Brisbane clinic between January 1993 and April 2003 with GA between 15 and 41 weeks, determined before examination from the last menstrual period date and concordant with the biometric-derived gestation published within the Australian Society for Ultrasound in Medicine (ASUM) policies and statements, were recruited into the prospective study if fulfilling the inclusion criteria. Biparietal diameter, femur length, abdominal circumference and head circumference measurements were recorded using ASUM standard protocol for mid and third trimester obstetric morphology scans. Statistical analyses were carried out using polynomial regression models and thorough diagnostic checks were undertaken. Included within the study were separate scans for 20,555 pregnancies from 17,660 women. Equations, means and 95% reference intervals for GA were derived for each sonographic measurement. These new population-specific regression equations complement those previously published in the same sample of Australian pregnancies. Once validated, we believe they should form the basis of a new Australian standard for ASUM.

Ultrasonic fetal size measurements in Brisbane, Australia.

The purpose of this paper was to construct population-specific charts of fetal biometry for 11-41 weeks gestation in relation to known gestational age from a large population of normal Australian pregnancies when examination is performed to a standard protocol by experienced operators. All consenting eligible women attending a large Brisbane clinic between January 1993 and April 2003 were recruited. Menstrual history was taken prior to examination. Measurements were performed to a standard protocol. Prospective assessment was made about the association between gestational age from the last menstrual period and biometry. Exclusion principles were applied. Statistical analyses were performed using polynomial regression models and thorough diagnostic checks were undertaken. Included within the study were separate scans for 20 555 pregnancies from 17 660 women. Equations, means and 95th reference intervals were derived and reported for the following sonographic measurements: biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL). Population-specific regression equations for BPD, HC, AC and FL have been proposed for Australian pregnancies. Once validated by others, we believe they will warrant consideration for adoption by the Australasian Society for Ultrasound in Medicine.

Population pharmacokinetics and use of Monte Carlo simulation to evaluate currently recommended dosing regimens of ciprofloxacin in adult patients with cystic fibrosis.

Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC ratio of >or=125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one- and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained from 1,213 CF patients enrolled in a large clinical trial. A Monte Carlo simulation was performed to estimate the fractional attainment of an AUC(0-24)/MIC ratio of >or=125. A two-compartment model best describes the serum drug concentration data. The mean fitted PK parameter values are volume of distribution in the central compartment, 0.29 liter/kg; volume of distribution at steady state, 1.1 liters/kg; total clearance, 0.34 liter/h/kg; distributional clearance, 0.89 liter/h/kg; half-life at alpha phase, 0.16 h; and half-life at beta phase, 2.9 h. The overall fractional attainment of achieving an AUC(0-24)/MIC ratio of >or=125 against P. aeruginosa isolates with ciprofloxacin (400 mg every 12 h [q12h] and 8 qh) were 10 and 30%, respectively. A clinical breakpoint MIC of <0.5 microg/ml for susceptibility is suggested, based on an examination of the fractional attainment of the AUC(0-24)/MIC target at each MIC. The recommended doses of 400 mg q8h or q12h may be inadequate to treat an acute pulmonary exacerbation when given alone. The poor and variable AUC(0-24)/MIC ratios support the use of TDM to monitor and adjust the dosage to optimize the efficacy of ciprofloxacin therapy in these patients.

Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus.

We have analyzed the blood B cell subpopulations of children with systemic lupus erythematosus (SLE) and healthy controls. We found that the normal recirculating mature B cell pool is composed of four subsets: conventional naive and memory B cells, a novel B cell subset with pregerminal center phenotype (IgD(+)CD38(+)centerin(+)), and a plasma cell precursor subset (CD20(-)CD19(+/low)CD27(+/++) CD38(++)). In SLE patients, naive and memory B cells (CD20(+)CD38(-)) are approximately 90% reduced, whereas oligoclonal plasma cell precursors are 3-fold expanded, independently of disease activity and modality of therapy. Pregerminal center cells in SLE are decreased to a lesser extent than conventional B cells, and therefore represent the predominant blood B cell subset in a number of patients. Thus, SLE is associated with major blood B cell subset alterations.

Estimation of creatinine clearance in patients with metastatic ovarian cancer.

The authors evaluated the predictive performance of four methods used to estimate creatinine clearance (Cl(cr)) in patients with metastatic ovarian cancer. Methods described by Cockcroft and Gault, Jelliffe, and two equations derived from cancer patients by Robinson and Tsubaki, were evaluated. Estimated Cl(cr) values obtained by each method using actual weight (ABW), ideal weight (IBW) and lower of ABW and IBW were compared with measured values determined by a 12- or 24-hour urine collection for 14 patients enrolled in a controlled clinical trial. The mean prediction errors (ME) and mean absolute errors (MAE) were calculated to evaluate the bias and precision, respectively, of each method. The relationship between predicted and measured Cl(cr) is poor (r = 0.38 to 0.54). Cockcroft and Gault using ABW (p = 0.21), Robinson using ABW (p = 0.44), and Jelliffe (p = 0.17) were equally unbiased predictors of measured Cl(cr). All other methods significantly underestimated measured Cl(cr). All methods appeared to be equally imprecise (p<0.05). The use of standard equations for estimating Cl(cr) in patients with ovarian cancer is predictive of the measured 24-hour value. The use of oncology specific equations does not improve the accuracy or precision of these estimates.

Pathophysiology and treatment of psoriasis.

The pathogenesis and treatment of psoriasis are reviewed. Psoriasis is characterized by defects in the normal cycle of epidermal development that lead to epidermal hyperproliferation, altered maturation of skin cells, and vascular changes and inflammation. The condition typically manifests as areas of thickened, flaky, silvery white and reddened skin that may hurt, itch, and bleed. Biochemical markers of psoriasis are changes in levels of keratins, keratinocyte transglutamase, migration inhibitory factor-related protein, skin-derived antileukoproteinase, involucrin, small protein rich protein 2, filaggrin, and cytokines. Types of psoriasis that may be clinically encountered include plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, and pustular psoriasis. Psoriasis is believed to be genetically linked but can also be triggered by mechanical, ultraviolet, and chemical injury; various infections; prescription drug use; psychological stress; smoking; and other factors. Topical treatment of psoriasis is usually the first line of therapy. Topical treatments consist of emollients and keratolytic agents, anthralin, coal tar, corticosteroids, vitamin D3 analogues, topical retinoids, and topical psoralens plus ultraviolet A (UVA) light. In patients who do not respond adequately to topical therapy, oral or injectable therapy, such as oral retinoids, methotrexate, cyclosporine, tacrolimus, and oral psoralens plus UVA light, may be warranted. Patients receiving systemic treatments should be carefully monitored for adverse effects and drug-drug interactions. Drug therapy is the mainstay of the treatment of psoriasis. The potential adverse effects and interactions necessitate vigilant monitoring.

Stability of Ranitidine Hydrochloride with Cefazolin Sodium, Cefbuperazone Sodium, Cefoxitin Sodium and Cephalothin Sodium during Simulated Y-Site Administration.

The compatibility and stability of ranitidine hydrochloride when comixed with four cephalosporins (cefazolin sodium, cefoxitin sodium, cephalothin sodium and cefbuperazone sodium) during simulated Y-site injection were studied. The mixtures were prepared by mixing equal volumes (2 mL) of ranitidine hydrochloride (1mg/mL) and each tested cephalosporin (20 mg/mL) in a 10 mL glass test tube. All study mixtures were prepared in triplicate and stored at room temperature under normal fluorescent room lighting. The physical appearaance and pH of each mixture were recorded; the chemical stability of each drug was immediatedly determined by stability-indicating high-performance liquid chromatography from samples stored for up to four hours after mixing. Stability was defined as the retention of more than 90% of the initial concentration of each drug. Visual inspection revealed no color or clarity change and the pH changes were less than 0.2 pH units in the tested mixtures for cefazolin and cefoxitin: however, there were significant pH changes for cefbuperazone and cephalothin after four hours of storage. Ranitidine retained greater than 90% of its original concentration within the tested period in the mixture with 20 mg/mL of each tested cephalosporin, except for cephalothin (86.6% of control). In the presence of 10 mg/mL cephalothin, however, ranitidine retained greater than 90% for four hours. Meanwhile, all four cephalosporins retained greater than 90% of their original concentrations for up to four hours in the mixture with ranitidine. From the results obtained, it is clear that ranitidine solution may be coadministered with a solution of either cefazolin, cefoxitin or cefbuperazone during Y-site administration for up to four hours after mxining. On the other hand, since ranitidine with cephalothin (20 mg/mL) fell below 90%, the amount of cephalothin should not exceed 10 mg/mL when coadminstered with ranitidine solution.

Citrobacter urinary tract infections in children.

BACKGROUND: Citrobacter species have been described as the etiologic agents in cases of bacteremia, meningitis, diarrhea and brain abscess, but little is known of their role as a cause of urinary tract infections in children. The purpose of this study was to define the role of Citrobacter species in pediatric urinary tract infections. METHODS: The project consisted of a retrospective chart review of microbiologic and medical records of patients younger than 18 years of age with urine cultures positive for Citrobacter species during a 3-year period. RESULTS: Thirty-four patients with 37 infections were included in the review. The average patient age was 6.9 years (range, 1 month to 18 years) and 71% were female. Fifty-six percent of the patients had urinary tract/renal anomalies or neurologic impairment and 26% represented nosocomial infections. Thirty-seven percent of patients were asymptomatic at the time of diagnosis, whereas 63% complained of at least one of the following findings: gastrointestinal symptoms; dysuria; fever; incontinence; penile/vaginal discharge; frequency; flank pain; and hematuria. Twenty-six of the isolates were Citrobacter freundii and 11 were Citrobacter koseri. Blood cultures were obtained in 9 patients and all were negative for Citrobacter isolates. CONCLUSIONS: Although it is uncommon Citrobacter can cause urinary tract infections in the pediatric population, which occur more frequently in children with underlying medical conditions. It appears that treatment similar to that of other gram-negative enteric organisms is the most prudent approach to these children until more information can be gathered.

Five-day Stability of Vinorelbine in 5% Dextrose Injection and in 0.9% Sodium Chloride Injection at Room Temperature.

The stability of vinorelbine tartrate in 5% dextrose injection or 0.9% sodium chloride injection stored in polyvinyl chloride minibags was studied. Vinorelbine was diluted to concentrations of 0.5 mg/mL or 2 mg/mL in the above vehicles, and the solution was placed at room temperature and exposed to constant fluorescent lighting. Three bags were prepared for each concentration and solution and each bag was assayed for vinorelbine concentration by stability-indicating high-performance liquid chromatography at 0, 24, 48, 96, and 120 hours. Each solution was inspected for clarity, color and precipitation. Throughtout the study, the mean concentration of vinorelbine remaining was more than 94% of the initial concentration in both vehicles. No precipitation, color change or haziness was seen. Vinorelbine, at concentrations of 0.5 mg/mL or 2 mg/mL in 5% dextrose injeciotn or 0.9% sodium chloride injection, was stable for at least 120 hours at room temperature under fluorescent lighting.

Stability of Milrinone Lactate 200 micrograms/mL in 5% Dextrose Injection and 0.9% Sodium Chloride Injection.

The stability of milrinone lactate 200 microgram/mL in either 5% dextrose injection or 0.9% sodium chloride injection was studied. The solutions were prepared in polyvinyl chloride bags and aliquots of 10 mL were withdrawn at times zero, one, three, seven and 14 days at room (20 to 25 deg C) and refrigerated (2 to 8 deg C) temperatures. The samples were then stored at -20 deg C and analyzed for potency using a stability-indicating high-performance liquid chromatography assay procedure. Stability was defined as 90% or greater of the original concentration remaining. Samples were inspected visually and no color change, haziness or precipitation was observed at any time during the study. Milrinone lactate 200 micrograms/mL mixed in either 5% dextrose injection or 0.9% sodium chloride injection is stable at room or refrigerated temperatures for 14 days.

Stability of Milrinone Lactate in 5% Dextrose Injection and 0.9% Sodium Chloride Injection at Concentrations of 400, 600, and 800 micrograms/mL.

Milirone lactate is a phosphodiesterase inhibitor that is used in the acute phase of congestive heart failure. It is available in ready-to-use intravenous piggybacks at a concentration of 200 micrograms/mL and in 10-mL and 20-mL vials at a concentration of 1 mg/mL. The stability of milrinone lactate at highter concentrations of 400, 600, and 800 micrograms/mL in 5% dextrose injection and 0.9% sodium chloride injection was studied. The solutions were prepared in polyvinyl chloride bags and aliquots of 10mL were withdrawn initially and after one, three and seven days at room and refrigerator temperatures under normal light. The aliquots were stored at -20 deg C and analyzed for potency using a high-performance liquid chromatography proceure. Both intraday and interday variations of the external standard were less than 4%. Stablility was defined as 90% or greater of the original concentration remaining. Milrinone lactate prepared in either 5% dextrose injection or 0.9% sodium chloride injection at concentrations of 400, 600, and 800 micrograms/mL is stable at room or refrigerated temperature for 14 days.

Compatibility and stability of ranitidine hydrochloride with six cephalosporins during simulated y-site administration.

The purpose of this project was to determine the visual compatibility and stability of ranitidine hydrochloride in admixtures during simulated Y-site administration with six individual cephalosporins: ceftizoxime sodium, cefuzonam sodium, cefoperazone sodium, cefmenoxime hydrochloride, moxalactam disodium and flomoxef sodium. Dilutions of ranitidine hydrochloride 1 mg (as the free base)/mL were prepared in 0.9% sodium chloride injection. Two milliliters of the ranitidine solution (1mg/mL) was mixed with 2mL of each cephalosporin (20 mg/ml) in 10 mL glass test tubes. Concentrations of each drug were determined by stability-indicationg high-performance liquid chromatographic assay methods following zero, one, two, and four hours after mixing. All six cephalosporins retained greater than 95% of their original concentrations for four hours in the admixture with ranitidine. Ranitidine retained greater than 95% of its original concentration for four hours in the admixture with four of the tested cephalosporins and apporximately 90% with moxalactam and flomoxef. Solutions containing ranitidine may be coadministered with solutions either ceftizoxime, cefuzonam, cefoperazone or cefmenoxime via Y-injection site over four hours. While the ranitidine concentration may be reduced to near 90% after four hours with moxalactam and flomoxef, the tested antibiotics were not affected in the presence of ranitidine over four hours.

Pharmacokinetics of aztreonam in critically ill surgical patients.

The pharmacokinetics of aztreonam in critically ill surgical patients with serious gram-negative infections were studied. Blood samples were taken before and at 30 minutes, 2.5 hours, and 5 hours after a dose of aztreonam 2 g i.v. every six hours. All patients had received at least two aztreonam doses before the dosage interval being studied. Aztreonam concentrations were measured by high-performance liquid chromatography. Aztreonam's pharmacokinetics, the severity of illness, and patient outcomes were examined. A total of 28 patients with 111 serum aztreonam concentrations were included in the analysis. The patients were young (mean age, 35 years) and predominantly male. The mean APACHE II score was 19.3, and 22 patients had sepsis. Four patients died. The mean volume of distribution (V) of 0.35 L/ kg was nearly twice the previously reported steady-state value for healthy volunteers (0.18 L/kg) and was highly variable. A slightly higher than normal mean V, 0.22 L/ kg, was seen in a subset of six patients whose infection occurred earlier in their intensive care and who had lower APACHE II scores. While with some antibiotics the elevated V would imply difficulty in achieving therapeutic drug levels, 99 (89%) of the 111 concentrations were at or above the in vitro susceptibility breakpoint of 8 micrograms/mL. Despite observations of markedly increased and highly variable V in critically ill surgical patients, a standard dosage of aztreonam was usually sufficient to maintain adequate serum drug levels.

Factors associated with antihypertensive prescribing.

OBJECTIVE: To investigate factors associated with treatment approaches to hypertension, a major risk factor for coronary heart and cerebrovascular disease and significant healthcare problem in the US. The study reports on three cross-sectional national surveys of patient-physician encounters. POPULATION: Visits were selected for adults with hypertension diagnoses from the National Ambulatory Medical Care Surveys, which represent office encounters during a given year. Years of observation included 1989, 1990, and 1991. METHODS: Multiple variable logistic regression was used to identify predisposing need, enabling, and health utilization characteristics associated with whether the visit resulted in a prescription of an antihypertensive. Additionally, the association of these visits with combination therapy is determined. RESULTS: For each of the 3 years, 69-75% of the encounters were associated with a prescription for drugs to treat hypertension. Prescribing is consistent with current literature demonstrating decreasing reliance on diuretics and beta-blockers, and increasing reliance on calcium antagonists. Combination therapy decreased as a percentage of prescriptions in 1990 and 1991. Variables associated with receiving an antihypertensive prescription included predisposing characteristics (patient age > 65 y), need characteristics (diagnosis of congestive hear failure [CHF]), and health utilization characteristics (physician specialty, previous diagnosis of hypertension). The most significant variables associated with combination therapy were predisposing characteristics (patient age > 65 y), need (CHF diagnosis, diagnosis of hypertension with end organ involvement), and health utilization characteristics (physician specialty). CONCLUSIONS: These national estimates reinforce previous regional data regarding the categories of hypertension medications used. Patient visits involving multiple diagnoses, cardiologists, or patients older than 65 years, are more likely to generate prescriptions for combination antihypertensive therapy.

Pharmacokinetics of meropenem in animals, healthy volunteers, and patients.

Meropenem is a carbapenem antibiotic that appears to be widely distributed in tissues and is eliminated by both excretion and metabolism. Approximately 70% of meropenem is excreted via the kidneys, thus dosage adjustments are required for patients with renal impairment. The pharmacokinetic parameters for meropenem are similar to those for imipenem/cilastatin, with the exception of meropenem's smaller volume of distribution. The urinary recovery of meropenem is as high as that of imipenem in combination with cilastatin, an inhibitor of renal dehydropeptidase. Therefore, unlike imipenem, meropenem can be used without dehydropeptidase inhibitors to obtain a consistently high concentration in the urine without nephrotoxic effects.