Kinetics of propranolol uptake in muscle, skin, and fat of the isolated perfused rat hindlimb

The tissue distribution kinetics of a highly bound solute, propranolol, was investigated in a heterogeneous organ, the isolated perfused limb, using the impulse-response technique and destructive sampling. The propranolol concentration in muscle, skin, and fat as well as in outflow perfusate was measured up to 30 min after injection. The resulting data were analysed assuming (1) vascular, muscle, skin and fat compartments as well mixed (compartmental model) and (2) using a distributed-in-space model which accounts for the noninstantaneous intravascular mixing and tissue distribution processes but consists only of a vascular and extravascular phase (two-phase model). The compartmental model adequately described propranolol concentration-time data in the three tissue compartments and the outflow concentration-time curve (except of the early mixing phase). In contrast, the two-phase model better described the outflow concentration-time curve but is limited in accounting only for the distribution kinetics in the dominant tissue, the muscle. The two-phase model well described the time course of propranolol concentration in muscle tissue, with parameter estimates similar to those obtained with the compartmental model. The results suggest, first that the uptake kinetics of propranolol into skin and fat cannot be analysed on the basis of outflow data alone and, second that the assumption of well-mixed compartments is a valid approximation from a practical point of view las, e.g., in physiological based pharmacokinetic modelling). The steady-state distribution volumes of skin and fat were only 16 and 4%, respectively, of that of muscle tissue (16.7 ml), with higher partition coefficient in fat (6.36) than in skin (2.64) and muscle (2.79. (C) 2000 Elsevier Science B.V. All rights reserved.

Soil carbon determination by high temperature combustion - A comparison with dichromate oxidation procedures and the influence of charcoal and carbonate carbon on the measured value

The measurement of organic carbon in soils has traditionally used dichromate oxidation procedures including the Wakley and Black and the Heanes methods. The measurement of carbon in soils by high temperature combustion is now widely used providing a rapid automated procedure without the use of toxic chemicals. This procedure however measures total carbon thus requiring some means of correction for soil samples containing carbonate and charcoal forms of carbon. This paper examines the effects of known additions of charcoal to a range of soil types on the results obtained by the Walkley and Black, Heanes and combustion methods. The results show, that while the charcoal carbon does not react under Walkley and Black conditions, some proportion does so with the Heanes method. A comparison of six Australian Soil and Plant Analysis Council reference soil samples by the three methods showed good agreement between the Heanes method, the combustion method and only slightly lower recoveries by the Walkley and Black procedure. Carbonate carbon will cause an overestimation of soil organic carbon by the combustion method thus requiring a separate determination of carbonate carbon to be applied as a correction. This work shows that a suitable acid pre-treatment of alkaline soils in the sample boats followed by a drying step eliminates the carbonate carbon prior to combustion and the need for an additional measurement. The measurement of carbon in soils by high temperature combustion in an oxygen atmosphere has been shown to be a rapid and reliable method capable of producing results in good agreement with one of the established dichromate oxidation procedures.

Commentary: Using the convection-dispersion model and transit time density functions in the analysis of organ distribution kinetics

The convection-dispersion model and its extended form have been used to describe solute disposition in organs and to predict hepatic availabilities. A range of empirical transit-time density functions has also been used for a similar purpose. The use of the dispersion model with mixed boundary conditions and transit-time density functions has been queried recently by Hisaka and Sugiyanaa in this journal. We suggest that, consistent with soil science and chemical engineering literature, the mixed boundary conditions are appropriate providing concentrations are defined in terms of flux to ensure continuity at the boundaries and mass balance. It is suggested that the use of the inverse Gaussian or other functions as empirical transit-time densities is independent of any boundary condition consideration. The mixed boundary condition solutions of the convection-dispersion model are the easiest to use when linear kinetics applies. In contrast, the closed conditions are easier to apply in a numerical analysis of nonlinear disposition of solutes in organs. We therefore argue that the use of hepatic elimination models should be based on pragmatic considerations, giving emphasis to using the simplest or easiest solution that will give a sufficiently accurate prediction of hepatic pharmacokinetics for a particular application. (C) 2000 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 89:1579-1586, 2000.

Determination of activation energy distributions for chemisorption of oxygen on carbon: an improved approach

The present paper proposes an approach to obtaining the activation energy distribution for chemisorption of oxygen onto carbon surfaces, while simultaneously allowing for the activation energy dependence of the pre-exponential factor of the rate constant. Prior studies in this area have considered this factor to be uniform, thereby biasing estimated distributions. The results show that the derived activation energy distribution is not sensitive to the chemisorption mechanism because of the step function like property of the coverage. The activation energy distribution is essentially uniform for some carbons, and has two or possibly more discrete stages, suggestive of at least two types of sites, each with its own uniform distribution. The pre-exponential factors of the reactions are determined directly from the experimental data, and are found not to be constant as assumed in earlier work, but correlated with the activation energy. The latter results empirically follow an exponential function, supporting some earlier statistical and experimental work. The activation energy distribution obtained in the present paper permits improved correlation of chemisorption data in comparison to earlier studies. (C) 2000 Elsevier Science Ltd. All rights reserved.

Altered kinetics and benzodiazepine sensitivity of a GABA(A) receptor subunit mutation [gamma(2)(R43Q)] found in human epilepsy

The gamma-aminobutyric acid type A (GABA(A)) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA(A) receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA(A) gamma(2)-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA(A) receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from alpha(1)beta(2)gamma(2) or alpha(1)beta(2)gamma(2)(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imiclazopyricline zolpidem. These results provide evidence of impaired GABA(A) receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.

Kinetics of photoacclimation in corals

Traditional models describing the relationship between photosynthesis (P) and irradiance (I) do not account for photoacclimation to short-term variation in irradiance. Here we develop and test a model that predicts the rate of photosynthesis under fluctuating irradiances at the scale of days to weeks. Using oxygen respirometry, we measured the rates of change in the P-I model parameters P-max (maximum rate of gross photosynthesis) and I-k (sub-saturation irradiance) of the photo-symbiotic coral Turbinaria mesenterina (Lamarck) following large and small increases and decreases in growth irradiance. We analyse the behaviour of the dynamic P-I model in turbid-water conditions using a dataset of 3-month continuous irradiance as the input variable. In response to upward or downward changes in experimental growth irradiance, I-k values decreased or increased exponentially, reaching new and stable levels within 5-10 days. I-k responded 4 times stronger than P-max to changes in growth irradiance. The kinetics of I-k did not show hysteresis, and changed in similar ways when irradiance was increased or decreased in small or large amounts. This suggests that mechanisms associated with photo-protection during increases in irradiance, and the maximisation of photosynthetic efficiency during decreases in irradiance, are equally potent. On the scale of months, the dynamic P-I model did not predict higher rates of photosynthesis than the static P-I model, but buffered the variation in photosynthesis during periods of reduced irradiance. Fourier analysis indicated that the kinetics of I-k closely matches the main periodicities in daily irradiance (1-2 weeks). The recorded kinetics of photoacclimation in the Turbinaria-zooxanthella symbiosis is comparable to that of free-living phytoplankton and faster than that of higher plants.

Experimental study of the deposition of combustion aerosols in the human respiratory tract

The total deposition of environmental tobacco smoke (ETS), diesel and petrol smoke in the respiratory tract of 14 non-smokers between the ages of 20 and 30 was determined experimentally. A scanning mobility particle sizer (SMPS) measuring a size range of 0.016-0.626 mu m was used to characterise the inhaled and exhaled aerosol during relaxed nasal breathing over a period of 10 min. The ETS, diesel, and petrol particles had average count median diameter (and geometric standard deviation) of 0.183 mu m (1.7), 0.125 mu m (1.7), and 0.069 mu m (1.7), respectively. The average total number deposition of ETS was 36% (standard deviation 10%), of diesel smoke 30% (standard deviation 9%), and of petrol smoke 41% (standard deviation 8%). The analysis of the deposition patterns as a function of particle size for the three aerosols in each individual showed that there is a significant difference between each aerosol for a majority of individuals (12 out of 14). This is an important result as it indicates that differences persist regardless of inter-subject variability. (C) 2005 Elsevier Ltd. All rights reserved.

The kinetics of baculovirus adsorption to insect cells in suspension culture

The influence of various culture parameters on the attachment of a recombinant baculovirus to suspended insect cells was examined under normal culture conditions. These parameters included cell density, multiplicity of infection, and composition of the cell growth medium. It was found that the fractional rate of virus attachment was independent of the multiplicity of infection but dependent on the cell density. A first order mathematical model was used to simulate the adsorption kinetics and predict the efficiency of virus attachment under the various culture conditions. This calculated efficiency of virus attachment was observed to decrease at high cell densities, which was attributed to cell clumping. It was also observed that virus attachment was more efficient in Sf900II serum free medium than it was in IPL-41 serum-supplemented medium. This effect was attributed to the protein in serum which may coat the cells and so inhibit adsorption. A general discussion relating the observations made in-these experiments to the kinetics of recombinant baculovirus adsorption to suspended insect cells is presented.

Fuel stagnation temperature effects on mixing with supersonic combustion flows

An experimental study of the effect of fuel stagnation temperature on mixing in a supersonic hydrogen-air flame is described, The combustor consisted of a constant-area rectangular duct with a centrally located fuel-injection strut that spanned the width. A high-enthalpy stream of air was supplied by a free-piston shock tunnel, and heated hydrogen fuel, supplied by a gun-tunnel, was injected into the freestream as a coflowing planar jet. The freestream total enthalpies were 5.6, 6.5, and 9 MJ/kg, and fuel stagnation temperatures were 300, 450, and 700 K, Raising the fuel stagnation temperature increased the fuel velocity to be near that of the airstream and resulted in a decrease in the mixing rate, Even as the fuel and air velocities became equal, significant mixing still occurred because of a large difference in density, Increasing the freestream enthalpy reduced the difference between the initial air temperature and the adiabatic flame temperature, which in turn reduced the heat addition, and subsequently, the amount of pressure rise in the duct.

The influence of collision energy and strain accumulation on the kinetics of mechanical alloying

The kinetics of mechanical alloying have been investigated by examining the effect that ball mass has on the rate at which titanium carbide forms from the elements. By varying the ball density while keeping the ball diameter and the charge ratio constant, the collision energy was independently controlled. Grinding media with a density from 3.8 g cm(-3) (agate) to 16.4 g cm(-3) (tungsten carbide) were used. The reaction rate increases exponentially with ball mass until a critical level is reached, which is determined by the induced temperature rise. Above this level, collisions of higher energy have no advantage. It is also shown that the reaction rate increases exponentially with the rate at which strain accumulates in the reactants. It is suggested that the strain accumulation rate in mechanically induced reactions is analogous to temperature in thermally induced chemical reactions.

Sintering kinetics of Mo-free cermets

Titanium carbonitride-based cermets are important materials for contemporary cutting tools. Ceramic powders of Ti(CN), TaC, WC were mixed, compacted and heat-treated at high temperatures to form (Ti, W, Ta)(C, N) solid solution, which was then ball-milled to fine powders before being mixed with metallic binder and compacted. Liquid-phase sintering of the samples was carried out in a nitrogen atmosphere at different sintering temperatures and holding times. The microhardness and porosity of the sintered cermets were studied. It is demonstrated that the microhardness increases with sintering temperature, but at the same time, the porosity level also goes up with temperature and time. At the beginning of sintering (zero holding time), the majority of the pores are small (0.1 similar to 1 mu m); during sintering, the larger ports grow at the expense of smaller pores and the resulting pores are all concentrated in the 10 similar to 100 mu m range. The number of larger pores increases with temperature and prolonged holding time, which results in deteriorated properties. (C) 1997 Elsevier Science S.A.

Effect of resinite on the combustion of New Zealand subbituminous coal

Oligocene resin from New Zealand's Rotowaro coalfield displays DTA and DTG traces similar to those of other fossil resins. It modifies the thermal behaviour of low rank coal in raising the peak combustion temperature and lowering its rate of combustion, a behaviour that may be common among liptinite macerals. The effect is not additive and unlike other coal constituents the resinite component does not deteriorate with time. (C) 1997 Elsevier Science B.V.

Modeling of subcutaneous absorption kinetics of infusion solutions in the elderly using technetium

Absorption kinetics of solutes given with the subcutaneous administration of fluids is ill-defined. The gamma emitter, technitium pertechnetate, enabled estimates of absorption rate to be estimated independently using two approaches. In the first approach, the counts remaining at the site were estimated by imaging above the subcutaneous administration site, whereas in the second approach, the plasma technetium concentration-time profiles were monitored up to 8 hr after technetium administration. Boluses of technetium pertechnetate were given both intravenously and subcutaneously on separate occasions with a multiple dosing regimen using three doses on each occasion. The disposition of technetium after iv administration was best described by biexponential kinetics with a V-ss of 0.30 +/- 0.11 L/kg and a clearance of 30.0 +/- 13.1 ml/min. The subcutaneous absorption kinetics was best described as a single exponential process with a half-life of 18.16 +/- 3.97 min by image analysis and a half-life of 11.58 +/- 2.48 min using plasma technetium time data. The bioavailability of technetium by the subcutaneous route was estimated to be 0.96 +/- 0.12. The absorption half-life showed no consistent change with the duration of the subcutaneous infusion. The amount remaining at the absorption site with time was similar when analyzed using image analysis, and plasma concentrations assuming multiexponential disposition kinetics and a first-order absorption process. Profiles of fraction remaining at the absorption sire generated by deconvolution analysis, image analysis, and assumption of a constant first-order absorption process were similar. Slowing of absorption from the subcutaneous administration site is apparent after the last bolus dose in three of the subjects and can De associated with the stopping of the infusion. In a fourth subject, the retention of technetium at the subcutaneous site is more consistent with accumulation of technetium near the absorption site as a result of systemic recirculation.

Diffusion modeling of percutaneous absorption kinetics: 2. Finite vehicle volume and solvent deposited solids

The diffusion model for percutaneous absorption is developed for the specific case of delivery to the skin being limited by the application of a finite amount of solute. Two cases are considered; in the first, there is an application of a finite donor (vehicle) volume, and in the second, there are solvent-deposited solids and a thin vehicle with a high partition coefficient. In both cases, the potential effect of an interfacial resistance at the stratum corneum surface is also considered. As in the previous paper, which was concerned with the application of a constant donor concentration, clearance limitations due to the viable eqidermis, the in vitro sampling rate, or perfusion rate in vivo are included. Numerical inversion of the Laplace domain solutions was used for simulations of solute flux and cumulative amount absorbed and to model specific examples of percutaneous absorption of solvent-deposited solids. It was concluded that numerical inversions of the Laplace domain solutions for a diffusion model of the percutaneous absorption, using standard scientific software (such as SCIENTIST, MicroMath Scientific software) on modern personal computers, is a practical alternative to computation of infinite series solutions. Limits of the Laplace domain solutions were used to define the moments of the flux-time profiles for finite donor volumes and the slope of the terminal log flux-time profile. The mean transit time could be related to the diffusion time through stratum corneum, viable epidermal, and donor diffusion layer resistances and clearance from the receptor phase. Approximate expressions for the time to reach maximum flux (peak time) and maximum flux were also derived. The model was then validated using reported amount-time and flux-time profiles for finite doses applied to the skin. It was concluded that for very small donor phase volume or for very large stratum corneum-vehicle partitioning coefficients (e.g., for solvent deposited solids), the flux and amount of solute absorbed are affected by receptor conditions to a lesser extent than is obvious for a constant donor constant donor concentrations. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:504-520, 2001.