Counterclockwise Hysteresis Loop Research Articles

Mechanism-based modeling of the effects of ibutilide (IB) on ventricular repolarization in patients with atrial fibrillation (AF).

Purpose To characterize the relationship between plasma concentrations of IB and QT prolongation in patients with AF. METHODS: Seven patients requiring direct current cardioversion of AF received a 10 min IV infusion of IB 1.0 mg. Blood samples were collected and plasma IB concentrations were determined by LC/MS. QT intervals were measured from 2 leads (II, V1) and corrected (QTc) by Bazett and Fredericia methods. PK/PD modeling was performed with ADAPT II and fit simultaneously for both leads. RESULTS: A 2 compartment model best fit the PK data; median (IQ) r2=0.95 (0.87,0.99). Plots of actual QTc versus ibutilide plasma concentrations exhibited a counterclockwise hysteresis loop that transformed into a clockwise direction, resembling a rebound phenomenon. A modified indirect response model with zero-order input and total plasma IB concentrations indirectly driving the inhibition of the output response (i.e. IKr inhibition with subsequent QTc prolongation) with an additional output rebound response was developed; median (IQ) r2=0.80 (0.65, 0.87). The rebound response was initiated at a threshold QTc increase from baseline. The median (IQ) %QTc increase, propagating a rebound response was 11.1% (8.0,14.1) with an IC50 of 6.4 μg/L (4.7,11.4) for IB. CONCLUSIONS: IB administration for cardioversion of AF prolongs QTc and is indirectly related to total IB plasma concentrations. Additionally, an overcompensating rebound effect was observed leading to a rapid QTc shortening. Clinical Pharmacology & Therapeutics (2004) 75, P97–P97; doi: 10.1016/j.clpt.2003.11.369

Non-volatile Thin Film Transistors Using Ferroelectric/ITO Structures.

ABSTRACTWe report ferroelectric-gate thin film transistors (TFTs) using indium tin oxide (ITO) as a channel material. Bottom-gate structure TFTs have been fabricated using ferroelectric Pb(Zr, Ti)O3 (PZT) film as a gate insulator and ITO channel. Ferroelectric and ITO layers were formed by the sol-gel technique and RF sputtering, respectively. Drain current-drain voltage (ID-VD) characteristics of PZT/ITO ferroelectric-gate TFTs exhibit typical n-channel transistor operations with clear current saturation and electrical properties were improved by the post annealing. Drain current-gate voltage (ID-VG) characteristics demonstrate clear counterclockwise hysteresis loop due to the ferroelectric gate insulator. The obtained memory window is 2 V. The on/off current ratio of more than 102 has been obtained, which indicates that the ITO channel is sufficiently depleted by the ferroelectric polarization.

CPU 86017 suppresses tachyarrhythmias induced by ouabain and myocardial infarction: Concentrations in plasma and different areas of the heart in dogs

AbstractCPU 86017 (p‐chlorobenzyl‐tetrahydroberberine) a derivative of berberine, possesses an antiarrhythmic effect against arrhythmias in animal models. Two canine arrhythmia models were established by i.v. infusion of ouabain and two‐stage ligation of coronary artery to generate sustained ventricular tachyarrhythmias in dogs. In the ouabain model CPU 86017 was infused at 0.96mg/kg divided into two doses of 0.36 and 0.6mg/kg; tachycardia was completely suppressed and reversed to control sinus rhythm. The canine heart was infarcted by two‐stage ligation of the anterior coronary artery and cardiac tachycardia occurred 20h after coronary ligation. A total dose of 0.5, 0.7, and 1.0mg/kg i.v. infusion of CPU 86017 was effective to suppress arrhythmic scores (0–7 score system) from the untreated 5.2±0.7 to 3.8±0.5, (P<0.05), 3.9±1.9 (P<0.05) and 2.6±2.0(P<0.01), respectively, and i.v. amiodarone 5mg/kg reduced arrhythmic scores to 2.3±1.3 (P<0.01). There was a counterclockwise hysteresis loop of the pharmacokinetic/pharmacodynamic relationship in both models attributed to a small Keo value. Concentrations were not different in the outer, middle, and inner layers of the left ventricle, but higher in the working myocardium against the SA node and AV node. They were also different in the myocardial levels in the infarcted, risk, and noninfarcted regions where concentrations were 0.267±0.09μg/ml, 0.948±0.399μg/ml, and 1.371±0.433μg/ml, respectively. By continuous infusion of high doses in ouabain‐receiving dogs the PR interval and QTc (QTc = QT/(R‐R)) were prolonged by 27.5% and 24.5%, respectively (P<0.001). The accumulation in the myocardium of CPU 86017 was evident against the rapid decrease in plasma levels. The toxicity to the heart by high doses of CPU 86017 is principally due to cardiac block and cardiac arrest rather than torsade de pointes. Drug Dev. Res. 58:131–137, 2003. © 2003 Wiley‐Liss, Inc.

Observation of bistability in a Vertical-Cavity Semiconductor Optical Amplifier (VCSOA)

We report, the first time to our knowledge, an observation of optical bistability in a Vertical-Cavity Semiconductor Optical Amplifier (VCSOA) operated in reflection mode. Counterclockwise hysteresis loops are obtained over a range of initial phase detuning and bias currents. One hysteresis loop is observed experimentally with an input power as low as 2 ìW when the device is biased at 98% of its lasing threshold. We also numerically simulate the optical bistability and obtain good agreement with our experimental observations. Bistable VCSOAs significantly advances the prospect of dense 2-D array of low switching-intensity all-optical logic and memory elements.

Thermal hysteresis loop, dynamical breakdown, and emission-current spike in quantum-well photodetectors

A nonadiabatic sequential-tunneling model is developed and applied to explore the common origin of the transient behavior of electrons in quantum-well photodetectors in the presence of different time-dependent external sources, including device temperature, electric field, and incident optical flux. For the time-dependent temperature, a counterclockwise hysteresis loop in the tunneling current as a function of the swept temperature is predicted and attributed to a blockade or an enhancement of the sequential tunneling of electrons between quantum wells by the space-charge-field effect when the device temperature is swept up and then down. When a time-dependent electric field is applied, a dynamical breakdown of the photodetectors is predicted, where the peak of total current linearly increases with the frequency of an ac electric field from its static value under a dc field. This is due to the presence of an additional dielectric current, which is proportional to the oscillation frequency of the ac electric field and whose peak value becomes larger than the value of the saturated tunneling-current peak in the high-frequency domain. Under the dynamical-breakdown condition, the quantum-well photodetectors behave just like a uniform dielectric medium. In the presence of a time-dependent optical flux, an emission-current spike is predicted as a result of the dominant enhancement of the escape probability of electrons from quantum wells over the loss of electron density when an applied dc electric field is small. The experimental observations of the transient behavior of electrons in quantum-well photodetectors are successfully reproduced by our numerical calculations.

Origin of rate bistability in Mn-O/Al2O3 catalysts for carbon monoxide oxidation : role of the Jahn-Teller effect

Peculiarities in catalytic activity in carbon monoxide oxidation as well as some structure, electronic and magnetic properties of the three oxide catalysts, Mn3+–O/Al2O3 (1), Mn3+–O–Fe/Al2O3 (Mn-substituted spinel, 2) and γ-Fe2O3/Al2O3 (3), were studied by kinetic measurements and by Mossbauer spectroscopy. The catalysts 1 and 2 showed a kinetic bistability with a sharp transition towards more reactive state at ∼200 °C (ignition point). In contrast, for catalyst 3, at 200–250 °C, the behavior of reaction rate against temperature did not display noticeable hysteresis. On cooling the catalysts 1 and 2, extinction was observed at about 170 and 120 °C, respectively, i.e., at 30–80 °C lower than the corresponding ignition points. Proximity of activation energy for the high and low activity (∼15–19 kJ/mol) for both Mn-containing catalysts suggests an increase in the number of active sites at high temperature with no changes in the reaction mechanism. The considerable difference between Mn-containing catalysts 1, 2 and Fe-containing catalyst 3 may be caused by Jahn–Teller (JT) type distortions of the oxygen polyhedron around Mn3+. A significant spontaneous axial bond stretching within the local polyhedron seems to diminish Mn–O binding energy, facilitate the participation of surface oxygen species, OS, in the oxidation of CO by a redox mechanism and promote oxygen vacancies at the surface that would cause considerable effect on the activity. An increase in the width of the counterclockwise hysteresis loop for the catalyst 2 compared to the catalyst 1 indicates that clusters of mixed spinel provide more active sites and more labile OS species than clusters of the binary Mn oxide.

Effect Of Uranyl Nitrate‐Induced Renal Failure On Morphine Disposition And Antinociceptive Response In Rats

1. The aims of the present study were to administer morphine (14.0 mumol/kg, s.c.) to male Hooded Wistar rats and to determine the effect of uranyl nitrate-induced renal failure on: (i) the antinociceptive effect of morphine; (ii) the pharmacokinetics of morphine and morphine-3-glucuronide (M3G); and (iii) the relationship between antinociceptive effect and the pharmacokinetics of morphine in plasma and brain. 2. Renal failure was induced by a single s.c. injection of uranyl nitrate and kinetic/dynamic studies were performed 10 days after its administration, when creatinine clearance was 17% of the control group. Antinociceptive effect was measured by the tail-flick method at various times up to 2 h post-drug administration. Concentrations of morphine and M3G in plasma and brain and concentrations of creatinine in urine and serum were determined by specific HPLC methods. 3. After morphine administration, the area under the antinociceptive effect-time curve was decreased by 44% in renal failure rats. There were no differences between control and renal failure rats in: (i) plasma morphine concentration-time curves; (ii) brain morphine concentration-time curves; and (iii) plasma M3G concentration-time curves. Morphine-6-glucuronide was not detected in any plasma or brain sample from rats administered morphine and no M3G was detected in brain. 4. For both control and renal failure rats, the relationships between antinociceptive effect and plasma morphine concentration were characterized by counterclockwise hysteresis loops, probably reflecting a delay for the relatively polar morphine to cross the blood-brain barrier. The relationship between antinociceptive effect and brain morphine concentration in control rats revealed no evidence of acute tolerance and was described by a sigmoidal function. In contrast, the relationship in renal failure rats was characterized by clockwise hysteresis, which is consistent with acute tolerance development.

Influence of arteriovenous sampling on remifentanil pharmacokinetics and pharmacodynamics.

Remifentanil is a new, short-acting, rapidly metabolized opioid. Because remifentanil is metabolized in blood and tissues by nonspecific esterases, there is a substantial difference between arterial and venous remifentanil concentrations. This difference may greatly affect the estimation of pharmacokinetic and pharmacodynamic parameters. To assess the effects of sampling site on the pharmacokinetic and pharmacodynamic characteristics of remifentanil. Ten healthy female subjects received intravenous remifentanil at an infusion rate of 3 microg/kg/min for 10 minutes. Serial blood samples were collected during and after drug administration from the radial artery and antecubital vein. A spectral edge measure was derived from the processed electroencephalographic and used as a measure of opioid effect. Venous concentrations were lower than arterial concentrations during the infusion of remifentanil. Pharmacokinetic parameters estimated from venous and arterial data differed significantly. When arterial concentrations were plotted against electroencephalographic effect, a classic counterclockwise hysteresis loop was observed, indicating a time-lag between changes in concentration and changes in effect. However, concentrations from venous blood produced a clockwise hysteresis loop that would classically suggest the development of acute tolerance. If this study had been conducted with venous samples alone, inappropriate conclusions such as acute tolerance could have been inferred. When designing studies to measure the acute time course (ie, non-steady state) of concentration and effect, the potential effects of sampling site on pharmacokinetic and pharmacodynamic characteristics must be carefully considered, particularly when the arteriovenous drug concentration difference is large.

Concentration-effect relationships of morphine and morphine-6 beta-glucuronide in the rat.

1. The aims of the present study were to determine the relationship between the antinociceptive effect and concentrations of morphine and morphine-6 beta-glucuronide (M6G) in plasma and in the brain. 2. Morphine (14.0 and 28.0 mumol/kg) or M6G (8.67 and 17.3 mumol/kg) were administered s.c. to male Hooded-Wistar rats. The antinociceptive effect was measured by the thermal tail-flick method at various times up to 2 h and concentrations of morphine, morphine-3 beta-glucuronide (M3G) and M6G in plasma and in the brain were determined. 3. With a two-fold increment in morphine dose, the areas under the antinociceptive effect-, plasma morphine concentration- and brain morphine concentration-time curves increased by 1.9-, 2.3- and 2.3-fold, respectively. The area under the plasma M3G concentration-time curve increased 2.7-fold. Morphine-6 beta-glucuronide was not detected in any sample. For M6G, doubling of the dose led to a 1.7-fold increase in the area under the curve for plasma-time M6G concentrations but an 8.7-fold increase in the area under the curve for the antinociception-time effect. Concentrations of M6G in the brain were below the limit of quantification. The relationship between antinociceptive effect and plasma morphine or M6G were characterized by counter-clockwise hysteresis loops, probably reflecting a delay in crossing the blood-brain barrier. 4. Morphine-6 beta-glucuronide was approximately equipotent to morphine on the basis of dose, but substantially more potent on the basis of brain concentration.

The effect of surface related grain boundary stresses on fatigue

While stresses can only be calculated indirectly by means of models that simulate the deformation of a grain that is embedded in various surrounding grains, Morris et al. (1987) have developed a model that takes into account the constraint represented by the plasticity of a given grain, in virtue of its neighboring grains. Within this framework, it is possible to explain the occurrence of counterclockwise hysteresis loops; in addition, the evaluation of local stresses yielded direct experimental evidence that surface grains undergo softening due to the interaction between enhanced plasticity and the precipitate structure. 16 refs.

Agonist-dependent modulation of Ca2+ sensitivity in rabbit pulmonary artery smooth muscle

The effects of the stable thromboxane analogue U46619, the alpha 1-adrenergic agent phenylephrine and depolarization with high K+ on cytoplasmic Ca2+ ([Ca2+]i) and force development were determined in rabbit pulmonary artery smooth muscle. Following stimulation with each of the excitatory agents, the time course of the [Ca2+]i/force relationship described counter-clockwise hysteresis loops with the rise and fall in [Ca2+]i leading, respectively, contraction and relaxation. The rank order of the force/[Ca2+]i ratios evoked by the different methods of stimulation was: U46619 greater than phenylephrine high K+. The difference between the actions of U46619 and phenylephrine was due to the lesser Ca2(+)-releasing and greater Ca2(+)-sensitizing action of U46619. Both U46619 and phenylephrine also released intracellular Ca2+ in intact (non-permeabilized) preparations. The effects of the two agonists on force, at constant free cytoplasmic [Ca2+] maintained with EGTA, were also determined in preparations permeabilized with staphylococcal alpha-toxin, in which intracellularly stored Ca2+ was eliminated with A23187. Sensitization of the contractile response to Ca2+ by agonists was indicated by the contractile responses of permeabilized muscles to U46619 and to phenylephrine, in the presence of constant, highly buffered [Ca2+]i. These contractions were inhibited by GDP [beta S] and could also be elicited by GTP. We conclude that, in addition to changing [Ca2+]i, pharmacomechanical coupling can also modulate contraction by altering the sensitivity of the regulatory/contractile apparatus of smooth muscle to [Ca2+]i, through a G-protein-coupled mechanism.

Different effects of depolarization and muscarinic stimulation on the Ca2+/force relationship during the contraction-relaxation cycle in the guinea pig ileum

The effects of K+ depolarization and of the muscarinic agonist carbachol on [Ca2+]i and force were investigated in smooth muscle sheets of the longitudinal layer of the ileum loaded with Fura-2. K(+)-rich solutions increased [Ca2+]i and force to an initial peak value, which was determined by the concentration of [K+]o. Thereafter, [Ca2+]i and force declined to a lower maintained level. The Ca2+/force relationship observed during this contraction-relaxation cycle is represented by a clockwise hysteresis loop. At 140 mM [K+]o, this loop consisted of three components while at lower [K+]o a two-component loop was observed. The stimulation with 0.1 mM carbachol resulted in a transient increase of [Ca2+]i and force followed by a continuous decline of these parameters despite the presence of the drug. Its EC50 of relaxation was around 270 nM [Ca2+]i. The Ca2+/force relationship proceeded along a counterclockwise hysteresis loop during the contraction-relaxation cycle. The extent of this loop decreased but remained unaltered in its direction during repeated stimulation with carbachol. These results suggest that (a) both agonists increase force and [Ca2+]i during stimulation; (b) during depolarization with K+, desensitization to CA2+ occurs resulting in a clockwise hysteresis loop; (c) during carbachol stimulation, a counterclockwise hysteresis is observed. This could be due to an increased sensitivity to Ca2+ mainly in tonic smooth muscle. These observations might be explained by a modulation of the Ca2+ sensitivity by sensitizing and desensitizing mechanisms. These modulations during different stimuli could be due to different myosin light-chain kinase/myosin light-chain phosphatase ratios.

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines I: Lorazepam

This investigation compares the time course changes in the central nervous system (CNS) impairment effects on psychomotor and cognitive skills and relates these changes to the plasma lorazepam concentrations in a pharmacokinetic-pharmacodynamic (PK-PD) model. Six male subjects received a single oral dose of lorazepam or placebo. The CNS effects were measured by using computerized continuous tracking (TRKN), body sway with eyes open (SWAY OPEN), and digit symbol substitution (DSS) tests. Plasma lorazepam concentrations were best characterized by a two-compartment model with first-order absorption. Plotting the plasma lorazepam concentration and measured effect across time revealed a counterclockwise hysteresis loop. Fitting the time course of the effects in an integrated PK-PD model required an effect compartment with the equilibrium rate constant between it and the plasma compartment. The magnitude of the temporal lag was quantified by the half-time of equilibration between concentration in the hypothetical effect compartment and the plasma lorazepam level (t1/2keo). The CNS effect measured by TRKN was characterized by a mean estimate of maximum predicted effect (Emax) of 418 with a t1/2keo of 0.43 hr, an estimate of effect site drug level to produce 50% of Emax (EC50) of 35.8 ng/ml and a power parameter (gamma) of 6.29. Corresponding parameter mean estimates for SWAY OPEN and DSS as measures of drug CNS effect were quite similar.

Semiparametric approach to pharmacokinetic-pharmacodynamic data.

A semiparametric model for analysis of pharmacokinetic (PK) and pharmacodynamic (PD) data arising from non-steady-state experiments is presented. The model describes time lag between drug concentration in a sampling compartment, e.g., venous blood (Cv), and drug effect (E). If drug concentration at the effect site (Ce) equilibrates with arterial blood concentration (Ca) slower than with Cv, a non-steady-state experiment yields E vs. Cv data describing a counterclockwise hysteresis loop. If Ce equilibrates with Ca faster than with Cv, clockwise hysteresis is observed. To model hysteresis, a parametric model is proposed linking (unobserved) Ca to Cv with elimination rate constant kappa ov and also linking Ca to Ce with elimination rate constant kappa oe. When kappa oe is greater than (or less than) kappa ov clockwise (or counterclockwise) hysteresis occurs. Given kappa oe and kappa ov, numerical (constrained) deconvolution is used to obtain the disposition function of the arterial compartment (Ha), and convolution is used to calculate Ce given Ha. The values of kappa oe and kappa ov are chosen to collapse the hysteresis loops to single curves representing the Ce-E (steady-state) concentration-response curve. Simulations, and an application to real data, are reported.