Final Sampling Time Research Articles

Experimental Study of a Representative Sample to Determine the Chemical Composition of Cast Iron.

In metallurgical practice, the material is considered of adequate quality if it meets the customer's expectations. It is necessary to take representative samples and perform quality testing to avoid financial and intangible losses. Sample contamination and matrix and surface quality play a significant role in the accuracy of chemical analyses. The purpose of this paper is to point out the advantages of specific methods of taking samples, such as immersion and spoon sampling of molten metal, and, in the experimental part, to assess the impacts of factors affecting the quality of the sampling. The influence of time of final sampling on determining the true amount of magnesium during a single melt and the influence of duration of mixing of molten cast iron on the accuracy of chemical analysis of the control sample were investigated. It is important that the time between the modification and casting of the liquid cast iron from the casting ladle be as short as possible. This is because the magnesium burns out and thus the chemical analysis of the sample taken is not accurate. Another important factor is ensuring the melt before sampling is homogenized and has the minimum prescribed temperature (1420 °C). Increasing sample collection time will cause changes in its chemical composition.

Absence of Clinically Meaningful Drug-Drug Interactions with Rezafungin: Outcome of Investigations.

Rezafungin is a novel once-weekly echinocandin for intravenous injection currently in development for the treatment of Candida infections and the prevention of Candida, Aspergillus, and Pneumocystis infections in allogeneic blood and marrow transplant recipients. While in vitro data indicated that rezafungin exposure was unlikely to be affected by commonly prescribed medicines, interactions resulting in the altered systemic exposure of some drugs coadministered with rezafungin could not be excluded. Two phase 1 open label crossover studies, conducted in healthy subjects, examined drug interactions between rezafungin and multiple drug probe cytochrome P450 (CYP) substrates and/or transporter proteins, immunosuppressants, and cancer therapies. Statistical analysis compared the outcomes for drugs coadministered with rezafungin to those for the drugs administered alone. The geometric mean ratio was reported, and a default 90% confidence interval (CI) no-effect equivalence range of 80 to 125% was used for the maximal plasma concentration (Cmax), the area under the curve from time zero to the final sampling time point (AUC0-t), and the AUC from time zero to infinity (AUC0-∞). Most probes and concomitant drugs were within the equivalence range. For tacrolimus, ibrutinib, mycophenolic acid, and venetoclax, the AUC or Cmax was reduced (10 to 19%), with lower bounds of the 90% CI values falling outside the no-effect range. The rosuvastatin AUC and Cmax and the repaglinide AUC0-∞ were increased (12 to 16%), with the 90% CI being marginally above the upper bound. Overall, the in vitro and in vivo data demonstrated a low drug interaction potential with rezafungin via CYP substrate/transporter pathways and commonly prescribed comedications, suggesting that coadministration was unlikely to result in clinically significant effects. Treatment-emergent adverse events were typically mild, and rezafungin was generally well tolerated. IMPORTANCE Antifungal agents used to treat life-threatening infections are often associated with severe drug-drug interactions (DDIs) that may limit their usefulness. Rezafungin, a newly approved once-weekly echinocandin, has been shown to be free of DDIs based on extensive nonclinical and clinical testing described in this study.

Oyster abundance on subtidal reefs depends on predation, location, and experimental duration

AbstractPredation affects community structure and functioning within marine habitats. Predator–prey interactions can change through space and time. Documenting how these interactions change is essential to improve our understanding of food web dynamics and to enhance our ability to manage preferred species. In this study, our goals were to determine whether the density of subtidal oysters (Crassostrea virginica) differed spatially by looking at three separate restored oyster sanctuaries within Pamlico Sound (North Carolina, USA), whether oyster density changed over an interval of 16 months, and whether oyster density was related to the presence of different‐sized predators by using an experimental approach. Multiple exclusion treatments were used in situ to exclude, selectively, different predator guilds from consuming oysters. Predator densities were also measured both within experimental treatments and on the restored oyster reefs by using multiple survey techniques. We found that oyster abundance differed among the four sample dates over the 16‐month study and differed among the three sites. Mud crabs—one of the smallest predators measured—had the greatest predator biomass per unit of area, but the presence of other predators was largely site‐dependent. Oyster abundance was affected by the exclusion of all predators, but this was dependent on sample date and location, which may suggest that mud crabs were the only predator to reduce oyster abundance in this study. In addition, large predators may have affected small predators, such as mud crabs and oyster drills, which were more abundant in treatments where large predators were excluded. The strongest evidence for top‐down effects on oyster reefs occurred at one of the three field sites at the first and final sampling time, suggesting that predator effects are complex, as well as spatially and temporally variable. Field experiments that assess variables through time and at multiple locations are needed as this information could improve the success of oyster reef conservation and restoration efforts.

Effect of Protracted Free-Choice Chlortetracycline-Medicated Mineral for Anaplasmosis Control on Escherichia coli Chlortetracycline Resistance Profile from Pastured Beef Cattle.

Anaplasmosis is an economically-significant, hemolytic, tick-borne disease of cattle caused by Anaplasma marginale which can cause clinical anemia and death. Current control options are limited, and FDA-approved antimicrobial control options do not have a defined duration of use. A practical and routinely used anaplasmosis control method involves feeding free-choice chlortetracycline (CTC)-medicated mineral to pastured cattle for several months. Constant antimicrobial use poses the risk of expediting the development and dissemination of antimicrobial resistance in off-target commensal bacteria in the bovine gastrointestinal tract. The objective of this study was to determine the CTC-susceptibility of Escherichia coli isolated from anaplasmosis endemic beef cattle herds provided different FDA-approved free-choice CTC-medicated mineral formulations, all intended to provide cattle a dosage of 0.5 to 2.0 mg CTC/lb bodyweight per day. A closed-herd, comprised of Hereford-Angus cows, naturally endemic for anaplasmosis, were grazed in five different pastures with one herd serving as an untreated control group. The other cattle herds were randomly assigned one of four FDA-approved CTC-medicated mineral formulations (700, 5000, 6000, and 8000 g CTC/ton) labeled for “the control of active anaplasmosis” and provided their respective CTC-medicated mineral formulation for five consecutive months. Fecal samples were collected monthly from a subset of cows (n = 6 or 10) per pasture. Fecal samples were cultured for E. coli isolates and the minimal inhibitory concentration of CTC was determined. Baseline CTC-susceptibility of E. coli was variable among all treatment and control groups. The susceptibility of E. coli isolates was significantly different between study herds over the treatment period (p = 0.0037 across time and 0.009 at the final sampling time). The interaction between study herds and treatment period was not significant (p = 0.075).

Response of potato cultivars to the northern root-knot nematode, Meloidogyne hapla, under field conditions in New York State, USA

Summary In New York and the Northeastern USA, the northern root-knot nematode, Meloidogyne hapla, is an important soil-borne pathogen of potato. The economic threshold for M. hapla in potato production has been 100 second-stage juveniles (J2) (100 g soil)−1, and is often used to dictate the need for prophylactic nematicides. However, the response of newer, popular potato cultivars under field conditions to M. hapla is unknown. The relationships between initial and final M. hapla populations and potato yield components in the popular cultivars ‘Genesee’, ‘Eva’ and ‘Lamoka’ were evaluated in three commercial production fields in New York, in 2016 and 2017. Following manual extraction from soil samples, M. hapla populations were quantified. Additionally, a glasshouse bioassay was performed to estimate M. hapla populations and correlate tuber yield. Populations of M. hapla over both years ranged from 0 to 519 J2 (100 g soil)−1 at the initial sampling, and from 0 to 10 294 J2 (100 g soil)−1 at the final sampling time. No significant correlation was observed between initial M. hapla populations and tuber yield, or between bioassay plant galling severity and tuber yield, among the cultivars included in the study in either year of the study. Yet correlations between bioassay plant galling severity and M. hapla populations were significant in both years, indicating the bioassay was adept at estimating M. hapla populations. These results will aid in directing future investigations into tolerance to M. hapla and nematode management.

Ecology of Porcine Astrovirus Type 3 in a Herd with Associated Neurologic Disease.

Astroviruses (AstVs) cause disease in a wide variety of species. Porcine AstVs are highly genetically diverse and conventionally assigned to five genetic lineages (PoAstV1-5). Due to the increasing evidence that porcine astrovirus type 3 (PoAstV3) is a cause of encephalomyelitis in swine and to elucidate important ecologic characteristics, the infection dynamics and environmental distribution of PoAstV3 were investigated in a herd with PoAstV3-associated neurologic disease. Over a 22 week period, the frequency of PoAstV3 fecal shedding varied by pig and age. The peak detection by RT-qPCR of PoAstV3 on fecal swabs (95%; 61 of 64) occurred at 3 weeks of age. The lowest frequency of detection was at 21 weeks of age (4%; 2 of 47); however, the frequency increased to 41% (19 of 46) at the final sampling time point (25 weeks of age). Viremia was rare (0.9%: 4 of 433). Detection in oral fluid was consistent with 75% to 100% of samples positive at each time point. Pens and feeders also had a high rate of detection with a majority of samples positive at a majority of sampling time points. Based on the data presented, PoAstV3 can be consistently detected in the environment with a majority of pigs being infected and a subset intermittently shedding the virus in feces out to 25 weeks of age. These findings suggest the importance of as-yet unidentified risk factors associated with the development of PoAstV3-associated polioencephalomyelitis.

New analytical method for chlorpyrifos determination in biobeds constructed in Brazil: Development and validation

A quick and efficient method was optimized and validated to determine chlorpyrifos in biobeds using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Chlorpyrifos was extracted from the matrix with 30 mL of a mixture of acetone, phosphoric acid and water 98:1:1 (v/v/v). After homogenization, centrifugation and filtration, 125 µL of the extract was evaporated and reconstituted in 5 mL of methanol acidified with 0.1% acetic acid. Validation was performed by studying analytical curve linearity (r2), estimated instrument and method limits of detection and limits of quantification (LODi, LODm, LOQi and LOQm, respectively), accuracy, precision (expressed as relative standard deviation, RSD), and matrix effect. Accuracy and precision were determined from the amount of pesticide recovered from biobed blank samples (i.e. without pesticide residue) spiked with chlorpyrifos at three different concentrations (2, 10 and 50 mg kg−1), with seven replicates at each concentration. For all three concentrations studied, the average recovery values obtained were between 96 and 115% with RSD values lower than 20%. The validated LOQ obtained was 2 mg kg−1 (from recovery studies) and the matrix effect observed was lower than ±20%, which demonstrated that there was neither considerable suppression nor enhancement of the analyte signal. The biobed system efficiently degraded chlorpyrifos in both 1) simulation of accidental spillage and 2) application of diluted pesticide solution. In the latter case, all the values obtained at the final sampling time (14 months) were below the validated LOQm.

Evaluation of Bacillus velezensis NKG-2 for bio-control activities against fungal diseases and potential plant growth promotion

Bacillus species exhibit potent biocontrol activity against a wide range of fungal pathogens, especially being tested as the most effective prevention strategy for Fusarium oxysporum. This study investigated the antifungal metabolites of Bacillus velezensis NKG-2, a bacterium isolated from the Qilian Mountains in China’s Qinghai Province. Experimental results showed this bacterium exhibited antagonistic activity against major plant fungal pathogens, namely Fusarium oxysporum, Fusarium graminearum, Botrytis cinerea, Alternaria alternata, Fulvia fulva, and Ustilaginoidea virens. In addition, the volatile organic compounds (VOCs) produced by Bacillus velezensis NKG-2 adversely affected the growth of these fungi. We also found that B. velezensis NKG-2 produced chitinase, cellulase, β-glucanase, and amylase enzymes and it promoted tomato plant growth as well, by producing indole-3-acetic acid (IAA) and siderophore. From in vivo biocontrol assay, tomato (Solanum lycopersicum L.) plants treated only with plant pathogenic fungi showed a disease severity of 65%, whereas bacterial-treated plants lacked any symptoms and their disease severity was only about 25% at the final sampling time. This comprehensive study explored and analyzed many benefits of B. velezensis NKG-2 for its use as a potential biocontrol agent and plant growth promoter, which could be used for improving economic and agricultural development.

Use and handling safety of Mini-Spike 2® chemo and puresite for safe chemotherapy compounding in a hospital pharmacy

We wanted to evaluate the impact of Mini-Spike 2® Chemo + Puresite (MSCP) use on contamination surface levels, professionals’ satisfaction and compounding time at pharmacy compared with Phaseal™.Presence of cyclophosphamide (CYP) and 5-fluorouracil (5FU) was evaluated at three sampling times: baseline; after a decontamination procedure and six months after MSCP use for CYP and 5FU compounding. Testing was carried out using an independent laboratory and wipe testing kit. To test compounding time, four different nurses followed the same compounding protocol with each device. We also developed a questionnaire to obtain feedback from the nurses.We did not find statistically significant differences in the median contamination surface levels between basal and final sampling time, CYP (0.140; 95% CI -1.135, 1.601), 5FU (−0.506; 95% CI -1.756, 0.287). We observed a difference of 10 s on compounding times between the two devices tested (p < 0.001) favoring MSCP. Finally, eight nurses answered the survey, with the best valued aspect as the aspiration/injection flow and resistance, and the worst value the comfort using Puresite and valve connection.MSCP maintains low surface contamination levels in our setting assuring compounding time standards. Satisfaction survey let us know which were the major advantages and disadvantages of the device

Pharmacokinetics and pharmacodynamics of linezolid in plasma/cerebrospinal fluid in patients with cerebral hemorrhage after lateral ventricular drainage by Monte Carlo simulation.

ObjectiveWe investigated the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of linezolid in patients who had suffered cerebral hemorrhage after lateral ventricular drainage.Materials and methodsTen patients with cerebral hemorrhage after lateral ventricular drainage with stroke-associated pneumonia who were given linezolid were enrolled. Plasma and cerebrospinal fluid (CSF) samples were taken at appropriate intervals after the first administration of linezolid and assayed by high-performance liquid chromatography (HPLC). Then, PK parameters were estimated, and a Monte Carlo simulation was used to calculate the probability of target attainments (PTAs) for linezolid achieving the PK/PD index at different minimal inhibitory concentrations (MICs).ResultsThe maximum concentration of linezolid in plasma and CSF was reached at 1.00 h and 3.10 h, respectively. The average penetration of linezolid in CSF was 56.81%. If the area under the plasma concentration vs time curve from zero to the final sampling time (AUC0–24 h)/MIC ≥ 59.1 was applied as a parameter, the PTA of linezolid in plasma could provide good coverage (PTA ≥ 90%) only for pathogens with a MIC of ≤2 μg/mL, whereas it could be achieved in CSF with a MIC of ≤1 μg/mL. If %T > MIC ≥ 40% was applied as a parameter, the PTA of linezolid in plasma/CSF could provide good coverage if the MIC was ≤4 μg/mL.ConclusionsFor patients with infection of the central nervous system and who are sensitive to the drug, the usual dosing regimens of linezolid can achieve a good therapeutic effect. However, for critically ill or drug-resistant patients, an increase in dose, the frequency of administration, or longer infusion may be needed to improve the curative effect.

Chromosome analysis in a case of a plutonium contaminated wound

Chromosome analysis of peripheral blood lymphocytes was undertaken over a 10 year period following an intake of plutonium through a hand wound. Frequencies of cells with unstable complex aberrations remained high throughout this time, probably reflecting direct exposure of lymphocytes as they passed plutonium which had transferred to regional lymph nodes. Analysis at the final sampling time also revealed cells with stable aberrations at a much higher frequency relative to the number of unstable cells than expected from direct exposure, and is therefore most likely to be reflecting exposure to lymphocyte precursor cells from plutonium that has become deposited on bone surfaces.

Development of phytotoxicity indexes and their correlation with ecotoxicological, stability and physicochemical parameters during passive composting of poultry manure

Both raw and composted poultry manure is applied as soil amendment. The aims of this study were: (1) to develop phytotoxicity indexes for organic wastes and composts, and (2) to assess the correlation among phytotoxicity indexes, ecotoxicological endpoints and stability and physicochemical parameters during passive composting of poultry manure. Six 2-m3 composting piles were constructed and four parameter groups (physicochemical and microbiological parameters, ecotoxicological endpoints, and biological activity) were determined at four sampling times during 92days. Extracts were used to carry out acute toxicity tests on Daphnia magna, Lactuca sativa and Raphanus sativus. Composting decreased average toxicity 22.8% for the 3 species and D. magna was the most sensitive species. The static respiration index decreased from 1.12 to 0.46mgO2gOMh−1 whilst organic matter reduced by 64.1% at the end of the process. Escherichia coli colonies remained higher than values recommended by international guidelines. The D. magna immobilization test allowed the assessment of possible leachate or run-off toxicity. The new phytotoxicity indexes (RGIC0.8 and GIC80%), proposed in this study, as well as salinity, proved to be good maturity indicators. Hence, these phytotoxicity indexes could be implemented in monitoring strategies as useful ecotoxicological tools. Multivariate analyses demonstrated positive correlations between ecotoxicological endpoints (low toxicity) and biological activity (stability). These two parameter groups were associated at the final sampling time and showed negative correlations with several physicochemical parameters (organic and inorganic contents). The final poultry manure compost was rendered stable, but immature and, thus, unsuitable for soil amending.

Damage caused by mite Tetranychus merganser (Trombidiformes: Tetranychidae) on Carica papaya (Violales: Caricaceae) plants and effect of two species of predatory mite

ABSTRACTPapaya (Carica papaya L.) is an important crop in all tropical countries including Mexico. Tetranychus merganser Boudreaux was recently detected in Mexico, and represents a potential threat to papaya production. There is little available information on this mite; therefore, research on this species is urgently required. We undertook a series of experiments to assess the effect of different initial densities of T. merganser on the level of leaf damage and photosynthetic activity of papaya; evaluations were made 21, 42 and 63 days after the experiments were initiated. We found that the greatest damage caused by T. merganser occurred after the final sampling time (63 days), regardless of the initial density of T. merganser; there were no differences among treatments in photosynthetic activity or chlorophyll content. We also evaluated how introduction of the generalist mite predators, Amblyseius swirskii Athias-Henriot (Gamasida: Phytoseiidae) or Neoseiulus californicus McGregor (Gamasida: Phytoseiidae), affected the relationship between the level of leaf damage and final densities of T. merganser at the end of the experiment. The introduction of predators resulted in a significant decrease in T. merganser densities. The need for early detection of this pest to reduce damage, and achieve the greatest impact of biological control is discussed.

Infection of Corn Ears by Fusarium spp. Induces the Emission of Volatile Sesquiterpenes

Infection of corn (Zea mays L.) ears with fungal pathogens of the Fusarium genus might result in yield losses and in the accumulation of mycotoxins. The aim of this study was to investigate whether volatile profiles could be used to identify Fusarium-infected corn ears. The volatiles released by corn ears infected by Fusarium graminearum, Fusarium verticillioides, and Fusarium subglutinans were studied. Volatile emission was recorded at 24 days postinoculation (dpi) and in a time series (from 4 to 24 dpi). Twenty-two volatiles were differentially emitted from Fusarium-infected versus healthy corn ears. These included C6-C8 compounds and sesquiterpenoids. All volatiles indicative of Fusarium infection were detectable as early as 4-8 dpi and continued to be produced to the final sampling time (early milk maturity stage). The induced emission of β-macrocarpene and β-bisabolene correlated with an increased transcript accumulation of corn terpene synthase 6/11 (tps6/11). Additionally, the modification of volatile profiles after Fusarium infection was accompanied by the induction of plant defense compounds such as zealexins and oxylipins. Together, these results reveal a broad metabolic response of the plant to pathogen attack. Volatile biomarkers of Fusarium infection are promising indicators for the early detection of fungal infection before disease symptoms become visible.

Foliar Absorption of Various Inorganic and Organic Nitrogen Sources by Creeping Bentgrass

ABSTRACTFoliar N fertilization often makes up a major portion of the total N inputs applied to creeping bentgrass (Agrostis stolonifera L.) golf greens. Many such applications are made using fertilizers that have been formulated and marketed as specialty foliar fertilizers. Various forms of inorganic and organic N are included in these specialty products. However, little is currently known about the foliar absorption efficiency among different chemical N forms routinely applied to putting greens. This project was conducted to evaluate the foliar uptake of N from several 15N‐labeled inorganic and organic sources. Three common N fertilizer forms {urea (NH2CONH2), ammonium sulfate [(NH4)2SO4], and potassium nitrate (KNO3)} were used in the trial along with three amino acids (glycine, l‐glutamic acid, and l‐proline). All treatments were applied at a rate of 0.5 g N m⁻2 on 18 Sept. 2008, 14 Oct. 2008, and 24 June 2010 to plots within a ‘Penn G2’ creeping bentgrass research green. Plant tissue samples were taken 1 and 8 h after application for N analysis. Foliar uptake of the various N compounds ranged from 31 to 56% of the N applied at the final sampling time of 8 h after application. Nitrogen source had a significant effect on the amount of N fertilizer recovered within plant leaves and shoots. Foliar absorption of KNO3 into aerial plant parts was lower than most of the chemical forms tested while most of the compounds supplied N to the plant in similar proportions.

Whole-body tissue distribution of total radioactivity in rats after oral administration of [14C]-bilastine

This study evaluated the tissue distribution of total radioactivity in male albino, male pigmented, and time-mated female albino rats after oral administration of a single dose of [14C]-bilastine (20 mg/kg). Although only 1 animal was analyzed at each time point, there were apparent differences in bilastine distribution. Radioactivity was distributed to only a few tissues at low levels in male rats, whereas distribution was more extensive and at higher levels in female rats. This may be a simple sex-related difference. In each group and at each time point, concentrations of radioactivity were high in the liver and kidney, reflecting the role of these organs in the elimination process. In male albino rats, no radioactivity was measurable by 72 hours postdose. In male pigmented rats, only the eye and uveal tract had measurable levels of radioactivity at 24 hours. Measureable levels of radioactivity were retained in these tissues at the final sampling time point (336 hours postdose), indicating a degree of melanin-associated binding. In time-mated female rats, but not in albino or pigmented male rats, there was evidence of low-level passage of radioactivity across the placental barrier into fetal tissues as well as low-level transfer of radioactivity into the brain.

Phase I Study of the Aurora B Kinase Inhibitor Barasertib (AZD1152) to Assess the Pharmacokinetics (PK), Metabolism and Excretion in Patients (pts) with Relapsed or Refractory Acute Myeloid Leukemia (AML)

Abstract 2602 Background:Barasertib is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA (bara-hQPA), a highly potent and selective inhibitor of Aurora B kinase with antitumor activity in a broad range of hematological malignancies including AML (Löwenberg et al. Blood 2009;114:abst 2080; Tsuboi et al. Leuk Res 2011; doi: 10.1016/j.leukres.2011.04.008). Methods:In this open-label, single-arm study (NCT01019161), AML pts received 1200 mg barasertib as a 7-day continuous iv infusion every 28 days. On Day 2 of Cycle 1 only, pts also received 14C-barasertib (250 μCi; 2-h infusion). Blood, urine and feces samples were collected at various time points during Cycle 1 to characterize the PK, metabolic and excretion profiles of barasertib. Results:Of the 6 pts enrolled (median age 63 years [range, 34–74]; 3 females), 5 commenced treatment and completed Cycle 1 and were therefore eligible for analysis. Of the 4 pts evaluable for disease response, 1 achieved a complete response. No new or unexpected safety findings were reported. Maximal plasma concentrations of barasertib and bara-hQPA were achieved by the first scheduled sample, taken 24 h from the start of infusion (SOI). During infusion, the mean concentration of bara-hQPA was approximately 3-fold higher than that of barasertib (Table). Following the end of infusion (EOI), plasma concentrations of barasertib fell rapidly, reaching the limit of quantification (LoQ) by 6 h after EOI, whereas bara-hQPA plasma levels declined in a triphasic manner, with low concentrations still detectable at the final sampling time point (Day 18). Bara-hQPA was extensively distributed to the tissues, with a relatively slow rate of total clearance (Table). Urine concentrations of barasertib were below LoQ at all time points. The mean urine concentrations of bara-hQPA were approximately 4–5 μg/mL during the infusion period, declining rapidly following EOI. The renal clearance (CLR) values for bara-hQPA represent approximately 10% of the total clearance of bara-hQPA from plasma.Overall, 72–82% of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51%) compared with urine (mean = 27%). The excretion of radioactivity in urine occurred predominantly within 72 h of 14C-SOI; however, there was large inter-patient variability in the rate of recovery of radioactivity in feces. Overall, the main excreta metabolites identified were: bara-hQPA (range, 13.2–33.7%), bara-hQPA N-acetic acid (range, 7.8–10.5%), bara-hQPA desfluoroaniline N-acetic acid (range, 5.1–9.5%), N-formyl or ethoxy bara-hQPA (range, 3.5–9.2%), and bara-hQPA desfluoroaniline (range, 1.6–5.5%). Desfluoroaniline metabolites made up a significantly larger proportion of the metabolites identified in excreta (∼15%) than in plasma (∼2%). The main pathways identified in human metabolism of barasertib were (i) cleavage of the phosphate group to form bara-hQPA, followed by oxidation, and (ii) loss of the fluoroaniline moiety to form bara-hQPA desfluoroaniline, followed by oxidation.Pharmacokinetics of barasertib and bara-hQPA in plasma and urineSampleParameter*Barasertib (n=5)‡Bara-hQPA (n=5)‡PlasmaAUC, ng.h/mL†NC40400 (0.4)AUC(0–t), ng.h/mL†13840 (0.4)40080 (0.4)AUC(0–192 h), ng.h/mL†NC38230 (0.4)CSS, ng/mL†85.6 (0.5)226.8 (0.4)CL, L/hNC31.4 (11.3)t½, hNC66.3 (36.1)λZ, h-1NC0.02 (0.02)VSS, LNC669.1 (344.9)VZ, LNC2805 (1708)UrineAe, mgNC96.9 (47.2)CLR, L/hNC2.85 (1.6)fe, %NC8.1 (3.9)AUC, area under plasma concentration–time curve; CSS, steady-state drug concentration; CL, total clearance; t½, half-life; λZ, slowest disposition rate constant; VSS, volume of distribution (apparent) at steady state; VZ, volume of distribution (apparent) during terminal (λZ) phase; Ae, cumulative amount of unchanged drug excreted; CLR, renal clearance of drug from plasma; fe, fraction of drug excreted into urine; NC, not calculable*All values are arithmetic mean (standard deviation) except where indicated†Values indicate geometric mean (coefficient of variation)‡Due to sampling issues, plasma concentration data were excluded for 1 pt Conclusions:The PK profile of bara-hQPA is similar to previous studies using the same dosing regimen. The majority of clearance of bara-hQPA occurred via hepatic metabolic routes. This study is the first to characterize the metabolic pathway of barasertib in humans. Disclosures:Oliver:AstraZeneca: Employment. D'Souza:AstraZeneca: Employment, Equity Ownership. Pike:AstraZeneca: Employment, Equity Ownership. Stockman:AstraZeneca: Employment, Equity Ownership.

Enhancement of percutaneous absorption of Finasteride by cosolvents, cosurfactant and surfactants

The enhancing effects of routinely used co-solvents, propylene glycol and 2-propanol, anionic and cationic surfactants and a co-surfactant with different concentrations were evaluated on the skin permeation of Finasteride. In vitro permeation experiments with rat skin revealed that the solvent mixture is a very important factor in the penetration of Finasteride through the skin. Unexpectedly, cationic and anionic surfactants in various concentrations did not show any enhancement effect on drug transdermal absorption but co-surfactant Transcutol P increased skin penetration of Finastride significantly. Transcutol P with 0.25% and 1% showed the best enhancement in the initial and final sampling time, respectively. Transcutol P in a concentration of 0.25% increased skin absorption of the drug nearly 3.6 times in the first 15 min. The highest enhancement ratio (ER) was gained in the presence of 1% Transcutol P (ER = 5.98). In this study, among the different topical Finastride formulations, Transcutol P 1% in combination with water, propylene glycol and 2-propanol (30, 10, and 60) showed the highest enhancement ratio.

Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: A phase I, randomized, open-label, crossover study in healthy volunteers

Background: Like itraconazole and ketoconazole, posaconazole, a broad-spectrum oral triazole antifungal, inhibits the activity of the cytochrome P450 (CYP) isozyme 3A4. Midazolam, a short-acting benzodiazepine, is metabolized by CYP3A4. Potential drug interactions can be expected in patients who are concurrently receiving inhibitors and substrates of CYP3A4 (eg, ketoconazole, posaconazole) and benzodiazepines (eg, midazolam). Because of the potential for drug interactions, it is important to determine the effects of posaconazole on the pharmacokinetic properties of midazolam. Objective: The aim of this study was to compare the effects of oral administration of posaconazole versus ketoconazole on the pharmacokinetic properties of orally and intravenously administered midazolam. Methods: This Phase I, randomized, open-label, crossover study was conducted at Swiss Pharma Contract Ltd., Allschwil, Switzerland. Healthy volunteers were randomly assigned to 1 of 2 treatment arms. Arm 1 received posaconazole 200 mg BID for 7 days, posaconazole 400 mg BID for 7 days, no drugs during a 28-day washout, and ketoconazole 400 mg once daily for 7 days. Arm 2 received posaconazole and ketoconazole in the reverse order, with a 28-day washout between treatments. An oral/IV midazolam sequence (oral midazolam 2 mg and IV midazolam 0.4 mg) was administered on days -2/-1, 6/7, 13/14 (arm 1), 36/17 (arm 2), 43/44, and 50/51 in both treatment arms. Blood samples were collected up to 24 hours after midazolam administration. Pharmacokinetic parameters, including C max, C min (before azole administration), terminal-phase t 1/2 (t 1/2z), and AUC to final measurable sampling time (AUC tf), were calculated using noncompartmental methods, and drug interactions were evaluated using analysis of variance. Adverse events were collected using physical examination, including vital sign measurements; clinical laboratory analysis; electrocardiography; and direct questioning at predefined time points throughout the study to assess tolerability. Results: A total of 12 subjects were enrolled (11 men, 1 woman; all white; mean age, 42.8 years [range, 28-53 years]; mean weight, 80.6 kg; and mean body mass index, 25.6 kg/m 2). All of the subjects completed the study. Based on point estimates of logarithm-transformed data, posaconazole 200 and 400 mg BID were associated with significant increases in midazolam C max (up to 1.3- and 2.4-fold) and AUC tf values (up to 4.6- and 6.2-fold), respectively. Ketoconazole 400 mg once daily was associated with significantly increased midazolam C max and AUC tf (up to 2.8- and 8.2-fold, respectively). When midazolam was concurrently administered with either azole, t 1/2z was prolonged. Seven of 12 (58%) subjects reported ≥1 adverse event during the study (5 with posaconazole alone and 4 with posaconazole + midazolam). The most common adverse events were diarrhea (3 subjects [25%] with posaconazole alone, 2 [17%] with ketoconazole alone, and 1 [8%] with posaconazole + midazolam) and flatulence (1 [8%] with posaconazole alone and 1 [8%] with midazolam alone). Conclusions: The results from this study in a small, all-white population of healthy volunteers suggest that posaconazole was a potent inhibitor of CYP3A4, but to a lesser extent than was ketoconazole. Monitoring patients for adverse events, the need for dose adjustments, or both during coadministration with posaconazole may be warranted in patients being treated with benzodiazepines that are predominantly metabolized through CYP3A4 (eg, midazolam).

Availability of Drug Information on Bioequivalence of Generic Products -Findings of Graduate Interns at a University Pharmacy-

Access to drug information (DI) needed to evaluate generic product bioequivalence was studied to identify problems with the current status of DI availability and encourage proper use of DI. Ten items were chosen from among the stock of branded products at the University Pharmacy, and five corresponding generics were selected for each item. Conditions of access to information on pharmacokinetic tests and dissolution tests were rated and the assigned ratings compared. In the case of pharmacokinetic parameters obtainable from makers of generic drugs, we also performed Welch's t-test to compare the difference between values reported for branded and generic products. From the standpoint of individual tests, the pharmacokinetic tests yielded higher scores on the whole than did the dissolution tests, and low scores were obtained for the half-life of blood drug concentration (T1/2). We observed a tendency for the adequacy of information to depend more upon the drug item itself than upon the nature of the test. The percentage of tests allowing for comparison with branded products varied from 0%-75% (average 49%). Parameter by parameter, the range of variation was from 35% of Tmax to 63% of Cmax. Factors precluding comparison included insufficient data on branded products, mismatch in assayed chemical species between branded and generic, mismatch between final sampling time in AUC(t) measurement, dosage inconsistency, and insufficient data on generic products. DI should be provided in a manner that facilitates comparison of information supplied by generic drug makers with data released by makers of branded products.