Effects of oral dosing paradigms (gavage versus diet) on pharmacokinetics and pharmacodynamics

In cancer chemopreventive studies, test agents are typically administered via diet, while the preclinical safety studies normally employ oral gavage dosing. Correspondence in pharmacokinetic and pharmacodynamic profiles between the two dosing approaches cannot be assumed a priori. Sulindac, a non-steroidal anti-inflammatory agent with potential chemopreventive activity, was used to assess effects of the two oral dosing paradigms on its pharmacokinetics and pharmacodynamics. Time-dependent concentrations of sulindac and its sulfone metabolite were determined in plasma and potential target organ, mammary gland. Prostaglandin E(2) was used as a pharmacodynamic biomarker and measured in mammary gland. An inverse linear relationship was detected between pharmacodynamic and pharmacokinetic markers, area under the curve for prostaglandin E(2) levels and sulindac sulfone concentrations, respectively, in the mammary tissue. Marked differences in pharmacokinetics and pharmacodynamics were observed after administration of sulindac by the two oral dosing paradigms. In general, oral gavage resulted in higher peak and lower trough concentrations of sulindac in plasma and mammary tissue, higher area under concentration-time curve in plasma and mammary tissue, and greater effect on prostaglandin E(2) levels than the corresponding diet dosing. This study illustrates potential pitfalls and limitations in trying to generalize based on data obtained with different oral dosing schemes and their extrapolation to potential efficacy and health risks in humans.     

Preillumination of excised spinach leaves with red light increases resistance of photosynthetic apparatus to UV radiation

Leaves of spinach (Spinacia oleracea, cv. Ispolinskii) were preilluminated by low-intensity light (1.0 and 1.5 W/m², 0.5?C3.0 h) with wavelengths ranging from 530 to 730 nm to study the effect of this pretreatment on the activity of photosystem II (PS II), content of photosynthetic pigments, and peroxidase activity in excised leaves exposed to UV-A irradiation. Irradiation of leaves with UV-A suppressed the activity of PS II, reduced the content of chlorophylls (a + b) and carotenoids, and increased the peroxidase activity. Preillumination of leaves with red light (RL, 620?C660 nm) alleviated the inhibitory action of UV-A on PS II activity and reduced the pigment losses but increased the peroxidase activity in leaves and thylakoid membrane preparations, as compared to the respective effects of UV-A light applied without preillumination. The preexposure of leaves to red light alternating with far-red light (FR, 730 nm) removed partly the influence of RL on the parameters under study, which indicates the involvement of phytochrome active form, P_FR into stress-induced defense responses in leaves. It is supposed that elevated resistance of photosynthetic apparatus to UV-A radiation was formed with the involvement of P_FR and the antioxidant system induced by oxidative stress after preillumination of leaves with red light     

Phytochrome B-dependent regulation of reductive phase of photosynthetic carbon assimilation

The experiments were conducted with 10-day-old seedlings of wheat (Triticum aestivum L). Phytochrome B was activated using an array of light diodes emitting light in the red spectral region (RL) and inactivated by an array of light diodes emitting far-red light (FRL). At the end of the night dark period (8 h), activity of the chloroplastic GAP-dehydrogenase complex (the sequence of reactions: 3-PGA → 1,3-PGA → 3-GAP) was 1.0?1.2 μmol of oxidized NADPH/(min g fr wt of the leaf). When the leaves of intact plants were exposed to a maximal dose of RL (20 min at 17.5 kJ/m²), enzyme activity rose by 100–120%. Longer exposure to RL (30 and 40 min) did not cause further activation. Successive exposure to RL and FRL (20 min at 3.0 kJ/m²) completely negated a stimulatory effect of RL. It was shown that as little as 5-min-long exposure to RL increased the rate of 3-GAP formation by 20–25%, and enzyme activity rose linearly when radiation dose was elevated. Determination of the lifetime of RL-activated state by its decrease in plants placed in darkness showed that decay occurred with τ_1/2 of 50?60 min when RL was switched off. Thus, a phytochrome B-induced regulation of reducing enzyme complex governing the reductive pentose phosphate cycle was discovered. Judging from the kinetics of attenuation of the activated state, phytochrome B apparently does not affect de novo synthesis of the enzyme. Since the investigated metabolic process consists of two coupled reactions controlled by kinase and dehydrogenase, the place and mechanism of action of the phytochrome system remain unknown.     

Effects of Physical Properties of the Lung Parenchyma and Airways on Cough Efficiency

The effects of the physical parameters of the parenchyma and airways on the temporal relationships between the volume flow rate and the linear velocity of airflow in the trachea during coughing were studied using a mathematical model. It was shown that the relationship between the volume flow rate and the duration of the act of conghing can be used for assessment of inertial and viscous properties of the posterior wall of the trachea and for assessment of the parameter characterizing the nonlinearity of the intrapulmonary airway resistance. Computations indicated that the linear air velocity in the trachea and, therefore, the cough efficiency depend weakly on the physical properties of the posterior wall of the trachea and lung parenchyma.     

Ionol (BHT) produces superoxide anion

In aqueous medium etiolated wheat seedlings release superoxide anion ( ). Interaction of a synthetic antioxidant, butylated hydroxytoluene (BHT, ionol), with oxygen in the aqueous medium is accompanied by formation. This suggests that under certain conditions BHT behaves as a prooxidant. A natural antioxidant, superoxide dismutase (SOD), and also a wound healing preparation, emulsified denatured placenta (EDP), do not exhibit the prooxidant properties. In contrast to BHT, they reduce production by the etiolated wheat seedling system.     

A comparative analysis of gut microbiota disturbances in the Gottingen minipig and rhesus macaque models of acute radiation syndrome following bioequivalent radiation exposures

In rodent studies, the gut microbiota has been implicated in facilitating both radioresistance, by protecting the epithelium from apoptotic responses and radiosensitivity, inducing endothelial apoptotic responses. Despite the observation that large animal models, such as the Chinese Rhesus macaque and the Gottingen Minipig, demonstrate similarity to human physiologic responses to radiation, little is known about radiation-induced changes of the gut microbiome in these models. To compare the two models, we used bioequivalent radiation doses which resulted in an LD50 for Gottingen Minipigs and Chinese Rhesus macaques, 1.9 Gy and 6.8 Gy, respectively. Fecal samples taken prior and 3 days post-radiation were used for 16S rRNA gene sequence amplicon high throughput sequencing (Illumina MiSeq). Baseline gut microbiota profiles were dissimilar between minipigs and rhesus macaques. Irradiation profoundly impacted gut microbiota profiles in both animals. Significant increases of intracellular symbionts were common to both models and to reported changes in rodents suggesting universality of these findings post-radiation. Remarkably, opposite dynamics were observed for the main phyla, with increase of Firmicutes and decrease of Bacteroidetes and Proteobacteria in minipigs but with enrichment of Bacteroidetes in rhesus macaques. Minipig changes in magnitude and in variety of species affected were more extensive than those observed in rhesus macaques. This pilot study provides an important first step in comparing the radiosensitive pig model to the comparatively more radioresistant macaque model, for the identification of microbial elements which may influence radiosensitivity.     

Some features of imaging of the processes occurring in an extended arc discharge in atmospheric-pressure air

Processes occurring in the low-temperature plasma of extended quasi-stationary arc discharges in air between graphite electrodes are investigated. Along with the conventional (constricted) discharge geometry, other discharge modes—diffuse (distributed) and diffuse-constricted—are studied. Contraction, stratification, and shunting processes are considered. Current oscillation modes are revealed that are caused by the interaction between the cathode and anode jets and the origination of plasma jets and solid particles from the locally overheated anode surface. 1 The use of graphite electrodes with standard atmospheric pressure excludes the presence of the liquid phase in the electrode spots     

Pharmacokinetic and tissue distribution study of [14C]fluasterone in male Beagle dogs following intravenous,oral and subcutaneous dosing routes

The purpose of this work was to compare the pharmacokinetics (PK) and tissue distribution of [¹⁴C]fluasterone following intravenous (iv), subcutaneous (sc) and oral (po) administration in male Beagle dogs. The main goal of the investigation was to discover if non-oral routes would alter parameters observed in this study following the administration of [¹⁴C]fluasterone. The oral formulation had a lower bioavailability (47%) compared to the sc formulation (84%). Po and sc administration resulted in a similar t_max; however, the observed C_max following sc dosing was less than half of that after oral dosing. The sc route had the greatest overall exposure (AUC_0–∞). Tissue distribution analysis 2 h post-intravenous dosing showed that connective tissue (adipose and bone), liver, and skeletal muscle accumulated relatively high levels of fluasterone. The majority of the dose was retained during the first 24 h. Elimination of [¹⁴C]fluasterone-derived radioactivity following intravenous dosing resulted in urine and feces containing 7.6% and 28%, respectively, of the total dose over the first 24 h. Elimination of [¹⁴C]fluasterone-derived radioactivity following subcutaneous dosing resulted in 4.6% in urine and 7.8% in feces of the total dose over the first 24 h. Following oral dosing, elimination resulted in 3.8% in urine and 36% in feces over the first 24 h. In conclusion, the sc route of administration offers some advantages to po and iv due to the prolonged release and increased retention through 24 h.