Flip-flop Phenomenon Research Articles

Quasi-atomistic Receptor Surrogates for the 5-HT2A Receptor: A 3D-QSAR Study on Hallucinogenic Substances

The 5-HT2A receptor is known to act as the biological target for a series of hallucinogenic substances including substituted phenylalkylamines, tryptamines and LSD. A prerequisite for a hallucinogenic effect is an agonistic binding mode to the high-affinity state of the receptor. Attempts to establish a quantitative structure-activity relationship for such compounds are typically based on homology models or 3D-QSAR. In this paper, we describe a surrogate for the 5-HT2A receptor derived by means of quasi-atomistic receptor modeling (software Quasar), a more recently developed 3D-QSAR technique. This approach allows for the simulation of local induced fit, H-bond flip-flop, and solvation phenomena. The QSARs are established based on a family of receptor-surface models, generated by a genetic algorithm combined with cross-validation. The surrogate for the 5-HT2A receptor yielded a cross-validated q2 of 0.954 for the 23 compounds defining the training set. A series of 7 test compounds was then used to validate the model, resulting in a RMS deviation of 0.40 kcal/mol between ΔG0prd. and ΔG0exp.. The largest individual deviation was 0.61 kcal/ mol, corresponding to an uncertainty of a factor 2.7 in the binding affinity. A scramble test with negative outcome (q2=0.144, slope=−0.019) demonstrates the sensitivity of the model with respect to the biological data. Subsequently, the surrogate was used to estimate the activity of a series of 53 hypothetical congeneric compounds, some of which are predicted to be close in activity to LSD.

330 菱形角柱群管路における角柱列数の違いによる後流特性

We discovered that the Coanda effect caused the formation of flow separation zones in both the single and double pairs of intersecting ducts, and flip-flop phenomena in multiple crossing ducts. However, the relationship between the flow produced by an impingement of two streams and the vortices induced by the separation which takes place following flow convergence still remains unexplored. Experimental study was performed to investigate characteristics of wake flows in diamond-shaped cylinder bundles. The velocity variations in their flow fields were measured using two-dimensinal laser Doppler velocimetry. It is found that the difference of flow patterns depends on the arrangement of the diamond-shaped islands, Reynolds number and numbers of row bundles. The characteristics of velocity variations in wake flows are also clarified.

Numerical Simulation of Jets Emitted into a Two-Dimensional Channel with Self-Induced Oscillation. (Active Control by Neural Network Observer)

Active control of jets emitted into a two-dimensional channel with insulated suction near the wall during monitoring with a neural network is described. The aim of this work is to simulate the possibility of controlling the flow pattern with a flip-flop phenomenon by suitable suction. In this case, the output of a neural network is estimated satisfactorily based on 3 flow patterns of teaching data. The periodic flow pattern at the Reynolds number Re=1.0×103 is reduced by a suction rate of less than 10% for primary jets. Then flow becomes stable as a result of feedback gain of the neural network. Since the control with suction need not be continuous, the power cost is reduced. The nonperiodic case at Re=1.0×104 is difficult to control, but we achieved good control by with the use of a suitable suction rate with the neural network.

Numerical Simulation of Jets Exhausting into a Two-Dimensional Channel with Self-Induced Oscillation. 4th Report. Active Control by Neural Network Observer.

Active control of jets exhausting into a two dimensional channel with insulated suction near the wall during monitoring with a neural network is described. The aim of this work is to simulate the possibility of controlling the flow pattern with a flip-flop phenomenon by suitable suction. In this case, output of a neural network is estimated satisfactorily based on 3 flow patterns from the teaching data. The periodic flow pattern at Reynolds number Re=1.0×103 is reduced by a less than 10% suction rate for primary jets. Then stable flow emerges as a result of feedback gain of the neural network. Since the control with suction does not have to be continuous, the power cost is reduced. The nonperiodic case at Re=1.0×104 is hard to control, but we achieved good control by use of a suitable suction rate with the neural network.

Multiple solutions, illegal parameter values, local minima of the sum of squares, and anomalous parameter estimates in least-squares fitting of the two-compartment pharmacokinetic model with absorption.

When the two-compartment model with absorption is fitted to data by nonlinear least squares, in general six different outcomes can be obtained, arising from permutation of the three exponential rate constants. The existence of multiple solutions in this sense is analogous to the flip-flop phenomenon in the one-compartment model. It is possible for parameter estimates to be inconsistent with the underlying physical model. Methods for recognizing such illegal estimates are described. Other common difficulties are that estimated values for two of the rate constants are almost identical with very large standard deviations, or that the parameter estimation algorithm converges poorly. Such unwanted outcomes usually signal a local (false) minimum of the sum of squares. They can be recognized from the ratio of largest to smallest singular value of the Jacobian matrix, and are, in principle, avoidable by starting the estimation algorithm with different initial values. There also exists a class of data sets for which all outcomes of fitting the usual equations are anomalous. A better fit to these data sets (smaller sum of squares) is obtained if two of the relevant rate constants are allowed to take complex conjugate values. Such data sets have usually been described as having "equal rate constants." A special form of the model equation is available for parameter estimation in this case. Precautions relating to its use are discussed.

Numerical Simulation for Jets Exhausting into a Two-Dimensional Channel with Self-Induced Oscillation. 1st Report. Chaotic Characteristics of Flip-Flop Jets.

Jets exhausting into a two-dimensional channel cause self-induced oscillation which is observed under a certain condition due to the instability of the Coanda effect. We call the above-mentioned flows as jets. Their behavior is governed by nonlinear features of the Navier-Stokes equations. Numerical results obtained by unsteady computations were compared, with chaotic data of the Rossler model for the spectrum of velocity variations and the Poincare map. Moreover, wavelet analysis was applied to our data. Since some similarities between the two kinds of data have been shown, we concluded that the flip-flop phenomena exhibit a chaotic behavior.

Pharmacokinetics of enrofloxacin after single intravenous, intramuscular and subcutaneous injections in lactating cows

Five Ayrshire cows were given enrofloxacin (5 mg/kg body weight) intravenously (i.v.), intramuscularly (i.m.) and subcutaneously (s.c.). The antimicrobial activity was measured in milk and serum samples using the agar-diffusion technique. High-performance liquid chromatography (HPLC) assay was used to study the extent of metabolism of enrofloxacin to ciprofloxacin. Analysis of the serum concentration-time data was based on statistical moment theory. Mean t1/2 beta of antimicrobial activity in serum was 1.7, 5.9 and 5.6 h after i.v., i.m. and s.c. administration, respectively. Both i.m. and s.c. routes were associated with a marked flip-flop phenomenon. Based on HPLC analysis of serum samples, the half-lives of enrofloxacin and ciprofloxacin were approximately the same. A marked proportion of enrofloxacin was metabolized to ciprofloxacin. The enrofloxacin fraction bound in vitro to serum proteins was 36-45%. About 0.2% of the total enrofloxacin dose was found in milk during the first 24 h and the amount transferred did not depend on the route of administration. Based on the HPLC data, enrofloxacin concentration in milk was parallel to that in serum, while ciprofloxacin was concentrated in milk. After i.v. injection, the peak concentration of enrofloxacin in milk was reached between 0.7 and 1.3 h but occurred much later for ciprofloxacin (tmax 5-8 h). After i.m. and s.c. administration the concentration-time curves for both enrofloxacin and ciprofloxacin in milk were shallow and there were no obvious peaks.

Period doubling bifurcation problems in the softening Duffing oscillator with nonstationary excitation

The Duffing oscillators are widely used to mathematically model a variety of engineering and physical systems. A computational analysis has been initiated to explore the effects of nonstationary excitations on the response of the softening Duffing oscillator in the region of the parameter space where the period doubling sequences occur. Significant differences between the stationary and nonstationary responses have been uncovered: (i) the stationary transitions from T to 2T, from 2T to 4T ... etc. branches at the stationary period doubling bifurcations are smooth, in nonstationary cases they exhibit jumps to the near stationary branches at the values of the control parameters greater than those for the stationary; this phenomenon is called penetration (delay or memory). The lengths of the penetrations is being compressed to zero with the increasing number of the iterations. (ii) The stationary and nonstationary responses eventually settle on different limit motions, the nonstationary has modulated components. (iii) The jumps appearing in the stationary bifurcation diagram at 2T from the upper to the lower branches of the (x, f) and (x, Ω), i.e., (displacement-forcing amplitude) and (displacement-forcing frequency), diagrams have been replaced by continuous transition in the nonstationary diagram climinating thus the discontinuity. Apart from these differences, some specific characteristic nonstationary responses have been observed not encountered in the stationary cases: (iv) the appearance of the ‘window’ in the nonstationary limit bifurcation diagrams. (v) The nonstationary limit motions located on the upper (lower) branches of the (x, f) or (x, Ω) diagrams expanded rapidly to the lower (upper) branches. (vi) The stationary and nonstationary bifurcation diagrams are extremely sensitive to the initial conditions, manifested by the mirror reflections, called the flipflop phenomenon. (vii) The nonstationary limit motion has been characterized by a complex phase portrait, the appearance of the Cantor-like set of the limit motion bifurcation plot, and continuous spectral density. For the purpose of comparison, a stationary period doubling sequence T, 2T,..., 2 n T,... stationary limit motion, χST which is known to be chaotic has been determined. A far reaching observation has been made in the process of this study: the determination of the nonstationary bifurcations, their branches and limit motions, has been independent of the calculations of the stationary ones, indicating, thus, the existence of an independent class of nonstationary (time varying) dynamics.

Relaxation Mechanism of Free Radicals in Silica Glass Studied by Pulsed-ESR Spectroscopy

The defects in γ- irradiated silica glass were investigated using the pulsed ESR technique. By exciting the spin packets both selectively and nonselectively, it was found that spin relaxation was induced mainly by the dipole-dipole interaction between electron spins of the identical species. By analyzing the dipole-dipole interaction between electron spins, the flip-flop phenomenon between them was found to be the main cause of electron spin relaxation.

Determination of Initial Concentration of an Analyte by Kinetic Detection of the Intermediate Product in Consecutive First-Order Reactions Using an Extended Kalman Filter

Many analytical reagents react with analytes according to a rate law described by a consecutive first-order reaction mechanism, A [yields][sup k(1)] B [yields][sup k(2)] C, where a product formation step is followed by a product degradation step. In many cases, consecutive first-order reactions are used to determine the initial concentration of analyte A by kinetic detection of the intermediate product B. In this work, the factors that affect the determination of the initial concentration of analyte and the kinetic parameters for this class of reactions have been investigated by computer simulations using an extended Kalman filter. The flip-flop phenomenon exhibited by this kinetic model is discussed, and a unique approach for the determination of the initial concentration of analyte is proposed. Empirical and residual methods for obtaining initial estimates for the rate constants and the initial concentration from the kinetic data, based on the model for consecutive first-order reactions, the initial concentration of analyte, the mismatch between the measured time and the real time, the data density, the fitting range, and the initial estimate for the background signal have been evaluated by using synthetic data with Gaussian-distributed noise. 15 refs., 6 figs.

Power analyses of moment analysis parameter in bioequivalence tests.

Simulated and experimental data were used to evaluate the mean residence time (MRT) as a parameter for estimating the rate of bioavailability in bioequivalence tests and to compare MRT with tmax (the time of peak drug concentration), both pharmaceutically and statistically. Although the values of MRT were more dependent on the elimination rate constant than tmax, MRTs were sufficiently sensitive to variations in the absorption rate. The statistical power of MRT infinity obtained by an extrapolation method was lower (especially when the flip-flop phenomenon occurred) than that of MRTt (calculated using data from zero time through the last sampling time). However, the power of MRTt was shown to be comparable to or higher than that of either AUCt or Cmax (the peak drug concentration) from simulated data. These results were also confirmed experimentally using previously obtained data. The effect of variances of plasma concentrations on the power of these parameters was also studied using a simulation technique. Even large variances near the last sampling time did not substantially affect the power of MRTt. Thus MRTt can be used as a parameter for estimating the rate of bioavailability from dosage forms in place of tmax in bioequivalence tests.

Estimation problem due to multiple solutions in pharmacokinetic curve fitting to two-compartment model and its avoidance.

A size of error in observed data for fitting curves and an estimation problem due to multiple solutions in a two-compartment model were studied by using two different non-linear least-squares regression programs, SALS and NONLIN. It was found that bolus intravenous data have generally 5-10 per cent errors and oral data contain 10-25 per cent errors against the fitted data with respect to total 151 data sets of 11 different drugs. Parameters of five drugs reported in references were used to obtain simulated concentrations at the sampling times, and five different data sets containing 25 per cent normally distributed random errors as a coefficient of variation were generated using each data set of these simulated concentration. In the two-compartment model with tri-exponential equations, unreasonable estimates were occasionally observed, resulting in reversed relative values to the theoretical ones of L/M, L/N, M/N or Ka/alpha, which are analogous to the well-known flip-flop phenomenon in the one-compartment model, when number of parameters to be estimated is not less than five or errors of data exceed about 10 per cent. In an attempt to avoid such unreasonable values, initial estimates for curve fitting was successfully obtained by using a microcomputer program SIMPLEX based on a simplex method. On the basis of these results, some problems in curve fitting of plasma drug concentration data are discussed.

The flip-flop hydrogen bonding phenomenon

In crystalline β-cyclodextrin undecahydrate (β-cyclodextrin · 11 H2O), flip-flop hydrogen bonds O-H⋯O-H⇋H-O⋯H-O have been detected by neutron diffraction studies. In this type of bond the directionality is inverted dynamically even in the crystalline state as could be shown by diffraction experiments carried out at 293 K and at 120 K. Molecular dynamics methods (MD) can be used to simulate the dynamics of molecular systems on a computer. In this paper, the atomic trajectories obtained by MD simulations, of β-cyclodextrin at 293 K and at 120 K and of α-cyclodextrin at 293 K, are analysed with respect to the occurrence of hydrogen bonds of flip-flop type. In all three simulations the hydrogen bonds with the highest percentage of occurrence correspond to the ones found in the neutron diffraction structure. In the simulation of crystalline β-cyclodextrin at 293 K over 19 ps, sixteen out of eighteen experimentally detected flip-flop bonds are reproduced. The other two hydrogen bonds are unidirectional, O-H⋯O, i.e. they have a lifetime larger than 19 ps. The four experimentally observed flip-flops at 120 K are not seen in a 20 ps MD simulation. For α-cyclodextrin a flip-flop hydrogen bond is predicted with low population, which may be observed experimentally. The good agreement between MD calculations and neutron diffraction studies suggests that the force field used in the simulations yields a good description of cyclodextrin crystal structure at room temperature, and even the energetically delicate dynamic hydrogen bond flip-flop phenomenon is satisfactorily reproduced.

Flip-flop phenomenon seen in 131I hippuran renal scintigraphy

Flip-flop phenomenon seen in 131I hippuran renal scintigraphy

Pharmacokinetics of two rectal dosage forms of ketoprofen in patients after anal surgery.

Two kinds of dosage forms of commercially available suppositories containing ketoprofen (KP), fatty suppositories (FS) and gelatin capsulated suppositories (GCS), were administered to patients immediately after anal surgery, and results obtained were compared. No difference was found in each corresponding pharmacokinetic parameter of the two dosage forms. However, when these parameters were compared with those from healthy subjects, significant differences were found in the values of peak level (Cmax), peak time (Tmax) and terminal phase half-life (t1/2). Cmax decreased by one half, and Tmax and t1/2 increased two and four times longer, respectively, those from healthy subjects. The absorption rate constant (ka) in patients was significantly (p less than 0.01) smaller than that in healthy subjects. However, the distribution volume/bioavailability (Vd/F), elimination rate constant (kel), and area under the curve (AUC) differed only slightly. Consequently, the flip-flop phenomena could be seen in the time profiles of plasma KP concentration of patients. These results suggested that the rectal suppository of KP should be administered with care, especially in the patients operated on under spinal anesthesia.

Pharmacokinetics and protein binding of trichothecene mycotoxins, T-2 toxin and HT-2 toxin, in dogs

A. Sintov, M. Bialer and B. Yagen. Pharmacokinetics and protein binding of trichothecene mycotoxins, T-2 toxin and HT-2 toxin, in dogs. Toxicon 26, 153 – 160, 1988. — The pharmacokinetics of T-2 toxin, following i.m. and i.v. administration (0.4 mg/kg), were investigated in five dogs. Following i.m. administration, the mean pharmacokinetic parameters for T-2 and HT-2 toxins were, respectively: apparent half-life 21 ± 5 and73 ± 7 min; peak plasma concentration 182 ± 42 and 74 ± 16 ng/ml; time to reach peak plasma concentration 9.4 ± 6.4 and 49 ± 11 min. Mean residence time calculation, using moment analysis, showed that the terminal slope of T-2 toxin plasma levels following i.m. administration corresponds to the absorption rate constant of the toxin due to the flip-flop phenomenon. T-2 toxin was completely absorbed following i.m. administration and its absolute bioavailability was 1.17 ± 0.25. A plasma protein binding study showed that in a concentration range of 70 – 500 ng/ml, T-2 and HT-2 toxins have a mean free fraction of 30.6 ± 3.1% and 32.6 ± 3.6% with no concentration dependency. At physiological conditions (temperature and pH), both T-2 and HT-2 toxins were unstable in whole blood and their in vitro stability half-lives were 6.9 and 0.84 hr, respectively. However, under similar conditions, these toxins were stable in plasma for 7 hr. Their instability in whole blood, therefore, may be related to enzymes present in the blood cells.

Evaluation of In Vivo Drug Release by Numerical Deconvolution Using Oral Solution Data as Weighting Function

Determination of in vivo drug release using compartmental model analysis is hampered by problems such as flip-flop phenomena and vanishing exponential terms. The usefulness of numerical deconvolution to estimate in vivo drug release was evaluated in this study by means of simulated data comparing solid dosage forms with a solution as a reference standard. Concentration-time data were generated using the standard linear two-compartment body model with various first-order release and absorption rate constants. Random errors of 5 and 10% were added to data sets for further analysis. The results of the study using error-free data afforded excellent agreement with the theoretical values except in one case where the release rate constant was overestimated by 6%. When random error was added to the data, the resulting in vivo release profile showed considerable fluctuation and no single rate constant could be assigned. However, further analysis showed that the method does not create additional error during the calculating process, as previously suggested, but merely reflects the inherent error added to the raw data. If the raw data are poor, no useful information can be obtained without using an arbitrary technique such as smoothing or fitting. In this regard, the time course of drug release obtained after numerical deconvolution merits investigation.

Rate-limiting diffusion processes following intrathecal administration of morphine.

Morphine concentrations in plasma in five patients following intrathecal (i.t.) administration and in five other patients following intravenous (i.v.) administration were measured by a specific RIA sensitive to 0.1 ng/ml. Pharmacokinetic analysis showed a similar apparent total body clearance of morphine following both i.t. and i.v. administration, and complete bioavailability of i.t. morphine to the systemic circulation. This indicates that morphine is probably not metabolised in the CNS and that all of an i.t. dose diffuses from CSF to the plasma compartment. However a marked decrease in the i.t. terminal rate constants, involving a flip-flop phenomenon, contributed to the prolonged terminal half-life of i.t. morphine. The slow diffusion of morphine from the i.t. space to the plasma compartment can account for the prolonged analgesia following i.t. administration.

Assessment of Drug Absorption After Oral Administration

Simulated data using a linear two-compartment body model (2CBM) with drugs having different absorption characteristics and dosage forms with different dissolution rates were used to evaluate the inherent problems of pharmacokinetic data analysis (flip-flop phenomenon and vanishing exponential terms). When absorption from solution is slow or release from the solid dosage form is rate limiting, the characteristic nose of the 2CBM was lost and a one-compartment model prevailed. After the 2CBM disposition kinetic parameters were obtained from solution data, absorption kinetics were evaluated by the Loo–Riegelman method. The data were also evaluated by the statistical moments method. The statistical moments method consistently demonstrated superiority in regard to providing reliable results and ease in calculation. The information provided can be particularly useful for in vivo–in vitro correlation.

“Flip-flop” phenomenon on retrograde ureterography establishes diagnosis of ureteral tumor

A case of bilateral upper urinary tract papillary transitional cell epithelioma is reported. Retrograde ureteropyelography with films taken during retrograde and antegrade flow of the contrast medium (flip-flop phenomenon) helped to establish the diagnosis of a papillary ureteral lesion.