Linear Increase In Area Research Articles

A detailed view of the Gaussian–Lorentzian sum and product functions and their comparison with the Voigt function

The Gaussian–Lorentzian sum (GLS) and product (GLP) functions remain important in X‐ray photoelectron spectroscopy (XPS) peak fitting. Here, we present a detailed view of these functions, comparing them with each other and with the Voigt function (the “LA(m)” function). First, we show the GLS, GLP, and LA(m) functions as a function of their mixing parameters, m, which reveals differences between them. We then illustrate the use of these functions to fit a series of spectra acquired at different pass energies (resolutions). Next, we show the underlying Gaussian and Lorentzian components of a series of GLS and GLP functions as a function of m, which confirms that the GLS is a simple linear combination of Gaussian and Lorentzian functions. However, one of the two functions used to make the GLP can be very wide, that is, at its extremes, one of these functions has infinite width. We then discuss a plot of the areas of the GLS, GLP, and LA(m) functions as a function of m, which reveals the expected, linear increase in area of the GLS, but nonlinear changes in the areas of the other two functions. Finally, to better understand them, we fit these functions to each other. These results indicate that the GLS and GLP better match the LA(m) function at lower and higher values of the mixing parameter, respectively.

Determining the nutritional boundaries for replacing lactose with glucose in milk replacers for calves fed twice daily

The effect of replacing lactose with glucose on the gastrointestinal system of young calves at levels above 20% diet inclusion in milk replacer (MR) is not well described. The aim of this study was to determine tolerance to glucose inclusion at the direct expense of lactose on glucose metabolism, health, and growth performance in Holstein male calves. In total, 110 Holstein male dairy calves (16 ± 2.5 d and 50.3 ± 0.2 kg) were acquired from a commercial collection center. After an adaptation period of 3 d, 100 calves were selected for the study based on health parameters. Calves were blocked based on body weight measured on d 4 after arrival. Within each block, calves were randomly assigned to 1 of 5 levels of glucose inclusion (replacing lactose): 0% (L1, n = 20), 10% (L2, n = 20), 20% (L3, n = 20), 30% (L4, n = 20), and 40% (L5, n = 20), leading to an estimated osmolality range from 417 (L1) to 586 mOsm/kg (L5). Carbohydrates were exchanged based on hexose equivalents, and glucose delivery was standardized across treatments, while the rest of the formula (60%) remained unchanged. Calves received L1 during the adaptation period of 3 d and were then exposed to their respective treatment until d 47 after arrival. Milk replacer was provided daily in 2 equally sized meals. Meal size was 2.0 L during the 3-d adaptation period and gradually increased to 4.0 L until weaning (d 35 after arrival). During weaning, meal size decreased from 4.0 to 2.0 L on d 36, and MR was withdrawn on d 48 after arrival. Straw and concentrates were offered ad libitum from d 25 onward. Calves had ad libitum access to water throughout the study. Measurements included daily feed intakes, weekly body weight, and weekly spot feces sampling in all calves. Blood samples were collected on d 18. Additionally, postprandial responses of insulin and glucose were measured in 6 calves per treatment on d 19, 20, and 21. Increasing glucose inclusion (at the direct expense of lactose) in MR did not affect growth but linearly increased mortality, which was as high as 25% (5/20) in L5. Mortality was primarily associated with gastrointestinal disorders (6/11). At higher glucose levels, calves needed greater serum insulin concentrations to control glycemia, as shown by a linear increase in the area under the curve for insulin. Furthermore, calves needed more time to control glycemia, as indicated by a linear increase in the maximal concentration of insulin. Consequently, there was a linear increase in area under the curve for glucose. Even though calves needed more time and higher insulin concentrations for 30% glucose inclusion and higher, the glucose-to-insulin ratio did not differ across treatments. However, high glucose inclusion levels in MR affected calf mortality and is not a suitable strategy for lactose replacement.

Sustained release and improved bioavailability in mice after subcutaneous administration of griseofulvin as nano- and microcrystals

The objective of the study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administrations of nano- and microparticle suspensions of griseofulvin to mice. The solubility of the compound was determined as approximately 40 µM, at 37 °C, independent of particle size, stabilizer mixtures investigated and solvent used for measurement. The present in vivo studies demonstrated non-linear absorption kinetics (in peak concentration, Cmax) for griseofulvin up to 50 mg/kg after s.c. administration of nanocrystals and microsuspensions but linear increase in area under the curve (AUC) at all occasions investigated. Cmax was higher for smaller particles administered. Both investigated suspensions, at 10 and 50 mg/kg, showed significantly sustained plasma profiles compared to i.v. and p.o. administration. Administering 10 and 50 mg/kg of griseofulvin nanocrystals as 10 mL/kg, instead of 2.5 mL/kg, improved Cmax but AUC was unchanged. The present study showed that the bioavailability of griseofulvin, administered as nano- and microparticles, increased significantly after s.c. administration (60–100%) compared with p.o. dosing (17%). The drug is currently orally administered and clearly exposed to a significant first pass metabolism, i.e. an ideal candidate for an alternative administration route, like s.c. injection.

Phase I Study of a Novel Oral Janus Kinase 2 Inhibitor, SB1518, in Patients With Relapsed Lymphoma: Evidence of Clinical and Biologic Activity in Multiple Lymphoma Subtypes

The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma. Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks. Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%. SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.

Determination and pharmacokinetics of [6]‐gingerol in mouse plasma by liquid chromatography–tandem mass spectrometry

This study describes the development of a rapid and sensitive high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) assay for the quantification of [6]-gingerol in mouse plasma and application to a pharmacokinetic study after dose ranging in mice. The assay involved a protein precipitation step with acetonitrile and an isocratic elution using a mobile phase consisting of acetonitrile and water containing 0.1% formic acid (80:20 v/v). The multiple reaction monitoring was based on the transition of m/z = 277.2 → 177.1 for [6]-gingerol and 294.2 → 137.1 for nonivamide (internal standard). The assay was validated to demonstrate the specificity, linearity, recovery, accuracy, precision and stability. The calibration curves were linear over the wide concentration range of 10-10,000 ng/mL (r ≥ 0.9988). The lower limit of quantification was 10 ng/mL using a small volume of mouse plasma (20 μL). The method was successfully applied to a pharmacokinetic study in mice after intravenous injection of [6]-gingerol at 1.5, 3 and 6 mg/kg doses. The pharmacokinetics of [6]-gingerol were linear over the dose range studied as demonstrated by the linear increase in area under the concentration-time curve (AUC(inf)) with no significant change in the systemic clearance (Cl(s)), volume of distribution (V(ss)) and elimination half-life (t(1/2)) as a function of dose.

Exposure–response analysis of tigecycline in pharmacodynamic simulations using different size inocula of target bacteria

This study explored tigecycline exposure–bacterial responses in pharmacodynamic simulations (in vitro kinetic model) using different inocula. One meticillin-resistant vancomycin-heteroresistant Staphylococcus aureus, one Enterococcus faecium and one extended-spectrum β-lactamase-producing Escherichia coli with equal tigecycline minimum inhibitory concentrations/minimum bactericidal concentrations (MICs/MBCs) (0.12/0.25 μg/mL) were used. A computerised pharmacodynamic bicompartmental model simulated three tigecycline twice-daily dosing regimens over 48 h: 50 mg (100 mg loading dose); 100 mg; and 150 mg. Areas under bacterial growth curves were calculated, and differences between the growth curve used as control and the killing curve of bacteria exposed to tigecycline (ABBC) were determined. With standard inocula [ca. 1 × 10 6 colony-forming units (CFU)/mL], linear increases in area under the concentration–time curve (AUC)/MIC (25.6 for 50 mg, 53.76 for 100 mg and 79.52 for 150 mg) produced linear increases in activity against Gram-positive organisms (mean ABBCs of 120.60, 143.20 and 195.80 log CFU × h/mL for S. aureus and of 95.75, 172.55 and 216.90 log CFU × h/mL for E. faecium, respectively), with the activity of the 150 mg regimen being significantly higher ( P < 0.01) than that of the other two regimens. ABBCs obtained with the 100 mg regimen using standard inocula were similar to those obtained with the 150 mg regimen when using high inocula (ca. 1 × 10 7 CFU/mL). Against E. coli, the highest dosing regimen was required to obtain significant antibacterial activity compared with control (mean ABBCs of 145.75 log CFU × h/mL with standard inocula and 63.33 log CFU × h/mL with high inocula). An increase in tigecycline dosing appears to be an interesting therapeutic option to maximise antibacterial activity owing to its linear pharmacokinetics and pharmacodynamics, especially when severe infections with high bacterial load are suspected.

Fish oil inhibits photochemically induced thrombosis in the guinea pig in a dose dependent manner

The dose–response effect of dietary fish oil was investigated in the photochemically induced thrombosis model in guinea pigs. In this arterial thrombosis model thrombus formation was evaluated by determination of different occlusion parameters (percentage of occlusion, area under the blood flow curve, time to first occlusion, spontaneous reflow). Sixty guinea pigs (7 weeks old) were randomly assigned to and fed a 40 energy % diet containing increasing amounts (0, 5.5, 17 and 36 energy %) of fish oil for four weeks. Arterial thrombosis was induced in the femoral artery by free radical damage and subsequent thrombus formation. Increasing fish oil concentrations in the diet were associated with a linear decrease ( p<0.001) in the percentage of occlusion (calculated as a decrease in blood flow) and a linear increase in area under the blood flow curve/begin flow ( p<0.001). The time to thrombus formation was not significantly prolonged in any group. However the frequency of animals in which complete occlusion of the femoral artery was not obtained during the thrombosis induction and subsequent observation period was higher in the groups receiving the two highest doses of fish oil. Spontaneous reflow correlated positively ( p<0.013) with increasing dietary fish oil content. In conclusion, our data indicates that dietary fish oil inhibits photochemically induced thrombosis in this animal model of arterial thrombosis in a dose dependent manner.

RELATIONSHIP OF DIETARY PROTEIN LEVELS TO PERFORMANCE AND CARCASS MERIT OF MARKET SWINE

Three trials, involving 108 Yorkshire SPF pigs, were conducted to study the protein requirements of growing-finishing pigs. The design of each trial was a 3 × 3 × 2 factorial involving three levels of protein in the grower (19.2, 17.4 and 15.5%), three levels of protein in the finisher (17.4, 15.5 and 14.2%) and two sexes (barrows and gilts). The study was considered as one experiment conducted as a randomized complete-block design with five replications. During the growing phase there was a linear increase in growth rate and curvilinear reduction in feed required per kg gain, due to higher dietary protein levels (P = 0.05). During the finishing phase, dietary protein levels did not influence rate of gain but feed required per kg gain increased linearly as protein level in the diet decreased (P = 0.05). Feeding the lowest level of protein throughout resulted in a slower rate of gain and increased the feed required per kg gain. The efficiency of feed utilization was the same for barrows and gilts, although barrows gained faster and consumed more feed per day (P = 0.05) than gilts. There were linear increases in area of Longissimus dorsi muscle due to increased protein level in the finisher diets. An interaction between sex and protein levels (P = 0.05) was observed in the finisher period for total ham weight and weight of ham lean.