bluuebunny/crossref_metadata_2025 huggingface dataset:
Age‐Specific Questionnaires Distinguish GERD Symptom Frequency and Severity in Infants and Young Children: Development and Initial Validation
Authors: Deal Linda , Gold Benjamin D , Gremse David A , Winter Harland S , Peters Suzanne B , Fraga Polly D , Mack Michael E , Gaylord Stefanie M , Tolia Vasundhara , Fitzgerald Joseph F
Published: July 2005

Two gastroesophageal reflux disease (GERD) symptom questionnaires were developed and tested prospectively in a pilot study conducted in infants (1 through 11 months) and young children (1 through 4 years) with and without a clinical diagnosis of GERD. A pediatric gastroenterologist made the clinical diagnosis of GERD. Parents or guardians at 4 study sites completed the questionnaires, providing information on the frequency and severity of symptoms appropriate to the 2 age cohorts. In infants, symptoms assessed were back arching, choking or gagging, hiccups, irritability, refusal to feed and vomiting or regurgitation. In young children, symptoms assessed were abdominal pain, burping or belching, choking when eating, difficulty swallowing, refusal to eat and vomiting or regurgitation. Respondents were asked to describe additional symptoms. Symptom frequency was the number of occurrences of each symptom in the 7 days before completion of the questionnaire. Symptom severity was rated from 1 (not at all severe) to 7 (most severe). An individual symptom score was calculated as the product of symptom frequency and severity scores. The composite symptom score was the sum of the individual symptom scores. The mean composite symptom and individual symptom scores were higher in infants (P < 0.001 and P < 0.05, respectively) and young children (P < 0.001 and P < 0.05, respectively) with GERD than controls. Vomiting/regurgitation was particularly prevalent in infants with GERD (90%). Both groups with GERD were more likely to experience greater severity of symptoms. We found the GERD Symptom Questionnaire useful in distinguishing infants and young children with symptomatic GERD from healthy children.
Testing the Association Between Gastroesophageal Reflux and Apnea in Infants
Authors: Mousa Hayat , Woodley Frederick W , Metheney Melissa , Hayes John
Published: July 2005

Background:

There is controversy regarding the association between gastroesophageal reflux and apnea. The controversy is further confused by the variety of ways reflux is detected, the varying methods of data analysis and the heterogeneity of subjects studied.

Objectives:

To determine if apnea is associated with reflux and to determine whether the association differs with acid or non acid reflux.

Methods:

We prospectively evaluated infants with apparent life‐threatening events or apnea by simultaneous pneumography, esophageal pH and multichannel intraluminal impedance monitoring. Apneic events and reflux frequency, duration, acidity and height were recorded. Apneic events were considered to be temporally linked to gastroesophageal reflux when they occurred during a gastroesophageal reflux episode or within 5 minutes after clearance of the refluxate. Data described with frequency tables, scatterplots and time series graphs were analyzed by regression analysis and χ2 testing.

Results:

Twenty‐five infants (10 males) aged 1 to 19 months were studied for up to 24 hours. Of 527 total apneic episodes, only 80 (15.2%) were temporally linked with gastroesophageal reflux: 37 (7.0%) with acid reflux and 43 (8.2%) with non‐acid reflux. Scatterplots revealed no significant correlation between apnea and frequency or duration of reflux episodes. Individual χ2 analyses within subjects found limited associations between reflux and apnea. Regression analyses showed a significant association between apnea and reflux in 4 of 25 subjects.

Conclusions:

We found little evidence for an association between apnea and total reflux, acid reflux or non‐acid reflux. There was no difference between acid gastroesophageal reflux and non‐acid gastroesophageal reflux in the frequency association with apnea. Either a χ2 statistic for each subject or R2 value computed from a lagged regression model for each subject can be used as an index of association in patient evaluation.
On the nature of constraints for continua undergoing dissipative processes
Authors: Rajagopal K.R , Srinivasa A.R
Published: July 2005

When dealing with mechanical constraints, it is usual in continuum mechanics to enforce ideas that stem from the seminal work of Bernoulli and D'Alembert and require that internal constraints do no work. The usual procedure is to split the stress into a constraint response and a constitutively determined response that does not depend upon the variables that appear in the constraint response (i.e. the Lagrange multiplier), and further requiring that the constraint response does no work. While this is adequate for hyperelastic materials, it is too restrictive in the sense that it does not permit a large class of useful models such as incompressible fluids whose viscosity depends upon the pressure—a model that is widely used in elastohydrodynamics.

The purpose of this short paper is to develop a purely mechanical theory of continua with an internal constraint that does not appeal to the requirement of worklessness. We exploit a geometrical idea of normality of the constraint response to a surface (defined by the equation of constraint) in a six-dimensional Euclidean space to obtain (i) a unique decomposition of the stress into a determinate and a constraint part such that their inner product is zero, (ii) a completely general constraint response—even constraint equations that are nonlinear in the symmetric part of the velocity gradient

D

as well as when the coefficients in the determinate part depend upon the constraint response and (iii) a second order partial differential equation for the determination of the constraint response. The geometric approach presented here is in keeping with the ideas of Gauss concerning constraints in classical particle mechanics.
Varying constants
Authors: Barrow JohnD
Published: July 2005

We review properties of theories for the variation of gravitation and fine structure ‘constants’. We highlight some general features of the cosmological models that exist in these theories with reference to recent quasar data that are consistent with time variation in the fine structure constant since a redshift of 3.5. The behaviour of a simple class of varying-alpha cosmologies is outlined in the light of all the observational constraints.
Bose–Einstein condensates and precision measurements
Authors: Dunningham Jacob , Burnett Keith , Phillips William D
Published: July 2005

An ongoing challenge in physics is to make increasingly accurate measurements of physical quantities. Bose–Einstein condensates in atomic gases are ideal candidates for use in precision measurement schemes since they are extremely cold and have laser-like coherence properties. In this paper, we review these two attributes and discuss how they could be exploited to improve the resolution in a range of different measurements.
The fundamental constants and theory
Authors: Mohr Peter J
Published: July 2005

The Committee on Data for Science and Technology has recently recommended a new self-consistent set of values of basic constants and conversion factors of physics and chemistry. These values are based on a least-squares analysis that takes into account all of the latest relevant experimental and theoretical information in a consistent framework. Theory plays a role, because the experimental data are compared to the corresponding theoretical predictions which are functions of the fundamental constants. The best values of the constants are taken to be those that give the best agreement between the data and these predictions, in the least-squares sense. An overview of the calculations that influence the recommended values of the constants will be given.
The development of modern metrology and its role today
Authors: Quinn Terry , Kovalevsky Jean
Published: July 2005

Modern metrology is the result of more than 200 years of development that began with the creation of the decimal metric system at the time of the French Revolution and the beginning, at about the same time, of mass production using interchangeable parts. This article traces these developments and describes how world metrology is organized today and gives examples of applications of metrology showing how it concerns us all in many aspects of our daily life.
Causal effect of early initiation on adolescent smoking patterns
Authors: Auld M. Christopher
Published: July 2005

Abstract.  A key concern in policy debates over youth smoking is whether preventing children from smoking will stop them from smoking as adults or merely defer initiation into smoking. This paper estimates determinants of smoking status in late adolescence viewing smoking at age 14 as an endogenous ‘treatment’ on subsequent smoking. This approach disentangles causation from unobserved heterogeneity and allows addictiveness to vary across individuals. Exploiting large tax changes across time and across regions in Canada in the early 1990s, the estimated model suggests that smoking is highly addictive for the average youth but less so for youths who actually do initiate early or who are likely to be induced to initiate early at the margin. Thus, policies that deter initiation will reduce eventual smoking rates, but not by as large a magnitude as conventional econometric models might suggest. JEL classification: I1, C3
Sex, equality, and growth
Authors: Lagerlöf Nils‐Petter
Published: July 2005

Abstract.  We set up a model of economic and demographic long‐run development, where inequality in income and reproductive success (polygynous mating) plays a central role. The model generates a slow and gradual compression of the income gap between landholders and landless, together with rising levels of human capital. This process spurts at some stage, as society endogenously transits into sustained growth. Simultaneously, inequality in income and reproductive success drops; society becomes monogamous.
Unbalanced growth
Authors: Krishna Kala , Pérez César A.
Published: July 2005

Abstract.  We study a model designed to understand the concept of unbalanced growth. We define leading sectors to be those that raise the profits from industrialization for other sectors the most. We identify the leading sectors and show that subsidizing them in sequence will raise welfare if the future is not discounted too strongly.
Gradual globalization and inequality between and within countries
Authors: Das Satya P.
Published: July 2005

Abstract.  This paper investigates the effects of gradual trade liberalization on intra‐country and inter‐country inequality. It assumes two countries, North and South, and two factors, skilled labour and unskilled labour. North is defined as the one that is relatively skilled‐labour abundant and larger. A marginal trade liberalization from autarky is shown to (a) increase (decrease) in skilled‐unskilled wage differential in the North (South) and (b) raise the inequality between North and South. As the global economy approaches free trade, a marginal trade liberalization has effects, which are the opposite of (a) and (b); that is, the relative wage falls in the North and rises in the South, and North‐South inequality decreases.
R&D cooperation with asymmetric spillovers
Authors: Atallah Gamal
Published: July 2005

Abstract.  This paper analyses R&D cooperation with asymmetric spillovers. It is shown that the change in R&D by a firm following cooperation is proportional to the gap between the spillover rate transmitted by that firm and a critical level of spillovers. In consequence, cooperation increases total R&D investments when the average of firms’ spillover rates is sufficiently high. Whereas with symmetric spillovers cooperation is always beneficial to firms, with asymmetric spillovers only a very limited range of spillovers makes cooperation beneficial to both firms. Asymmetries also create a potential conflict between maximizing total welfare and maximizing effective cost reduction. JEL classification: L13, O33
A discipline without sympathy: the happiness of the majority and its demise
Authors: Peart Sandra J. , Levy David M.
Published: July 2005

Abstract. Experimental economists frequently invoke Adam Smith's notion of sympathy, and experimental treatments typically examine sympathy in situations where two groups are involved. We explore additional implications of sympathy suggested by the work of later classical economists. We link the notion of sympathy to their majoritarian welfare analysis. Since sympathy provides a source of moral obligation, classical economists held that agents in democratic politics will refrain from unjust acts. We also consider how sympathetic agents may effect reforms that involve more than two parties, in which the benefits from the action accrue to someone who is not part of the ‘exchange.’ JEL classification: B12, D63
Optimal risk‐sharing under adverse selection and imperfect risk perception
Authors: Chassagnon Arnold , Villeneuve Bertrand
Published: July 2005

Abstract.  The present paper thoroughly explores second‐best efficient allocations in an insurance economy with adverse selection. We start with a natural extension of the classical model, assuming less than perfect risk perception. We characterize the constraints on efficient redistribution, and we summarize the incidence of incentives on the economy with the notions of weak and strong adverse selection. Finally, we show in what sense improving risk perception enhances welfare.
Inflation targeting and core inflation
Authors: Smith Julie K.
Published: July 2005

Abstract.  This paper examines the interaction of core inflation and inflation targeting as a monetary policy regime. Interest in core inflation has grown because of inflation targeting. Core inflation is defined in numerous ways giving rise to many potential measures; this paper defines core inflation as the best forecaster of inflation. A cross‐country study finds before the start of inflation targeting, but not after, core inflation differs between non‐inflation targeters and inflation targeters. Through conditional regressions, inflation expectations as measured by core inflation have not changed with the advent of inflation targeting nor do they differ from non‐targeters. JEL classification: E52 and E31
The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces
Authors: Kaetzel Charlotte S.
Published: July 2005

Summary:  Secretory antibodies of the immunoglobulin A (IgA) class form the first line of antigen‐specific immune protection against inhaled, ingested, and sexually transmitted pathogens and antigens at mucosal surfaces. Epithelial transcytosis of polymeric IgA (pIgA) is mediated by the polymeric immunoglobulin receptor (pIgR). At the apical surface, the extracellular ligand‐binding region of pIgR, known as secretory component (SC), is cleaved and released in free form or as a component of secretory IgA (SIgA). SC has innate anti‐microbial properties, and it protects SIgA from proteolytic degradation. Expression of pIgR is regulated by microbial products through Toll‐like receptor signaling and by host factors such as cytokines and hormones. Recent studies of the structure of the extracellular ligand‐binding domain of pIgR have revealed mechanisms by which it binds pIgA and other ligands. During transcytosis, pIgA has been shown to neutralize pathogens and antigens within intracellular vesicular compartments. The recent identification of disease‐associated polymorphisms in human pIgR near the cleavage site may help to unravel the mystery of how pIgR is cleaved to SC. The identification of novel functions for SC and SIgA has expanded our view of the immunobiology of pIgR, a key component of the mucosal immune system that bridges innate and adaptive immune defense.
Rapidly changing perspectives about mast cells at mucosal surfaces
Authors: Vliagoftis Harissios , Befus A. Dean
Published: July 2005

Summary:  Mast cells (MCs) are major effector cells of immunoglobulin E (IgE)‐mediated allergic inflammation. However, it has become increasingly clear that they also play important roles in diverse physiological and pathological processes. Recent advances have focused on the importance of MCs in both innate and adaptive immune responses and have fostered studies of MCs beyond the myopic focus on allergic reactions. MCs possess a variety of surface receptors and may be activated by inflammatory mediators, IgE, IgG, light chains, complement fragments, proteases, hormones, neuropeptides, and microbial products. Following activation, they produce a plethora of pro‐inflammatory mediators and participate in inflammatory reactions in many organs. This review focuses on the role of MCs in inflammatory reactions in mucosal surfaces with particular emphasis on their role in respiratory and gastrointestinal inflammatory conditions.
Oral tolerance
Authors: Faria Ana M. C. , Weiner Howard L.
Published: July 2005

Summary:  Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T‐helper 2 [interleukin (IL)‐4/IL‐10] and Th3 [transforming growth factor (TGF)‐β] T cells plus CD4+CD25+ regulatory cells and latency‐associated peptide+ T cells. Induction of oral tolerance is enhanced by IL‐4, IL‐10, anti‐IL‐12, TGF‐β, cholera toxin B subunit, Flt‐3 ligand, and anti‐CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non‐obese diabetic (NOD) mouse, plus non‐autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at‐risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen‐specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy.
Organizing a mucosal defense
Authors: Newberry Rodney D. , Lorenz Robin G.
Published: July 2005

Summary:  Gastrointestinal associated lymphoid tissue can be divided into loosely organized effector sites, which include the lamina propria and intraepithelial lymphocytes, and more organized structures, such as mesenteric lymph nodes (LNs), Peyer's patches (PPs), isolated lymphoid follicles, and cryptopatches (CPs). These organized structures in the gastrointestinal tract have been hypothesized to play the role of primary lymphoid organ, supporting the extrathymic development of T lymphocytes (CPs), secondary lymphoid organs involved in the induction of the mucosal immune response (PPs), and tertiary lymphoid structures whose function is still under debate (isolated lymphoid follicles). The most widely studied lymphoid structure found in the small intestine is the PP. PPs are secondary lymphoid structures, and their development and function have been extensively investigated. However, single lymphoid aggregates resembling PPs have been also described in humans and in the murine small intestines. These isolated lymphoid follicles have both germinal centers and an overlying follicle‐associated epithelium, suggesting that they also can function as inductive sites for the mucosal immune response. This review compares and contrasts the development and function of the four main organized gastrointestinal lymphoid tissues: CPs, isolated lymphoid follicles, PPs, and mesenteric LNs.
IELs: enforcing law and order in the court of the intestinal epithelium
Authors: Cheroutre Hilde
Published: July 2005

Summary: The intestinal intraepithelial lymphocytes (IELs) are mostly T cells dispersed as single cells within the epithelial cell layer that surrounds the intestinal lumen. IELs are, therefore, strategically located at the interface between the antigen‐rich outside world and the sterile core of the body. The intestine of higher vertebrates has further evolved to harbor numerous commensal bacteria that carry out important functions for the host, and while defensive immunity can effectively protect against the invasion of pathogens, similar immune reactions against food‐derived antigens or harmless colonizing bacteria can result in unnecessary and sometimes damaging immune responses. Probably as a result of this unique dilemma imposed by the gut environment, multiple subsets of IEL have differentiated, which all display characteristics of ‘activated yet resting’ immune cells. Despite this common feature, IELs are heterogeneous with regard to their phenotype, ontogeny, and function. In this review, we discuss the different subtypes of IELs and highlight the distinct pathways they took that led to their unique differentiation into highly specialized effector memory T cells, which provide the most effective immune protection yet in a strictly regulated fashion to preserve the integrity and vital functions of the intestinal mucosal epithelium.
Innate and adaptive immunity in female genital tract: cellular responses and interactions
Authors: Wira Charles R. , Fahey John V. , Sentman Charles L. , Pioli Patricia A. , Shen Li
Published: July 2005

Summary:  The mucosal immune system in the female reproductive tract (FRT) has evolved to meet the unique requirements of dealing with sexually transmitted bacterial and viral pathogens, allogeneic spermatozoa, and the immunologically distinct fetus. Analysis of the FRT indicates that the key cells of the innate and adaptive immune systems are present and functionally responsive to antigens. Acting through Toll‐like receptors in the Fallopian tubes, uterus, cervix, and in the vagina, epithelial cells, macrophages, natural killer cells, and neutrophils confer protection through the production of chemokines and cytokines, which recruit and activate immune cells, as well as bactericidal and virucidal agents, which confer protection at times when adaptive immunity is downregulated by sex hormones to meet the constraints of procreation. The overall goal of this paper is to define the innate immune system in the FRT and, where possible, to define the regulatory influences that occur during the menstrual cycle that contribute to protection from and susceptibility to potential pathogens. By understanding the nature of this protection and the ways in which innate and adaptive immunity interact, these studies provide the opportunity to contribute to the foundation of information essential for ensuring reproductive health.
Intestinal macrophages: unique effector cells of the innate immune system
Authors: Smith Phillip D. , Ochsenbauer‐Jambor Christina , Smythies Lesley E.
Published: July 2005

Summary:  The gastrointestinal mucosa is the largest reservoir of macrophages in the body. These important effector cells are derived from blood monocytes that are recruited to the lamina propria by endogenous chemoattractants in the non‐inflamed mucosa and by inflammatory chemokines and bacterial products during inflammation. In the non‐inflamed mucosa, newly recruited pro‐inflammatory monocytes are exposed to lamina propria stromal (extracellular matrix) factors that induce phenotypic and functional differentiation into non‐inflammatory macrophages. As a consequence of this differentiation, resident lamina propria macrophages are strikingly downregulated for the expression of innate response receptors, such as the receptors for lipopolysaccharide, immunoglobulin G (IgG), and IgA, and the production of pro‐inflammatory cytokines, including interleukin‐1 (IL‐1), IL‐6, IL‐8, and tumor necrosis factor‐α. Despite downregulated pro‐inflammatory function, strong phagocytic and bactericidal activities remain intact. Thus, in the non‐inflamed intestinal mucosa, lamina propria macrophages are non‐inflammatory but retain avid scavenger and host defense functions, a unique but ideal phenotype and functional profile for effector cells in close proximity to immunostimulatory microorganisms and products.
Mucosal immunoglobulins
Authors: Woof Jenny M. , Mestecky Jiri
Published: July 2005

Summary:  Due to their vast surface area, the mucosal surfaces of the body represent a major site of potential attack by invading pathogens. The secretions that bathe mucosal surfaces contain significant levels of immunoglobulins (Igs), which play key roles in immune defense of these surfaces. IgA is the predominant antibody class in many external secretions and has many functional attributes, both direct and indirect, that serve to prevent infective agents such as bacteria and viruses from breaching the mucosal barrier. This review details current understanding of the structural and functional characteristics of IgA, including interaction with specific receptors (such as FcαRI, Fcα/µR, and CD71) and presents examples of the means by which certain pathogens circumvent the protective properties of this important Ig.
Defects in mucosal immunity leading to Crohn's disease
Authors: Cobrin Gena M. , Abreu Maria T.
Published: July 2005

Summary:  Crohn's disease (CD) is characterized by patchy transmural inflammation involving any part of the intestinal tract. Animal models have provided a great deal of insight into the pathogenesis of CD, but no animal model has recapitulated the full spectrum of manifestations witnessed in human disease. The defects in mucosal immunity in CD can be divided into those that involve the epithelial barrier, those that involve the innate immune response, and finally, defects in the adaptive immune response. Defects in the epithelial barrier in CD include an increase in intestinal permeability, increased adherence of bacteria, and decreased expression of defensins. Murine and human studies have demonstrated an increased expression of T‐helper 1 (Th1) cytokines by lamina propria lymphocytes. This increased Th1 cytokine expression is driven by interleukin‐12 (IL‐12)/IL‐23 and tumor necrosis factor‐like 1A (TL1A) production by antigen‐presenting cells, resulting in Tbet expression by CD4+ T cells. Another dimension of the inappropriate immune response in CD is T‐cell and B‐cell reactivity to luminal microbes. With the identification of the nucleotide‐binding oligomerization domain 2 (NOD2) gene as a susceptibility gene, defects in the innate immune response are beginning to be explored. One may consider a model in which defective innate immune clearance of pathogens or commensal bacteria in CD leads to an inappropriate adaptive immune response to the commensal flora.
Innate and adaptive immunity: the Yin and Yang of celiac disease
Authors: Jabri Bana , Kasarda Donald D. , Green Peter H. R.
Published: July 2005

Summary:  Celiac disease is a multigenetic complex inflammatory disorder with an autoimmune component, induced by gluten, a protein found in wheat. It is a unique human disease model to dissect the innate and adaptive immune mechanisms underlying T‐cell‐mediated tissue destruction and the development of T‐cell lymphoma in conditions of chronic T‐cell activation.
Non‐classical MHC class I molecules on intestinal epithelial cells: mediators of mucosal crosstalk
Authors: Shao Ling , Kamalu Okebugwu , Mayer Lloyd
Published: July 2005

Summary:  The mucosal immune environment consists of a complex combination of lymphoid cells, non‐lymphoid cells, and lumenal bacteria. Signals from lumenal bacteria are constantly transmitted to the underlying tissues across the intestinal epithelial barrier. Intestinal epithelial cells (IECs) can sense these signals, integrate them, and interpret them for lamina propria lymphoid populations. One mechanism by which these signals are communicated is by the expression of non‐classical major histocompatibility complex (MHC) class I molecules by IECs. Epithelial cells can express a surprising variety of non‐classical MHC class I molecules. In some cases, IECs can act as non‐professional antigen‐presenting cells utilizing the expression of such non‐classical MHC class I molecules to directly present bacterial antigens. In other cases, the expression of non‐classical MHC class I molecules may act as a co‐stimulatory molecule or adhesion molecule that can modify the mucosal immune response. Finally, the expression of these molecules on IECs can lead to a broad array of responses ranging from tolerance to inflammation. Overall, the IEC, via the expression of non‐classical MHC class I molecules, is a central mediator of the constant crosstalk between the intestinal lumen and the mucosal immune system.
Equivalent lung deposition of budesonide in vivo: a comparison of dry powder inhalers using a pharmacokinetic method
Authors: Lähelmä Satu , Kirjavainen Merja , Kela Marjo , Herttuainen Jukka , Vahteristo Mikko , Silvasti Matti , Ranki‐Pesonen Marjut
Published: July 2005

Aims

The aim of this study was to compare lung deposition of budesonide administered from two dry powder inhalers, Giona® Easyhaler® 200 µg/dose and Pulmicort® Turbuhaler® 200 µg/dose by utilizing a pharmacokinetic method.

Methods

This was an open, randomized, crossover study in 33 healthy subjects. The study consisted of four treatment periods separated by at least 4 wash‐out days. Equivalence in lung deposition was assessed after a single inhaled 1000 µg (5 × 200 µg) dose of budesonide from Giona® Easyhaler® and from Pulmicort® Turbuhaler®. Concomitant oral charcoal administration (40 g) was used to prevent gastrointestinal (GI) absorption of budesonide. The efficacy of the charcoal was studied after oral administration of a budesonide 2 mg capsule. The subjects were trained to inhale the study drugs with controlled flow rates, which resulted in an equal pressure drop (4 kPa) across both inhalers. Venous blood samples for the determination of budesonide concentrations in plasma were drawn before and at predetermined time points up to 8 h after drug administration. Budesonide concentrations in plasma were determined using liquid chromatography‐tandem mass spectrometry. Several pharmacokinetic parameters were estimated, the area under the budesonide concentration in plasma vs time curve from dosing to infinity (AUC(0, ∞)) being the primary response variable. Equivalence in lung deposition was concluded if the 90% confidence interval (CI) for the Easyhaler® : Turbuhaler® ratio of AUC(0, ∞) fell within the limits of 0.8–1.25.

Results

The mean AUC(0,∞) value after Easyhaler® treatment was 3.48 (standard deviation (SD) 0.93) ng ml−1 h and after Turbuhaler® treatment 3.46 (1.13) ng ml−1 h. The Easyhaler® : Turbuhaler® AUC(0, ∞) ratio was 1.02 and the 90% CI was from 0.96 to 1.09. The mean Cmax values (SD) for budesonide in plasma after Easyhaler® and Turbuhaler® treatments were 1.22 (0.41) ng ml−1 and 1.29 (0.44) ng ml−1, respectively. There was no statistically significant difference (P = 0.39) between the median tmax for Easyhaler® (30 min) and Turbuhaler® treatment (23 min). Charcoal impaired the GI absorption of budesonide by 96%. The occurrence of adverse events was similar during both treatments.

Conclusions

The results show that the lung deposition of budesonide from Giona® Easyhaler® 200 µg/dose and Pulmicort® Turbuhaler® 200 µg/dose dry powder inhalers is equivalent. The charcoal block used to prevent GI absorption of swallowed budesonide was found to be effective.
Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV‐1‐infected patients
Authors: Kappelhoff Bregt S. , Huitema Alwin D. R. , Crommentuyn Kristel M. L. , Mulder Jan W. , Meenhorst Pieter L. , Van Gorp Eric C. M. , Mairuhu Albert T. A. , Beijnen Jos H.
Published: July 2005

Aims

The aim of this study was to develop and validate a population pharmacokinetic model of ritonavir, used as an antiviral agent or as a booster, in a large patient population and to identify factors influencing its pharmacokinetics.

Methods

Ambulatory HIV‐1‐infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, the Netherlands, who were being treated with a ritonavir‐containing regimen were included. During regular visits, blood samples were collected for the determination of ritonavir plasma concentrations and several clinical chemistry parameters. Furthermore, complete pharmacokinetic curves were available in some patients. Single and multiple compartment models with zero‐order and first‐order absorption, with and without absorption lag‐time, with linear and nonlinear elimination were tested, using nonlinear mixed effect modelling (NONMEM). Pharmacokinetic parameters and interindividual, interoccasion and residual variability were estimated. In addition, the influence of several factors (e.g. patient characteristics, comedication) on the pharmacokinetics of ritonavir was explored.

Results

From 186 patients 505 ritonavir plasma concentrations at a single time‐point and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations. In total 62% of the patients used ritonavir as a booster of their protease inhibitor containing antiretroviral regimen. First order absorption in combination with one‐compartment disposition best described the pharmacokinetics of ritonavir. Clearance, volume of distribution and absorption rate constant were 10.5 l h−1 (95% prediction interval (95% PI) 9.38–11.7), 96.6 l (95% PI 67.2–121) and 0.871 h−1 (95% PI 0.429–1.47), respectively, with 38.3%, 80.0% and 169% interindividual variability, respectively. The interoccasion variability in the apparent bioavailability was 59.1%. The concomitant use of lopinavir resulted in a 2.7‐fold increase in the clearance of ritonavir (P value < 0.001). No patients characteristics influenced the pharmacokinetics of ritonavir.

Conclusions

The pharmacokinetic parameters of ritonavir were adequately described by our population pharmacokinetic model. Concomitant use of the protease inhibitor lopinavir strongly influenced the pharmacokinetics of ritonavir. The model has been validated and can be used for further investigation of the interaction between ritonavir and other protease inhibitors.
Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain
Authors: Lennernäs B. , Hedner T. , Holmberg M. , Bredenberg S. , Nyström C. , Lennernäs H.
Published: July 2005

Aims

It is estimated that two‐thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated.

Methods

Eleven Caucasian patients (seven male and 4 female, aged 34–75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double‐blind, cross‐over trial, consisting of three 1‐day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 µg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography‐mass spectrometry/mass spectrometry (LC‐MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire.

Results

The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 µg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted Cmax (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400–100µg) in dose adjusted AUC from the three‐period crossover analysis was −0.016 min·ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25–40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. tmax increased from 39.7 ± 17.4 to 48.7 ± 26.3 and 56.7 ± 24.6 min for the 100, 200 and 400 µg doses, respectively. Adverse events were few and did not increase with increasing dose.

Conclusion

With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8–11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.
Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes
Authors: Glaeser H. , Drescher S. , Eichelbaum M. , Fromm M. F.
Published: July 2005

Aims

To investigate the potential induction by rifampicin of intestinal CYP2C8, CYP2C9, CYP2D6 and CYP3A4 using preparations of human enterocytes.

Methods

Using a multilumen perfusion catheter shed human enterocytes were collected from 6 healthy subjects before and after 10 days of 600 mg day−1 oral rifampicin administration. The protein expression of CYP2C8, CYP2C9, CYP2D6 and CYP3A4 as well as that of CYP3A4 mRNA was determined using Western blotting and RT‐PCR, respectively.

Results

CYP3A4 mRNA expression in shed enterocytes increased from 74.6 ± 44.2 to 143.2 ± 68.4 a.u. (P < 0.05, 95% CI: 21.8–115.3). Expression of CYP2C8 and CYP2C9 increased from 5.1 ± 0.9 to 10.4 ± 2.3 pmol mg−1 protein (P < 0.01, 95% CI: 2.8–7.7) and from 4.2 ± 1.4 to 5.7 ± 1.1 pmol mg−1 protein (P < 0.01, 95% CI: 0.6–2.4), respectively. No significant difference in CYP2D6 expression before and during rifampicin intake was observed. Rifampicin administration also resulted in a significant induction of CYP3A4 protein (34.1 ± 10.7 vs. 113.9 ± 31.1 pmol mg−1 protein (P < 0.001, 95% CI: 51.8–107.6)). Ex vivo incubation of enterocyte homogenates with verapamil resulted in a significantly increased production of the metabolites formed via CYP3A4 (D‐617: 125.9 ± 118.8 vs. 277.2 ± 145.5 pmol min−1 mg−1 protein (P < 0.05, 95% CI: 30.1–272.5); norverapamil: 113.0 ± 57.9 vs. 398.4 ± 148.2 pmol min−1 mg−1 protein (P < 0.05, 95% CI: 47.2–523.6)).

Conclusion

Our findings indicate that shed enterocytes are a useful tool to study the expression, regulation and function of drug metabolizing enzymes. Induction of intestinal CYP2C8 and CYP2C9 might contribute in part to rifampicin – mediated drug interactions, in addition to their hepatic counterparts and intestinal and hepatic CYP3A4.
A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first‐pass hepatic extraction
Authors: Gordi Toufigh , Xie Rujia , Huong Nguyen V. , Huong Dinh X. , Karlsson Mats O. , Ashton Michael
Published: July 2005

Aims

Previous studies have shown that the antimalarial drug artemisinin is a potent inducer of its own metabolism in both patients and healthy subjects. The aim of this study was to characterize the time‐dependent pharmacokinetics of artemisinin in healthy subjects.

Methods

Twenty‐four healthy males were randomized to receive either a daily single dose of 500 mg oral artemisinin for 5 days, or single oral doses of 100/100/250/250/500 mg on each of the first 5 days. Two subjects from each group were administered a new dose of 500 mg on one of the following days after the beginning of the study: 7, 10, 13, 16, 20, or 24. Artemisinin concentrations in saliva samples collected on days 1, 3, 5, and on the final day were determined by HPLC. Data were analysed using a semiphysiological model incorporating (a) autoinduction of a precursor to the metabolizing enzymes, and (b) a two‐compartment pharmacokinetic model with a separate hepatic compartment to mimic the processes of autoinduction and high hepatic extraction.

Results

Artemisinin was found to induce its own metabolism with a mean induction time of 1.9 h, whereas the enzyme elimination half‐life was estimated to 37.9 h. The hepatic extraction ratio of artemisinin was estimated to be 0.93, increasing to about 0.99 after autoinduction of metabolism. The model indicated that autoinduction mainly affected bioavailability, but not systemic clearance. Non‐linear increases in AUC with dose were explained by saturable hepatic elimination affecting the first‐pass extraction.

Conclusion

Artemisinin produces a rapid onset of enzyme induction, resulting in a decrease in its own bioavailability over time. The proposed model successfully described the time‐course of the onset and normalization of the autoinduction of metabolism in healthy subjects receiving two different dosage regimens of the compound.
A comparison of plethysmography, spirometry and oscillometry for assessing the pulmonary effects of inhaled ipratropium bromide in healthy subjects and patients with asthma
Authors: Houghton C. M. , Woodcock A. A. , Singh D.
Published: July 2005

Aims

We  have  compared  the  ability  of  plethysmography  (sGaw),  impulse  oscillometry (IOS) and spirometry (FEV1, MMEF) to detect bronchodilation in response to an anticholinergic.

Methods

IOS (R5, R20, X5, RF), sGaw and spirometry were measured in 12 healthy subjects and 12 asthmatics. Variability was assessed by performing two measurements, 30 min apart and the effect of increasing the number of readings for each sGaw measurement was also studied. Ipratropium bromide (IB) 10, 20, 100 and 200 µg was administered and the sensitivity of the methods compared by determining the lowest dose that caused changes greater than variability.

Results

In healthy subjects significant changes (P ≤ 0.05) occurred at 10 µg for FEV1 (mean [95% CI]; 1.3%[0.3–2.3]), R5 (mean [95% CI]; −7.9%, [−13.2–2.6]) and R20 (mean [95% CI], −6.4%, [−11.4–1.4]). No significant change was detected when the mean of 3 sGaw readings was used, but with 10 readings significant change was observed at 20 µg; (mean increase [95% CI] 15.2%[8.3–22.1]). In asthmatics significant changes (P ≤ 0.05) occurred with IB 10 µg for sGaw (mean [95% CI] 25.6%[11.1–40.1]), R5 (mean [95% CI]−11.3%, [−15.5–7.2]), RF (mean [95% CI] 11.7%[6.1–16.3]), FEV1 (mean [95% CI] 5.1%[2.6–7.7]) and MMEF (mean [95% CI] 12.3%[2.3–22.2]).

Conclusion

IOS and spirometry are more sensitive than sGaw in healthy subjects, but the sensitivity of sGaw improved when the number of readings was increased. The most sensitive method for assessing bronchodilation in asthmatics was sGaw.
Mothers’ voice: a qualitative study on feeding children with cerebral palsy
Authors: Sleigh G.
Published: July 2005

Background  Around one third of children with cerebral palsy have severe difficulty eating and drinking and are at risk of undernourishment. A gastrostomy feeding tube may be offered as a way of providing nourishment as it bypasses the main physical difficulties. For the families feeding and concerns about the method of feeding affect many areas of their daily life but we know little about what the experience is actually like. This study aimed to explore mothers’ experience of feeding children with cerebral palsy.

Methods  Ten principal carers for children with cerebral palsy and severe eating difficulty were interviewed. Four of the children, one girl and three boys aged 2.5 to 4.5 years were being fed solely by mouth and six children, three girls and three boys, aged 4.5 years to 15 years and 10 months, were fed via a gastrostomy feeding tube. Long, loosely structured tape recorded interviews were transcribed and manually analysed using a phenomenological approach. This involved extracting and coding each relevant phrase that contained meaning; then through sequential stages of ordering and reduction into themes the invariant meanings were uncovered. The transcripts were analysed in two groups, oral and gastrostomy feeding, in an identical manner.

Results  Phenomenological analysis resulted in two prose accounts that described in depth the essence of the experience. The accounts were mutually informative. Both groups treasured feeding by mouth suggesting that support for oral feeding should be given a higher priority. The accounts explained why some professional encounters added to families’ stress and why consistency of care is so important. The study gives insight about the kinds of support families find helpful.

Conclusions  This study should help those involved to understand the families’ predicament better and so make a contribution towards providing more appropriate support.
Feeding practices in 105 counties of rural China
Authors: Wang X. , Wang Y. , Kang C.
Published: July 2005

Background  China has the largest population in the world with more than 70% of the people living in rural areas. Over 34% of children under the age of 5 years are responded to show moderate or severe growth stunting, so United Nations International Children's Emergency Fund and Chinese Ministry of Health conducted this large‐scale survey in China. This study aimed to learn the feeding practice, to find the problems in child‐feeding practice and to provide evidence for the government to develop an approach to child malnutrition in rural China.

Methods  A structured  questionnaire  was  used  to  survey  21 036  mothers  of  children  with  age  of 0–24 months.

Results  Of the 20 915 children, 98.22% were breastfeeding and 24.36% were exclusively breastfeeding. The proportion of children with weekly protein intake was 78.47%. Among the infants under 4 months, the risk of pneumonia in the group of exclusive breastfeeding was 1.69%, while in the group of non‐exclusive breastfeeding was 3.63%, showing a statistically significant difference between the two groups. The risk of diarrhoea in the group of exclusive breastfeeding and in the group of non‐exclusive breastfeeding among the infants under 4 months was 24.37% and 40.86%, respectively, also showing a statistically significant difference between the two groups. For children with age 4–6 months, the complementary feeding contributed to a higher prevalence of diarrhoea, but not pneumonia.

Conclusions  The breastfeeding was very common, but the exclusive breastfeeding was quite low and the exclusive breastfeeding for children under the age of 4 months decreased the risks of pneumonia and diarrhoea. For children with age 4–6 months, the exclusive breastfeeding could decrease the risk of diarrhoea, too. Protein intake was insufficient for children in rural China. The rural people lacked health knowledge and were greatly influenced by traditional feeding practices.