Exposure-time Profile Research Articles

Study of chloride penetration profiles and surface chloride content of concrete structures exposed to marine environment evaluated at different exposure times

DOI: 10.7764/RDLC.18.3.545 Nowadays, some studies have shown the increasing chloride content of concrete surface (Cs) exposed to marine environments over time. To evaluate this behavior, a comparative analysis was conducted between the chloride profiles in tetrapods located in southern Brazil, obtained from samples extracted at 5 and 9.5 years from four microenvironments To this end, the equation of Fick's second lawconsiders the time-dependent Cs variation, a model was prepared for each exposure time profile measured from each microenvironment, which considered the Cs variation since it increased significantly from 5 to 9.5 years. The models obtained from the profiles measured at 5 years were used to estimate the profile at the exposure time of 9.5 years and then compared with the real profiles measured at 9.5 years. The same procedure was used for the profiles measured at 9.5 years, that is to say, a 5-year profile was estimated and compared with a profile measured at the same exposure time. This shows the efficiency of the model. According to the research results, profiles of about 5 years are still too premature to be used as an estimate of the residual useful life of a structure, even considering the Cs variation. However, profiles of approximately ten years can be used, and their Cs values may increase. Therefore, research of the Cs values must continue to obtain the corresponding older chloride profiles to assess the behavior of the curves and the efficiency of the suggested model.

The treatment with dual release hydrocortisone in patients with adrenal insufficiency: correlation between change of the evening cortisol exposure time profile and change in metabolic profile, depression status and quality of life

The treatment with dual release hydrocortisone in patients with adrenal insufficiency: correlation between change of the evening cortisol exposure time profile and change in metabolic profile, depression status and quality of life

Improved evening and nocturnal cortisol exposure time profile in patients with adrenal insufficiency treated with dual release hydrocortisone: correlation with improvement in metabolic profile

Improved evening and nocturnal cortisol exposure time profile in patients with adrenal insufficiency treated with dual release hydrocortisone: correlation with improvement in metabolic profile

The impact of obesity on oesophageal acid exposure time on and off proton pump inhibitor therapy.

Obesity is associated with increased oesophageal acid exposure time (AET) in patients with gastro-oesophageal reflux (GER), and may decrease the effects of proton pump inhibitors (PPIs). To evaluate the effects of increased body mass on the ability of PPI therapy to decrease AET in patients with reflux symptoms. Acid exposure time profiles collected from adult patients using wireless pH-metry while on or off PPI therapy was retrospectively reviewed. Patients were separated into five body mass index (BMI) categories as defined by the World Health Organization. A multivariable logistic regression evaluated the association between abnormal AET and BMI groups while controlling for age, gender and pH capsule placement methods. The study group comprised 968 patients with 336 (34.7%) studied on a PPI and 632 (65.3%) studied off PPI therapy. AET (total greater than 5.3%) was found more frequently in the overweight (67%) and obese classes (74-80%) compared to those who were normal weight (40%) while off acid-suppressing medications (P<0.001). No significant differences were found between these groups when studied on acid-suppressing medications, and the proportion of patients with abnormal AET across BMI classes was similar regardless of taking a PPI either once or twice daily. This is the largest study to report on the relationship between BMI and oesophageal acid exposure time in patients with GER on and off PPI therapy. We conclude that obesity is related to increased acid exposure time, but with no significant difference in acid exposure time among different weight-based groups when taking a once or twice-daily PPI.

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency.

ObjectiveThe objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI).DesignRandomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden.MethodsSixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness).ResultsIn stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure.ConclusionsThis long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation

Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation

Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation

Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile. The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets. We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers. The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM). The same daily dose of hydrocortisone was administered as OD dual-release or TID. We evaluated cortisol pharmacokinetics. Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004). The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.

Long-Acting Growth Hormone for Replacement Therapy

GH replacement therapy has shown important beneficial effects on body composition, bone metabolism, lipid metabolism, and quality of life in adults with GH deficiency with a good safety profile (1, 2). Current management is based on daily sc injections before bedtime that are often experienced as cumbersome by the patient and may therefore affect adherence to treatment. Sustainedrelease GH formulations or long-acting GH for less frequent injections have therefore been developed. The paper by Biller et al. (3) published in this issue of the JCEM reports the results from a large 6-month study of adults with GH deficiency demonstrating efficacy and safety of a sustained-release formulation of GH with once weekly sc administration. The study concluded that the treatment was well tolerated and all clinical beneficial end-points were met, such as reduction in fat mass. GH is a powerful metabolic hormone with lipolytic actions, protein anabolic effects, and insulin antagonistic effects (4). The plasma pattern of GH, including pulse frequency, basal levels, and total integrated levels is influenced by several factors, including gender, age, and adiposity (5). Therefore, pattern of GH delivery and GH exposure may have an impact on the effects obtained by treatment. The importance of the mode of GH administration is supported by a number of animal studies demonstrating that a changed pattern of GH exposure has different effects on growth and metabolism (6). The GH secretion is suppressed by food and augmented by fasting. It is therefore a fasting hormone mobilizing energy from fat stores by lipolysis, inducing gluconeogenesis in the liver, and preserving protein mass during fasting through its protein anabolic action, i.e. in many aspects the reverse action to insulin in the postprandial state (7). Moreover, the gene expression and activity of some important regulatory enzymes in the liver are dependent on the pattern of GH exposure (8, 9). The clinical importance for safety and efficacy of not delivering GH in a physiological pulsatile manner is therefore something to consider in the pharmaceutical development of GH products for treatment. Current practice of GH treatment both in children and in adults is to administer GH as a bedtime sc injection. The basis for this practice comes from early observations that daily sc injections gave a better growth response in GHdeficient children than three injections per week (10). Moreover, the closest similarity to a normal diurnal metabolite pattern was achieved with evening sc injections of GH to GH-deficient adults (11). The diurnal plasma GH profile following daily sc evening injections is, however, an intermediate between a pulsatile and a continuous GH exposure time profile (12) and is therefore not physiological. The bedtime administration of GH means that most of the GH action occurs during the night in the fasting state. This is, however, the regime that has proved its safety and efficacy of modern GH therapy in children and in adults (1). Having a more continuous exposure, such as during treatment with long-acting GH, means that GH exerts its action both in fasting and in the fed state during the day, meaning that the normal interaction and balance with insulin is further set aside. The clinical importance of this is not clear. Whether the same efficacy and safety can be obtained by moving the GH exposure toward a more continuous pattern has been studied mainly in adults. In one small pediatric study, however, GH delivered either as daily sc injections or as a continuous GH administration using a sc pump demonstrated the same growth rate by the two treatment modes, but the serum IGF-I response was higher in the group receiving continuous GH (13). Studies in adults comparing the same dose of GH administered as a daily sc injection or as a continuous infusion have, in agreement with the pediatric experience, shown that the IGF-I and ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2011-0689 Received April 20, 2011. Accepted April 22, 2011.

Modeling Gastrointestinal Drug Absorption Requires More In Vivo Biopharmaceutical Data: Experience from In Vivo Dissolution and Permeability Studies in Humans

The majority (84%) of the 50 most-sold pharmaceutical products in the US and European markets are given orally. The dominating role of this route in drug therapy is a consequence of it being safe, efficient and easily accessible with minimal discomfort to the patient in comparison with other routes of drug administration. A successful drug discovery and development of oral pharmaceutical products require an in-depth understanding of multiple biochemical and physiological processes that determine the dissolution rate, intestinal permeability, gastrointestinal transit, first-pass extraction and systemic exposure-time profiles of drugs. It is crucial to realize that these basic biopharmaceutic and pharmacokinetic properties are crucial to focus on to allow successful drug development. Identification of the rate-limiting step(s) in order to overcome these barriers and understanding of the sources of variability are important in the selection of suitable candidate molecules in drug development. Several reports based on in vitro investigations in various cell models have suggested that carrier-mediated intestinal efflux may be a major reason for incomplete absorption and variable bioavailability of drugs, as well being a site for drug-drug and specific food-drug interactions. However, many drugs which were initially suggested to undergo significant efflux in vitro were later shown to be completely absorbed in vivo. This apparent discrepancy between in vitro and in vivo results may be due to several factors that will be discussed in this review. Novel data on solubility and dissolution in human gastrointestinal derived fluids will be reviewed. The effect of food intake on solubility and dissolution rate of a range of drugs including felodipine, danazol, griseofulvin, cyclosporine, probucol and ubiquinone in simulated and real intestinal fluids is discussed. The biopharmaceutic and physicochemical data discussed here can potentially be used as a benchmark set for validation of new experimental techniques or in silico models in future. Factors such as structural diversity, commercial availability, price and a suitable analytical technique for quantification were considered in the selection of a specific drug set. Using the compiled data set lipophilicity as determined by reverse phase HPLC and permeability across Caco-2 cell monolayers were determined; means to overcome the experimental difficulties due to the diversity of the data are also discussed.

Analysis of n-alkanes in water samples by means of headspace solvent microextraction and gas chromatography

A simple and efficient headspace solvent microextraction (HSME) was developed for the simultaneous determination of the trace concentrations of some n-alkanes in water samples. Therefore, a microdrop of an organic solvent was extruded from the needle tip of a gas chromatographic syringe to the headspace above the surface of the solution in a sealed vial. Then the volatile organic compounds are extracted and concentrated in the microdrop. Next, the microdrop was retracted into the microsyringe and injected directly into the gas chromatograph. Experimental parameters which control the performance of HSME such as the type of microextraction solvent, organic drop and sample volume, sample stirring rate, sample solution and microsyringe needle temperatures, salt addition and exposure time profiles were investigated and optimized. Finally, the enrichment factor, dynamic linear range (DLR), limit of detection (LOD) and precision of the method were evaluated. Using optimum extraction conditions, good linearity with correlation coefficients in the range of 0.995 < r 2 < 0.999, suitable precision (%2.3 < R.S.D. < %7.2) and low detection limits (0.1–4.0 μg/l) were achieved. The HSME was performed for determination of n-alkanes in different types of natural water samples and acceptable recoveries were obtained. The results demonstrated that HSME is a rapid, accurate and effective sample preparation method and could be successfully applied for the determination of n-alkanes in water samples.

Issues in Exposure and Dose Assessment for Epidemiology and Risk Assessment

Epidemiologic studies have been effective in identifying human environmental and occupational hazards. However, most epidemiologic data has been difficult to use in quantitative risk assessments because of the vague specification of exposure and dose. Toxicologic animal studies have used applied doses (quantities administered, or exposures with fixed duration) and well characterized end points to determine effects. However, direct use of animal data in human risk assessment has been limited by uncertainties in the extrapolation. The applied dose paradigm of toxicology is not suited for cross species extrapolation, nor for use in epidemiology as a dose metric because of the complexity of human exposures. Physiologically based pharmacokinetic (PBPK) modeling can estimate the time course of tissue concentrations in humans, given an exposure-time profile, and it has been used for extrapolating findings from animals to humans. It is proposed that human PBPK modeling can be used in appropriately designed epidemiologic studies to estimate tissue concentrations. Secondly, tissue time courses can be used to form dose metrics based on the type and time course of adverse effects. These dose metrics will strengthen the determination of epidemiologic dose-response relationships by reducing misclassification. Findings from this approach can be readily integrated into quantitative risk assessment.

Cysteic acid is the chemical mediator of automotive clearcoat damage promoted by dragonfly eggs

The damage caused by dragonfly eggs on automotive clearcoats exposed to sunlight occurs by a chemical mechanism similar to that caused by acid rain. Cysteine and cystine residues present in dragonfly eggs are oxidized during the egg hardening process, which releases hydrogen peroxide, to a cysteic acid derivative, a strong acid capable to catalyze the hydrolysis of acrylo/melamine clearcoat polymer. Cysteic acid was indeed identified and quantified by ion-exchange HPLC in dragonfly egg extracts submitted to oxidation by H2O2 followed by acid digestion. Moreover, H2O2 concentration, temperature, and exposure time profiles of cysteic acid formation as well as an apparent activation energy for cysteine (in dragonfly eggs) oxidation to cysteic acid by H2O2 (32 ± 2 kJ/mol) were determined. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 81: 1549–1554, 2001