Zero-order Phase Research Articles

Effect of Acute Ethanol Administration on Toloxatone Pharmacokinetics in Rabbits

The pharmacokinetics of toloxatone and ethanol were determined in plasma and cerebrospinal fluid of conscious rabbits. According to a cross-over design, rabbits (n= 5) randomly received on three separate occasions either toloxatone (5 mg/kg), ethanol (1 g/kg), or toloxatone and ethanol (5 mg/kg and 1 g/kg, respectively) by intravenous injection. Toloxatone and ethanol concentrations were measured by HPLC with UV detection and GC with flame ionization detection, respectively. Ethanol concentration profiles in plasma were characterized by a rapid decline occurring within the first 30 min after administration followed by a linear (zero-order) phase that persisted for the length of the experiment. The maximum ethanol elimination rate was 0.31 ± 0.20 g/h.kg. Toloxatone concentrations in plasma and cerebrospinal fluid were characterized by a multiexponential decay with effective half-lives of 0.39 ± 0.06 and 0.56 ± 0.07 hr, respectively. Toloxatone passage through the blood brain barrier was rapid and important. Our results also demonstrate that acute ethanol administration had no effect on toloxatone pharmacokinetics and that toloxatone administration had no effect on ethanol pharmacokinetics.

Effect of Acute Ethanol Administration on Toloxatone Pharmacokinetics in Rabbits

The pharmacokinetics of toloxatone and ethanol were determined in plasma and cerebrospinal fluid of conscious rabbits. According to a cross-over design, rabbits (n = 5) randomly received on three separate occasions either toloxatone (5 mg/kg), ethanol (1 g/kg), or toloxatone and ethanol (5 mg/kg and 1 g/kg, respectively) by intravenous injection. Toloxatone and ethanol concentrations were measured by HPLC with UV detection and GC with flame ionization detection, respectively. Ethanol concentration profiles in plasma were characterized by a rapid decline occurring within the first 30 min after administration followed by a linear (zero-order) phase that persisted for the length of the experiment. The maximum ethanol elimination rate was 0.31+/-0.20 g/h x kg. Toloxatone concentrations in plasma and cerebrospinal fluid were characterized by a multiexponential decay with effective half-lives of 0.39+/-0.06 and 0.56+/-0.07 hr, respectively. Toloxatone passage through the blood brain barrier was rapid and important. Our results also demonstrate that acute ethanol administration had no effect on toloxatone pharmacokinetics and that toloxatone administration had no effect on ethanol pharmacokinetics.

On-axis phase-only computer-generated holograms based on a minimal etching process

Diffractive optical elements able to generate on-axis (zero-order) phase as well as amplitude distributions are described. The proposed elements are surface-relief plates, that is phase-only elements, that are based on concepts of computer-generated masks followed by lithographic and etching processes. The proposed encoding method assumes variable spatial partitioning of the cell and a fixed phase value allocated to each subcell. This method requires the minimal number of etching levels needed for full representation of the wave front, that is three, but can be applied with improved efficiency using more etching levels. The reconstructed amplitude and phase distributions contain some noise owing to the encoding process. Discussion of the error sources is given.

Antiprogestin pharmacodynamics, pharmacokinetics, and metabolism: implications for their long-term use.

Antiprogestins represent a relatively new and promising class of therapeutic agents that could have significant impact on human health and reproduction. In the present work, the pharmacodynamics, pharmacokinetics, and metabolism of mifepristone (MIF), lilopristone (LIL), and onapristone (ONA) in humans are reviewed, and characteristics bearing important clinical implications are discussed. Although MIF has gained notoriety as an "abortion pill," antiprogestins may more importantly prove effective in the treatment of endometriosis, uterine leiomyoma, meningioma, cancers of the breast and prostate, and as contraceptive agents. MIF pharmacokinetics display nonlinearities associated with saturable plasma protein (alpha 1-acid glycoprotein, AAG) binding and characterized by lack of dose dependency for parent drug plasma concentrations (for doses greater than 100 mg) and a zero-order phase of elimination. LIL and ONA pharmacokinetics are less well characterized but ONA does not appear to bind AAG and displays a much shorter t1/2 than the other agents. The three antiprogestins are substrates of cytochrome P450 (CYP) 3A4, an enzyme exceedingly important in human xenobiotic metabolism. Even more implicative of likely drug-drug interactions subsequent to their long-term administration are recent data from our laboratory indicating that they inactivate CYP3A4 in a cofactor- and time-dependent manner, suggesting that complexation and induction of the enzyme may occur in vivo via protein stabilization. Moreover, it has been demonstrated that MIF increases CYP3A4 mRNA levels in human hepatocytes in primary culture, indicative of message stabilization and/or transcriptional activation of CYP3A4 expression. Finally, MIF has also been shown to inhibit P-glycoprotein function. Whether LIL and ONA share these latter two characteristics with MIF has not yet been determined but they illustrate properties that, in addition to diminished antiglucocorticoid activities and altered pharmacokinetic characteristics, warrant consideration during the development of these and never antiprogestational agents.

Spin-locking spectral lineshapes of the central transition of half-integer quadrupole systems under magic-angle spinning

The spin-locking spectra of the central transition of half-integer quadrupole systems under magic-angle spinning (SLMAS) can be exactly calculated. The lineshape patterns are much more diverse than predicted by the previous theoretical analysis based on energy level diagrams and empirical functions. The lineshapes were investigated for various values of the parameter α introduced by A.J. Vega (J. Magn. Reson., 96 (1992) 50) but the lineshapes cannot be completely characterized by α. Relaxation during spin-locking ( T 1 ϱ ) was found to be important in determining the lineshape change for different experimental parameters. An SLMAS spectrum is generally zero-order phase distortive unless the spin-locking time is the multiple of rotor spinning period. Dispersive lineshapes were demonstrated under certain conditions. The relationship between SLMAS and CPMAS is also discussed. Both theoretical and experimental results are provided.

Single-excimer-pulse writing of fiber gratings by use of a zero-order nulled phase mask: grating spectral response and visualization of index perturbations

Optical fiber Bragg reflectors have been written by irradiating the fiber from the side through a phase mask with a single pulse of high-power 249-nm excimer-laser light. Efficient tapping of light to the radiation modes has been achieved for light at wavelengths shorter than the Bragg wavelength. The photoinduced periodic refractive-index perturbations have been observed directly with an optical microscope and are shown to have the same period as the phase mask and to be highly localized on one side, the irradiated side of the fiber core-cladding boundary.

A knowledge‐based approach to minimize baseline roll in chemical shift imaging

A method has been developed to minimize baseline roll in chemical shift imaging (CSI). The technique is fully automated and employs knowledge based data processing in the frequency domain. The key feature of the algorithm is the computation of the "trough" and "ripple" components in the CSI data. The baseline roll can be regarded as an artifact that appears as a result of the summation of several sinc functions. Using prior knowledge, a mirror component corresponding to the artifact is created and added to the delayed spectrum. The method compensates for noise and zero-order phase error when computing the roll artifact. The results obtained on implementing the baseline roll minimization procedure on simulated time-delayed spectra indicated that the peak heights and areas were between 91% and 97% in magnitude when compared with the same peaks in the nondelayed spectra. The correction procedure was also assessed on clinical in vivo spectra. Nonlocalized 31P MR spectra of the liver were obtained with and without an acquisition delay of 2.1 ms, and the time delayed spectra subjected to the baseline minimization routine. Metabolite peak heights and areas in the corrected spectra were approximately 94% in magnitude when compared with the same peaks in the original nondelayed whole volume spectra. Implementation of the baseline minimization procedure on in vivo localized spectra with varying signal to noise ratios produced good results. It takes approximately 13 s to implement the baseline roll minimization procedure. In this paper, the technique will be referred to as BaseLine Artifact Suppression Technique (BLAST) routine.

Removing effects of eddy currents in proton MR spectroscopy.

The use of pulsed gradients to define a volume of interest for localized magnetic resonance spectroscopy produces magnetic field perturbations which distort both the free induction decay and the spectrum after Fourier transformation. A technique is presented that removes the artifacts from eddy currents from a sampled free induction decay. To linearize the phase, the nonlinear phase of a reference free induction decay is subtracted from the phase of a sample free induction decay. Next, to move the frequency to resonance and perform a zero-order phase correction, the line fit from a linear regression is subtracted from the phase. After reconstructing the free induction decay, the resulting frequency spectra are sorted into absorption mode and dispersion mode components.

The role of calcium ions and bile salts on the pancreatic lipase-catalyzed hydrolysis of triglyceride emulsions stabilized with lecithin.

Lecithin-stabilized triglyceride emulsions are subject to hydrolysis by pancreatic lipase. The time profiles of these reactions are characterized by a lag-phase and a zero-order phase. Lag phases are more pronounced with long-chain triglycerides. Ca2+ is effective in reducing the lag-phase and activating lipase. Kinetic analysis of the reactions suggests that, like previous findings by others, taurodeoxycholate (TDC) micellar solutions combine with the lipase-colipase complex to form another catalytically active enzyme form. This enzyme form exhibits reduced activity in the absence of Ca2+. In the presence of Ca2+ the mixed micelle-lipase complex becomes more active and opens a new pathway for lipolysis. It is suggested that this enzyme form can bind more easily to interfaces with different physicochemical properties. Under these conditions, Ca2+ activates the lipolysis of short-, medium-, and long-chain triglycerides by a similar mechanism. Maximum activities were measured in the presence of approximately 6 mM TDC and 30 mM Ca2+. The experimental conditions approximate the physiological conditions in the gastrointestinal tract since all of the factors studied here have been reported to be necessary for in vivo lipolysis and/or absorption of triglycerides. A mechanistic model for lipolysis in the presence of Ca2+ and the bile salt TDC is proposed which accounts for most of the experimental observations in a quantitative manner.

Semiclassical phase space evolution of Fermi resonance spectra

The evolution of the semiclassical phase space of a Fermi resonance spectrum is investigated as the strength of the resonance coupling is varied between zero and the strong coupling limit. The phase space evolution gives information beyond that contained in the phase space profile of the experimental spectrum alone. The zero-order phase space is found to be different in important respects from that of the pendulum model of a nonlinear resonance. In the weak coupling regime, the phase space evolution is essentially like that of a dynamical barrier picture. In the strong coupling regime of ‘‘intrinsic resonance,’’ the phase space structure is much different. Topology change appears to take place in a more discontinuous manner than in the weak coupling regime. The phase space evolution shows that some levels are problematic for an adiabatic switching treatment. The origin of some anomalous levels seen both in phase space profiles of experimental spectra and in semiclassical quantization studies is clarified.

Hard-pulse sequences for solvent suppression which only need a zero-order phase correction

Among the various methods which have been proposed to achieve solvent suppression, the binomial hard-pulse sequences (1-8) are rather attractive. Their popularity in conventional NMR spectroscopy is undoubtedly due to several advantages. They produce little radiofrequency power dissipation in the sample, they lead to a water suppression factor which is insensitive to Bi inhomogeneities, and they can be easily implemented on most FT NMR spectrometers. Furthermore, the short total duration of binomial sequences allows the observation of slowly exchanging protons or of resonances with short T2. However, their main drawback is that, except for the jump and return sequence (i.e., 90°-T-900), they generally require a linearly frequencydependent (first-order) phase correction. In the case of a large residual solvent peak such a correction results in a rolling baseline (2, 3). Recently pulse sequences which only require a small frequency-dependent phase correction have been reported (9, HO). In this contribution we propose a new class of hard-pulse sequences which achieve good suppression of the solvent signal and which only require a frequency-independent (zero-order) phase correction. The basic concept is to exploit some interesting refocusing properties of phasecycled pulse sequences symmetrical or antisymmetrical in time (II). Let us consider the BX--7-8X binomial pulse sequence (2,5). Neglecting off-resonance effects during the pnlses and effects of spin-spin coupling, the corresponding propagator can be written as P = exp(+iU,)exp( iwTl,)exp( iU,). Cl

Dose and sex-dependent disposition of ketoconazole in rats.

The disposition of the antifungal drug ketoconazole was studied in mature (60-day-old) male and female rats given single intravenous doses of 10, 20 or 40 mg/kg body weight. The plasma profiles of ketoconazole were characterized by an initial rapid decline, followed by an apparent zero-order decline and a subsequent first-order elimination phase. In male animals the zero-order phase was less pronounced, resulting in a 3-5 times higher overall rate of elimination. A consequence of the dose-dependent disposition was that a 4-fold increase in dose resulted in a 9- and 17-fold increase in the area under the plasma concentration-time curve (AUC) of females and males, respectively. Terminal half-lives were independent of dose in both sexes. The disproportionate increase in AUC with dose, together with the observation that no intact ketoconazole was excreted in urine and only very small amounts in bile (less than 1% of given dose), suggest that the dose-dependent disposition is caused by saturation of metabolizing enzymes. These enzymes are most likely under the influence of androgens, since the capacity of males to eliminate ketoconazole was reduced by castration and in females this capacity was increased by testosterone treatment.

A New Phase Correction Method in NMR Imaging Based on Autocorrelation and Histogram Analysis

A new statistical approach to phase correction in NMR imaging is proposed. The proposed scheme consists of first-and zero-order phase corrections each by the inverse multiplication of estimated phase error. The first-order error is estimated by the phase of autocorrelation calculated from the complex valued phase distorted image while the zero-order correction factor is extracted from the histogram of phase distribution of the first-order corrected image. Since all the correction procedures are performed on the spatial domain after completion of data acquisition, no prior adjustments or additional measurements are required. The algorithm can be applicable to most of the phase-involved NMR imaging techniques including inversion recovery imaging, quadrature modulated imaging, spectroscopic imaging, and flow imaging, etc. Some experimental results with inversion recovery imaging as well as quadrature spectroscopic imaging are shown to demonstrate the usefulness of the algorithm.

In vivo voltammetric characterization of low affinity striatal dopamine uptake: Drug inhibition profile and relation to dopaminergic innervation density

Electrical stimulation of the median forebrain bundle evoked dopamine release in the ipsilateral striatum which was monitored with high-speed cyclic voltammetry. After stimulation, the extracellular concentration of dopamine fell due to uptake in a biphasic manner, showing zero-order and first-order components. The zero-order phase corresponded to a V max of 42.8 ± 1.8nmol/min/g tissue. The uptake system could be blocked by d-amphetamine, methylphenidate and nomifensine, but not by benztropine, amfonelic acid or mazindol. The density of uptake sites showed a correlation with the density of striatal dopamine innervation.

Role of carbonate in acid neutralization of aluminum hydroxide gel.

The role of carbonate in the acid neutralization of a carbonate-containing aluminum hydroxide gel was studied. The pH-stat neutralization reaction was comprised of three phases: an initial, immediately reacting phase; a slow, zero-order phase; and a terminal, fast zero-order phase. The evolution of carbon dioxide and the appearance of aluminum ions were monitored during neutralization. Acid neutralization is believed to occur predominantly at the aluminum-carbonate bond during the slow phase of neutralization. The reaction of structural carbonate disrupts the gel structure and increases the porosity and surface area of the gel. The diffusion of acid into the gel structure is facilitated and accelerates the neutralization rate, as seen in the final phase of the pH-stat titrigrams. The behavior of carbonate is probably responsible for the rapid and complete neutralization of acid generally observed with carbonate-containing aluminum hydroxide gel.

Alteration of the Kinetics of Thrombin-catalyzed Hydrolysis of Amino Acid Ester Substrates by Sodium Cholate and Other Steroids

Thrombin-catalyzed hydrolysis of TAME proceeds by an initial zero-order phase which later falls off into an apparent first order reaction as substrate becomes limiting. Optimum amounts of sodium cholate not only accelerated TAME hydrolysis but also altered its kinetics to apparent zero-order to complete substrate hydrolysis. As this implies, the rate of hydrolysis in the presence of cholate was found to be independent of substrate concentration, provided concentrations TAME and cholate were low enough to prevent precipitation of some TAME-cholate as an insoluble complex. The formation of a soluble complex composed of polymeric molecules of TAME and cholate may explain both the acceleration and the change in reaction order. Although the pH and temperature optima for TAME hydrolysis by thrombin rising pH and temperature on the ascending protion of the curves. This is believed to be due to the greater solubility of the TAME-cholate complex. The effects of cholate on thrombin-catalyzed hydrolysis of other arginine esters as well as esters of lysine, histidine and phenylalanine were also studied. Solutions of sodium desoxycholate and androsterone-3-sulfate accelerated TAME hydrolysis as did supensions of testosterone, etiocholanolone, androsterone, androsterone-3-hemisuccinate and pregnandiol-3-glucuronidate. However, isoandrosterone, progesterone, pregnandiol, estradiol, estrone, estriol, estrone-3-sulfate, cholesterol, corticosterone, hydrocortisone and hydrocortisone-3-phosphate had no significant effect on TAME hydrolysis by thrombin. The ability of the andorogenic hormones to accelerate hydrolysis appeared to depend to some extent on the configuration of the substituent group at C3 and the hydrogen at C5. Androsterone-3-hemisuccinate was, like cholate, able to accelerate the hydrolysis of TAME at apparent zero-order kinetics to complete substrate hydrolysis.

Kinetics of the pyrolysis of cellulose in the temperature range 250–300°C.

AbstractSamples of α‐cellulose, containing 0.11–0.14% ash, were isothermally pyrolyzed in a fluidized bath in a nitrogen environment at 250–298°C. Results were reported in terms of volatilization (based on weight‐loss measurements) and decomposition (in term of glucosan loss). The findings show three distinct stages of pyrolysis: (1) an initial period of rapid decomposition and weight loss; (2) a range in which both the volatilization and decomposition are of zero order; (3) a region in which the volatilization follows a first‐order rate, leaving a char deposit which does not undergo further pyrolysis. The degree of decomposition and volatilization occurring during the zero‐order phase increases with increasing temperature. A single activation energy of 42 kcal./mole describes both the decomposition and volatilization rates in the zero‐order phase over the entire 250–298°C. range.

The application of variational methods to atomic scattering problems III. The elastic scattering of electrons by helium atoms

The variational method of Hulthèn has been applied to the elastic scattering of slow electrons by helium atoms, the effect of exchange being taken into account in calculating the zero-order phase shift. Satisfactory agreement has been obtained with the results given by numerical integration of the integro-differential equation determining the scattering when the total wave function is taken to be completely antisymmetric. Even at very low electron energies (0·04 eV) the agreement with experiment is good.

The application of variational methods to atomic scattering problems - I. The elastic scattering of electrons by hydrogen atoms

The variational methods proposed 'by Hulthèn and by Kohn have been applied to the investigations of the elastic scattering of slow electrons by hydrogen atoms. Allowance has been made for both exchange and polarization effects in determining the zero-order phase shift. By comparison with results obtained by direct numerical integrations of the differential equations determining the scattering when the total wave function is assumed to have a separable form, it seems likely that both variational methods, which yield very nearly the same results, give satisfactory results except in certain sensitive cases, even when simple trial functions are employed. It is found that the inclusion of polarization (in the form of a nonseparable wave function) is less important when exchange is included than when it is not. Reasons why this would be expected are given. Detailed results are obtained for electrons with energies up to 50 eV.

The Errors of Approximation in Jeffreys's Phases

The errors occurring in a large number of Jeffreys's phases for neutral chlorine have been determined. A discussion of the source of these errors is given, from which it appears that errors in the phases of zero order and of order unity are due to a cumulative error over the range of integration. A method of correcting for this error is obtained. This method is of easy practical application, and it reduces the error almost to zero for phases of these orders.The error occurring in higher order phases is found to be mainly due to errors in the two π/4 terms, which take into account the exponential tails of the waves in the totally reflecting region. For phases of high order these errors in the two π/4 terms cancel each other, and consequently the total error in phases of high order is practically zero.A correction graph for the zero-order phase is given from which the error in this phase for atoms of atomic number up to 36 can be read off. The graph is such that an extrapolation to higher atomic number would not involve much error.