Fractional Rate Constants Research Articles

A Minimal PBPK Model Describes the Differential Disposition of Silica Nanoparticles In Vivo.

Nanoparticles (NPs) have emerged as promising candidates for drug delivery due to their tunable physical and chemical properties. Among these, silica nanoparticles (SiNPs) are particularly valued for their biocompatibility and adaptability in applications like drug delivery and medical imaging. However, predicting SiNP biodistribution and clearance remains a significant challenge. To address this, we developed a minimal physiologically-based pharmacokinetic (mPBPK) model to simulate the systemic disposition of SiNPs, calibrated using in vivo PK data from mice. The model assesses how variations in surface charge, size, porosity, and geometry influence SiNP biodistribution across key organs, including the kidneys, lungs, liver, and spleen. A global sensitivity analysis identified the most influential parameters, with the unbound fraction and elimination rate constants for the kidneys and MPS emerging as critical determinants of SiNP clearance. Non-compartmental analysis (NCA) further revealed that aminated SiNPs exhibit high accumulation in the liver, spleen, and kidneys, while mesoporous SiNPs primarily accumulate in the lungs. Rod-shaped SiNPs showed faster clearance compared to spherical NPs. The mPBPK model was extrapolated to predict SiNP behavior in humans, yielding strong predictive accuracy with Pearson correlation coefficients of 0.98 for mice and 0.92 for humans. This model provides a robust framework for predicting the pharmacokinetics of diverse SiNPs, offering valuable insights for optimizing NP-based drug delivery systems and guiding the translation of these therapies from preclinical models to human applications.

Optimizing ruminant nutrition: Insights from a comprehensive analysis of silage composition and in vitro gas production dynamics using nonlinear models

Achieving sustainable livestock management necessitates optimizing animal production while minimizing environmental impact. To achieve this, feed efficiency must be enhanced, and nutrition blueprints must be understood. In ruminant nutrition, this is of paramount importance, as it exposes degradation kinetics and nutritional benchmarks, allowing feed management and formulations to be more ecologically balanced. Previous research efforts have focused on exploring the relationship between a restricted set of nutrient parameters and the in vitro gas production dynamics. In the current study, an extensive dataset derived from freeze-dried kefir culture treated white clover silage was used to examine intricate relationships between eight nonlinear models and diverse variables. This dataset contains in vitro gas production data along with nutritional composition, microbial populations, fermentation quality, digestibility, mineral concentration, and fatty acid profiles. Through rigorous application of mathematical models, the performance in capturing gas production dynamics was critically assessed. Among these, the Michaelis‒Menten (MM) and Mitscherlich (MIT) models fit the data well and offer superior predictions of gas production dynamics. Asymptotic gas volume was negatively correlated with crude protein content, emphasizing the influence of protein on gas production. Fiber composition plays a significant role in fermentation kinetics, as evidenced by significant correlations between degradation rate constant and crude protein concentrations. The degradation rate constant of insoluble fraction exhibited significant positive correlations with crude protein and neutral detergent fiber contents. Moreover, mineral content had significant effects on gas production dynamics. Zinc content showed a strong and significant positive correlation with the gas production rate coefficient, underscoring its crucial role in enhancing microbial activity. Conversely, calcium content displayed a significant but weak negative correlation with the final asymptotic gas volume, indicating its potential to modulate gas production. In summury, this study provides detailed insights into the intricate relationship between mathematical models and various variables in rumen fermentation. The MM and MIT models have proven to be robust tools, offering nuanced perspectives on gas production dynamics. These findings pave the path for improving sustainable ruminant nutritional practices and refining feed management strategies.

Synchronization of discrete time fractional order neuromuscular models in the presence and absence of stimulus

This article proposes a fractional order discrete-time neuromuscular model incorporating calcium kinetics to study the essential role of the neuromuscular system in facilitating rapid information transmission between nerve cells and muscles for bodily functions. The study conducts a dynamical analysis to investigate the stability and periodic oscillations of the system in the presence and absence of tetanus stimuli from neurons. Bifurcation diagrams are generated for different fractional orders and rate constants, highlighting the occurrence of chaotic dynamics. The region of chaos is determined using the largest Lyapunov exponents and the Jacobian matrix method. The study also achieves synchronization of the systems by employing nonlinear control functions with feedback gains. Emphasizing the significance of constructing the biological model using fractional order operators, the article provides a chemical interpretation of the analytical findings. Moreover, the article employs dynamic plots to visually depict the changing system variables over time, allowing for an examination of the concurrent presence of multiple attractors through bifurcation diagrams and phase plane portraits. By studying how chemical kinetics and muscle activation are interrelated, the article uncovers captivating revelations that could guide the formulation of strategies to combat muscle disorders. The article also underscores the potential utility of synchronization in managing neuromuscular conditions, thus emphasizing its practical implications in disease control.

Why only half of the added ansa-metallocene catalyst active in the E/P/diene polymerization: catalyst evaluation in terms of active center [Zr]/[C*] fraction and polymerization propagation rate constants

To understand how the silyl-bridged metallocene catalysts rac-Me2Si(2-Me-4-Ph-Ind)2ZrCl2 behave against dienes under the same reaction condition because of its importance as a commercial polymerization catalyst and ethylene propylene diene monomers (EPDM). Adding diene depressed the catalytic activity, especially 5-ethylidene-2-norbornene (ENB) exerted the most substantial deactivation effect. Firstly, we examine the (ENB, vinyl norbornene (VNB) and 4-vinylcyclohexene (VCH)) non-conjugated and conjugated (isoprene (IP), butadiene (BD)) diene and address how polymerization catalysts behave against these dienes. For example, the catalytic activity was enhanced with IP and BD (3–3.3106 gm/mmolMt·h) compared to ENB, VNB and VCH. The VNB incorporation rate was prolonged (5.4 mol%), but with IP and BD, it was relatively moderate. E/P/IP and E/P/BD with higher incorporation of E produced a higher MW, which means that the chain transfer reaction with ethylene is slower than P. Secondly, we address how the dienes exocyclic and exocyclicπ bonds of non-conjugated and conjugated properties of IP and BD affect the kinetic measurements such as active centers [Zr]/[C*] fraction, EPDM chain propagation, termination, and isomerization. Finally, we compare [Zr]/[C*] and kpPE, kpP and kpDienes for different EPDM. After collecting these kinetic parameters, we can describe the mechanism’s intricacy and the existence of considerable catalyst dormancy with dienes under identical reaction conditions.

In vitro ruminal fermentation parameters of canola meal protein in response to incremental doses of gamma irradiation

Rapid ruminal degradation of canola meal (CM) limits its feed value for high-producing ruminants. Attempts to reduce ruminal degradability of CM through gamma irradiation have generated conflicting results. While this strategy has the potential to reduce CM degradability, the optimal radiation dose is unknown for this valuable co-product. Therefore, this in vitro ruminal fermentation study was designed to evaluate the efficacy of gamma irradiation to protect CM protein from ruminal degradation. Canola meal was irradiated at 0 (CM0), 15 (CM15), 30 (CM30), 45 (CM45), 60 (CM65), 75 (CM75), and 90 kGy (CM90). Irradiated CM was then analysed for proximate composition and incubated with rumen fluid to determine in vitro degradability of dry matter (DMD) and nitrogen (ND). The data were evaluated for linear and quadratic effects using response surface regression analysis. Neutral detergent fibre and acid detergent fibre linearly decreased as irradiation dosage increased. Quadratic responses were observed for total nitrogen (N) content, DMD12, and DMD36 in response to increasing irradiation dosage. Gamma irradiation linearly increased the rapidly soluble fraction (a) and effective degradability (ED) of dry matter. There were no irradiation effects on ND12, ND36, ND48, fractional rate constant (c), and potential degradability, but significant quadratic trends were observed for ND24, a, slowly degradable fraction (b), and ED of N. It was concluded that although gamma irradiation altered the chemical composition of CM, it was not an effective method to protect CM from extensive ruminal degradation

Kinetic modelling of dissolution dynamic nuclear polarisation 13 C magnetic resonance spectroscopy data for analysis of pyruvate delivery and fate in tumours.

Dissolution dynamic nuclear polarisation (dDNP) of 13 C-labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised 13 C-labelled pyruvate (13 C1 -pyruvate) and urea (13 C-urea), a nonmetabolised marker. A general mathematical model of pyruvate-lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, Kip , and the forward and reverse fractional rate constants for pyruvate-lactate signal exchange, kpl and klp . An analogous model was developed for urea, enabling estimation of urea tumour losses and the blood clearance parameter, Kiu . A spectral fitting procedure to blood time-course data proved superior to assuming a gamma-variate form for the AIFs. Mean arterial blood pressure marginally correlated with clearance rates. Kiu equalled Kip , indicating equivalent permeability of the tumour vasculature to urea and pyruvate. Fractional loss rate constants due to effluxes of pyruvate, lactate and urea from tumour tissue into blood (kpo , klo and kuo , respectively) indicated that T1 s and the average flip angle, θ, obtained from arterial blood were poor surrogates for these parameters in tumour tissue. A precursor-product model, using the tumour pyruvate signal time-course as the input for the corresponding lactate signal time-course, was modified to account for the observed delay between them. The corresponding fractional rate constant, kavail , most likely reflected heterogeneous tumour microcirculation. Loss parameters, estimated from this model with different TRs, provided a lower limit on the estimates of tumour T1 for lactate and urea. The results do not support use of hyperpolarised urea for providing information on the tumour microcirculation over and above what can be obtained from pyruvate alone. The results also highlight the need for rigorous processes controlling signal quantitation, if absolute estimations of biological parameters are required.

Photodissociation branching ratios of12C16O from 110 500 to 113 045 cm−1: first observation of the C(1S) channel

Carbon monoxide (CO) is one of the most abundant molecular species in comets. Its photodissociation by the solar radiation in the vacuum ultraviolet (VUV) region produces excited atomic fragments C(1D), C(1S), and O(1D), which radiate at characteristic wavelengths when they decay to lower states. The fractional rate constants for generating these fragments from CO photodissociation under the entire range of the solar radiation field are key input values in modelling the observed atomic emission intensities from comets. In this study, the branching ratios of the four lowest dissociation channels C(3P)+O(3P), C(1D)+O(3P), C(3P)+O(1D), and C(1S)+O(3P) of the12C16O photodissociation are measured in the VUV energy range between the threshold of producing the C(1S)+O(3P) channel (~110 500 cm−1) and the ionisation energy (IE) of12C16O (~113 045 cm−1). We measured these ratios using the VUV time-slice velocity-map ion imaging apparatus. We observe a number of high Rydberg states in the aforementioned energy range, with most of them mainly producing ground C(3P) and O(3P) atomic fragments, and only a few of them producing a significant amount of excited C(1D) or O(1D) fragments. We also observe the excited C(1S) fragment from CO photodissociation and measured its branching ratio for the first time. Based on the photodissociation branching ratios measured in the current and previous studies, we are able to estimate the relative percentages of the excited atomic fragments C(1D), C(1S), and O(1D) from the solar photolysis of12C16O below its IE. We discuss the implications for the photochemical modelling of the CO-dominated comet C/2016 R2 (Pan-STARRS).

PSIX-17 Investigation of rumen starch and protein degradation kinetics in relation to corn processed by super-conditioned pelleting, extruding and puffing

Abstract The objective of this study was to investigate the rumen dry matter (DM), starch and protein degradation kinetics of an Iranian corn grain (single crass 702) processed using different thermal processing methods including 1) grinding (G, 2mm), 2) super-conditioned pelleting (SCP; moisture 20%, retention time 6 min and conditioning temperature 95°C), 3) puffing (PUF; puffing temperature 200°C, hot air velocity 25 m/s, feed rate 100 g/m) and 4) extruding (EX; moisture 20%, temperature of melting zone 75°C and die zone 125°C and time 150s). Three lactating Holstein cows fitted with a ruminal cannula were used. Samples were incubated into the rumen for 2, 4, 8, 12, 24, and 48 h. Rumen degradation kinetics were fitted based on equations. Data were analyzed by GLM procedure of SAS (P < 0.05) using a completely randomized design with 6 replications for every treatment. Rapidly soluble fraction (a) and fractional rate constant (c) of DM were higher (P < 0.01) in PUF and EX corns than SCP. The lowest (P < 0.05) slowly degradable fraction (b) of DM was found in SCP. The highest (P < 0.01) effective rumen degradability of DM (ERDM), starch (ERDS) and protein (ERDP) were observed in the EX, followed by PUF, SCP and G corns. Fraction a of starch and protein was significantly greater (P < 0.01) in EX, PUF and SCP than G. The rate of degradability (c) of starch, DM and protein in EX and PUF were similar and higher (P < 0.01) than SCP and G, but c for starch in EX was greater (P < 0.01) than PUF and fallowed by SCP and G corns. In conclusion, the super-conditioning of corn as a new method of corn processing increased rapidly soluble fraction starch similar to PUF and EX corns and effective rumen degradability of starch was significantly increased in SCP corn.

Thermal inactivation of pectin methylesterase from different potato cultivars (Solanum tuberosum L.)

Pectin methylesterase (PME) is an important enzyme that can alter the texture of potato products during processing and storage. To manage the textural properties of potato based products, low and/or high temperature blanching can be used to promote or inactivate PME, respectively. However, the many potato cultivars being used for processing may contain PMEs with a different thermal stability. Therefore, the thermal inactivation of PME extract from three different potato cultivars (Fontane, Royal and Innovator) was studied. A thermostable and thermolabile enzyme fraction were found in all three cultivars, being inactivated at temperatures from 45 °C and 57.5 °C on, respectively. Innovator may contain a lower level of thermostable PME than the other cultivars tested. The inactivation rate constant of the thermostable PME fraction was lower than the rate constant of the labile fraction at a reference temperature of 55 °C, but no significant differences between the respective rate constants of the different cultivars were found. The thermal inactivation kinetics of PME extract from Fontane were investigated in detail and represented by a first order model that allows the calculation of temperature-time combinations to reach a target residual PME activity.

Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging.

Transvascular water exchange plays a key role in the functional integrity of the blood-brain barrier (BBB). In white matter (WM), a variety of imaging modalities have demonstrated age-related changes in structure and metabolism, but the extent to which water exchange is altered remains unclear. Here, we investigated the cumulative effects of healthy aging on WM capillary water exchange. A total of 38 healthy adults (aged 36-80 years) were studied using 7T dynamic contrast enhanced MRI. Blood volume fraction (vb ) and capillary water efflux rate constant (kpo ) were determined by fitting changes in the 1 H2 O longitudinal relaxation rate constant (R1 ) during contrast agent bolus passage to a two-compartment exchange model. WM volume was determined by morphometric analysis of structural images. R1 values and WM volume showed similar trajectories of age-related decline. Among all subjects, vb and kpo averaged 1.7 (±0.5) mL/100 g of tissue and 2.1 (±1.1) s-1 , respectively. While vb showed minimal changes over the 40-year-age span of participants, kpo declined 0.06 s-1 (ca. 3%) per year (r = -.66; P< .0005), from near 4 s-1 at age 30 to ca. 2 s-1 at age 70. The association remained significant after controlling for WM volume. Previous studies have shown that kpo tracks Na+ , K+ -ATPase activity-dependent water exchange at the BBB and likely reflects neurogliovascular unit (NGVU) coupled metabolic activity. The age-related decline in kpo observed here is consistent with compromised NGVU metabolism in older individuals and the dysregulated cellular bioenergetics that accompany normal brain aging.

Pharmacokinetics of xylazine after 2-, 4-, and 6-hr durations of continuous rate infusions in horses.

Intravenous (i.v.) bolus administration of xylazine (XYL) (0.5mg/kg) immediately followed by a continuous rate infusion (CRI) of 1mgkg-1 hr-1 for 2, 4, and 6hr produced immediate sedation, which lasted throughout the duration of the CRI. Heart rate decreased and blood pressure increased significantly (p>.05) in all horses during the first 15min of infusion, both returned to and then remained at baseline during the duration of the infusion. Compartmental models were used to investigate the pharmacokinetics of XYL administration. Plasma concentration-time curves following bolus and CRI were best described by a one-compartment model. No differences were found between pharmacokinetic estimates of the CRIs for the fractional elimination rate constant (Ke ), half-life (t1/2e ), volume of distribution (Vd ), and clearance (Cl). Median and range were 0.42 (0.15-0.97)/hr, 1.68 (0.87-4.52)hr, 5.85 (2.10-19.34)L/kg, and 28.7 (19.6-39.5)mlmin-1 kg-1 , respectively. Significant differences were seen for area under the curve ( ) (p<.0002) and maximum concentration (Cmax ) (p<.04). This indicates that with increasing duration of infusion, XYL may not accumulate in a clinically relevant way and hence no adjustments are required in a longer XYL CRI to maintain a constant level of sedation and a rapid recovery.

Carbon Mineralization Kinetics from Legume Residues Applied to a High Altitude Acidic Soil

An incubation study was conducted for 56 days under room temperature in a high altitude acidic soil (pH = 4.2) to evaluate carbon(C) mineralization from pea (Pisum sativum L.) residues and leaves from two agroforestry species (Calliandra calothyrsus Meisnand Gliricidia sepium (Jacq.) Walp. Carbon dioxide (CO2) evolution was measured at 7, 14, 21, 28, 42 and 56 days of incubation.Carbon mineralization was best fit to a sequential decomposition model with a rapid and slow phase, each described by first-order kinetics. Percent rapid, rapid and slow fraction rate constants and half-lives were determined. At the completion of the study, percent decomposition was higher for Pisum sativum L. (77.3 %) followed by Calliandra calothyrsus Meisn (60.8 %) andGliricidia sepium (Jacq.) Walp (56.7 %). Similarly, higher percent rapid fractions (78 %), higher decomposition rate constants (kr= 0.053 day-1 ; ks = 0.012 day-1 ) and lower half-lives [t0.5(r) = 13 days; t0.5(s) = 58 days] were also observed with Pisum sativum L.residues. From the findings of this investigation, it appears that the higher lignin content of the two agroforestry species, Gliricidiasepium (Jacq.) Walp (6.33 %) and Calliandra calothyrsus Meisn (4.16 %) was the limiting factor of their decomposability, as compared to Pisum sativum L. which had zero lignin content. This study highlighted pea (Pisum sativum L.) residue as the mosteffective in C mineralization.

Population pharmacodynamics of cilostazol in healthy Korean subjects.

Cilostazol is used for the treatment of intermittent claudication, ulceration and pain. This study was conducted to develop a population pharmacodynamic (PD) model for cilostazol's closure time (CT) prolongation effect in healthy Korean subjects based on a pharmacokinetic (PK) model previously developed. PD data were obtained from 29 healthy subjects who participated in a study conducted in 2009 at Severance Hospital. The PK model used was a two-compartment model with first order absorption. CT data were best described by a turnover model with a fractional turnover rate constant (Kout) inhibited by drug effects (Eff), which were represented by a sigmoid Emax model [Eff = Emax · Cγ / (EC50γ+Cγ)] with Emax being maximum drug effect, EC50 drug plasma concentration at 50% of Emax, C drug plasma concentrations, and γ the Hill coefficient. For the selected PD model, parameter estimates were 0.613 hr−1 for Kout, 0.192 for Emax, 730 ng/ml for EC50 and 5.137 for γ. Sex and caffeine drinking status significantly influenced the baseline CT, which was 85.36 seconds in male non-caffeine drinkers and increased by 15.5% and 16.4% in females and caffeine drinkers, respectively. The model adequately described the time course of CT. This was the first population PD study for cilostazol's CT prolongation effect in a Korean population.

Quantitative analysis of the effect of end-tidal carbon dioxide on regional cerebral oxygen saturation in patients undergoing carotid endarterectomy under general anaesthesia.

Regional cerebral oxygen saturation (rSO2 ) is currently the most used measure in clinical practice to monitor cerebral ischaemia in patients undergoing carotid endarterectomy (CEA). Although end-tidal carbon dioxide (PET CO2 ) is known as a factor that influences rSO2 , the relationship between PET CO2 and rSO2 has not been quantitatively evaluated in patients with severe arteriosclerosis. This study aimed to evaluate the effect of PET CO2 on rSO2 in patients undergoing CEA under general anaesthesia. The intervention to change PET CO2 was conducted between skin incision and clamping of the carotid artery. The rSO2 values were observed by changing PET CO2 in the range of 25-45mmHg. The PET CO2 -rSO2 relationship was characterized by population analysis using a turnover model. In total, 1651 rSO2 data points from 30 patients were used to determine the pharmacodynamic characteristics. Hypertension (HTN) and systolic blood pressure (SBP) were significant covariates on the slope factor in the stimulatory effect of PET CO2 on rSO2 and fractional turnover rate constant (kout ), respectively. The estimates of the parameters were kout (min-1 ): 3.59 for SBP<90mmHg and 0.491 for SBP ≥90mmHg, slope: 0.00321 for patients with HTN and 0.00664 for patients without HTN. The presence of HTNattenuates the response of rSO2 after a change in PET CO2 . When cerebral blood flow is in a state of decline caused by a decrease in SBP to <90mmHg, the response of rSO2 to PET CO2 is increased. It is advisable to maintain SBP >90mmHg in patients with HTNduring CEA.

A novel approach to tracer-kinetic modeling for (macromolecular) dynamic contrast-enhanced MRI.

To develop a novel tracer-kinetic modeling approach for multi-agent dynamic contrast-enhanced MRI (DCE-MRI) that facilitates separate estimation of parameters characterizing blood flow and microvascular permeability within one individual. Monte Carlo simulations were performed to investigate the performance of the constrained multi-agent model. Subsequently, multi-agent DCE-MRI was performed on tumor-bearing mice (n = 5) on a 7T Bruker scanner on three measurement days, in which two dendrimer-based contrast agents having high and intermediate molecular weight, respectively, along with gadoterate meglumine, were sequentially injected within one imaging session. Multi-agent data were simultaneously fit with the gamma capillary transit time model. Blood flow, mean capillary transit time, and bolus arrival time were constrained to be identical between the boluses, while extraction fractions and washout rate constants were separately determined for each agent. Simulations showed that constrained multi-agent model regressions led to less uncertainty and bias in estimated tracer-kinetic parameters compared with single-bolus modeling. The approach was successfully applied in vivo, and significant differences in the extraction fraction and washout rate constant between the agents, dependent on their molecular weight, were consistently observed. A novel multi-agent tracer-kinetic modeling approach that enforces self-consistency of model parameters and can robustly characterize tumor vascular status was demonstrated.

Opposite control of frontocortical 2-arachidonoylglycerol turnover rate by cannabinoid type-1 receptors located on glutamatergic neurons and on astrocytes

This study examined the respective influences of cannabinoid type-1 (CB1) receptors expressed either in forebrain GABAergic neurons, in cortical glutamatergic neurons, or in astrocytes on the turnover rates of the endocannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), and the non-cannabinoid N-acylethanolamides, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA), in mouse forebrain regions. To this end, conditional mutant mice lacking CB1 receptors from either of these cell types were pre-treated systemically with JZL195, a dual inhibitor of fatty acid amide hydrolase, the enzyme degrading AEA, PEA, and OEA, and of monoacylglycerol lipase, the main 2-AG-degrading enzyme. The analyses of frontocortical, hippocampal, and striatal AEA, 2-AG, PEA, and OEA concentrations revealed that their respective baseline concentrations were not influenced by the mouse genotype. On the other hand, the accumulation of frontocortical and/or hippocampal 2-AG levels in JZL195-pre-treated mice was dependent on the mouse genotype. Thus, JZL195-induced 2-AG accumulation rates were diminished in the frontal cortex of mice lacking CB1 receptors in glutamatergic neurons while their respective values were increased in the frontal cortex and hippocampus of mice lacking these receptors in astrocytes. These genotypic differences occurred with parallel and proportionate changes in the fractional rate constants for degradation of 2-AG, thus providing a mechanism whereby the baseline levels of 2-AG remained constant between genotypes. Besides suggesting a cell-type-specific control of frontocortical and/or hippocampal 2-AG synthesis and degradation rates by CB1 receptors, this study highlights the interest of assessing endocannabinoid turnover rates when questioning the status of the endocannabinoid system.

Prediction of the stability of meropenem in intravenous mixtures.

The purpose of this study was to predict the stability of meropenem in a mixed infusion. The hydrolysis of meropenem in aqueous solution was found to be accelerated by pH, and by increasing concentrations of sodium bisulfite (SBS) and L-cysteine. Equations were derived for the degradation rate constants (kobs) of pH, SBS and L-cysteine, and fractional rate constants were estimated by the nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the characteristic pH curve. From these results, an equation was derived giving the residual ratio (%) of meropenem at any time after mixing an infusion containing SBS and/or L-cysteine at any temperature, and in the pH range 4.0-10.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).

Prediction of the Stability of Octreotide in a Mixed Infusion

The purpose of this study was to predict the stability of octreotide in a mixed infusion containing sodium bisulfite (SBS). In aqueous solution the hydrolysis of octreotide was found to be accelerated by pH, and by increasing concentrations of SBS. Equations for the degradation rate constants (kobs) of pH and SBS were derived. The fractional rate constants were estimated by the nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of octreotide at any time after mixing an infusion containing SBS at any temperature in the pH range 4.0-7.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).

Prediction of the Stability of Imipenem in Intravenous Mixtures

The purpose of this study was to predict the stability of imipenem in a mixed infusion. The hydrolysis of imipenem in aqueous solution was found to be accelerated by pH, and by increasing concentrations of sodium bisulfite (SBS) and L-cysteine. Equations were derived for the degradation rate constants (k(obs)) of pH, SBS and L-cysteine and fractional rate constants were estimated by nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of imipenem at any time after mixing an infusion containing SBS and/or L-cysteine at any temperature and at pH 4.0-10.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).

δ13C as a marker to study digesta passage kinetics in ruminants: a combined in vivo and in vitro study

The aim of the current study was to explore the use of the tracer 13C as an internal marker to assess feed fraction-specific digesta passage kinetics through the digestive tract of dairy cows. Knowledge on feed-specific fractional passage rates is essential to improve estimations on the extent of rumen degradation and microbial protein efficiency; however, this information is largely lacking. An in vivo and in vitro experiment was conducted with grass silages (Lolium perenne L.) that were enriched with 13C by growing the grass under elevated 13CO2 conditions. In a crossover design, two dairy cows received pulse doses of two 13C-enriched grass silages and chromium-mordanted neutral detergent fibre (Cr-NDF) into the rumen. The two 13C-enriched grass silages used differed in digestibility and were grown under identical field conditions as the bulk silages fed to the animals. Faecal excretion patterns of 13C-enriched dry matter (13C-DM), neutral detergent fibre (13C-NDF) and Cr-NDF were established, and a nonlinear multicompartmental model was used to determine their rumen passage kinetics. In addition, the 13C-enriched silages were incubated in rumen liquid in an in vitro batch culture system at different time intervals to determine the effect of fermentation on 13C-enrichment in the residue. The in vitro study showed that the 13C : 12C ratios in DM and NDF residues remained stable from 24 h of incubation onwards. In addition, in vitro fractional degradation rates for 12C in the DM and NDF did not differ from those of 13C, indicating that fermentative degradation does not affect the 13C : 12C ratio in the DM nor in the NDF fraction of the residue. Model fits to the faecal excretion curves showed a significant difference in fractional rumen passage rates between Cr-NDF, 13C-DM and 13C-NDF (P ⩽ 0.025). Silage type had no clear effect on rumen passage kinetics (P ⩾ 0.081). Moreover, it showed that peak enrichments for 13C-DM and 13C-NDF in faeces were reached at 30.7 and 41.7 h post dosing, respectively. This is well after the time (24 h) when the 13C : 12C ratios of the in vitro unfermented residues have reached stable enrichment level. Fractional rate constants for particle passage from the rumen are estimated from the descending slope of faecal excretion curves. The present study shows that the decline in 13C : 12C ratio after peak enrichment is not affected by fermentative degradation and therefore can be used to assess feed component-specific fractional passage rates.