Steady-state Curve Research Articles

Extended-Release Divalproex Sodium for Patients With Side Effects From Delayed-Release Divalproex Sodium

Back to table of contents Previous article Next article Letter to the EditorFull AccessExtended-Release Divalproex Sodium for Patients With Side Effects From Delayed-Release Divalproex SodiumLANCE P. LONGO, M.D., LANCE P. LONGOSearch for more papers by this author, M.D., Milwaukee, Wis.Published Online:1 Aug 2005https://doi.org/10.1176/appi.ajp.162.8.1548AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We read with interest the article by Franca Centorrino, M.D., et al. (1). For similar reasons—enhanced patient compliance resulting from once-daily dosing and the potential for greater tolerability because of less peak-trough blood-level fluctuation—we also performed a pilot switching study that we presented at the 2001 APA annual meeting and would like to share with your readers.Ten patients with bipolar I or bipolar II disorder (some with other axis I or axis II comorbidity) who exhibited side effects that limited their compliance or tolerability to delayed-release divalproex sodium were switched to the once-daily extended-release formulation. The patients were switched based on bioavailable dose data and available tablet strength. In two multiple-dose studies, the average bioavailability of extended-release divalproex given once daily was 81%–89% relative to delayed-release divalproex tablets given b.i.d. (2). The patients were evaluated over 12 weeks to monitor their clinical status (Clinical Global Impression and Global Assessment of Functioning scales), and side effects were measured with a 7-point Likert rating scale. No additions, deletions, or dose changes of concomitant medications occurred in any patients during the 12-week observation period. Laboratory assessments included baseline and follow-up divalproex blood levels, liver function tests, and CBCs. Our case series was unblinded, open label, and naturalistic. All patients were maintained in their usual outpatient treatment settings, with no alteration in the type or frequency of their clinic appointments.Six male and four female patients ages 27 to 52 who were currently taking divalproex for a DSM-IV diagnosis of bipolar I, bipolar II, or schizoaffective disorder were followed. This study was approved by the Aurora Healthcare Institutional Review Board, and all subjects provided appropriate informed consent. All patients had liver function tests with results within normal limits and had no history of hepatitis, pancreatitis, or hematological abnormalities. All patients had at least one side effect attributed to divalproex (namely, gastrointestinal discomfort, sedation, weight gain, or tremor) that prompted their desire to switch to a potentially more tolerable extended-release formulation.Our 12-week follow-up results substantiated that extended-release divalproex was effective (nine of 10 patients showed equal or mildly improved clinical status), well tolerated (five of 10 had reductions in side effects), and led to enhanced medication compliance in certain individuals. Pharmacokinetic data from extended-release divalproex studies suggest that its peak and trough blood levels do not fluctuate significantly compared to the conventional divalproex formulation (2). Peak levels may be associated with increased side effects, and adequate trough levels are thought to affect the efficacy of divalproex. Thus, the extended-release formulation of divalproex (which has a more level steady-state curve) may confer the dual advantage of lesser side effects (tolerability) and more sustained efficacy.Studies have suggested that noncompliance with pharmacological treatments for bipolar disorders is as high as 50%, and compliance increases as the number of daily doses decreases (3). Thus, once-daily dosing should improve patient compliance and, consequently, may improve treatment outcomes. This may be especially important in the treatment of individuals with bipolar disorder, for whom noncompliance often not only precipitates acute decompensation but also leads to the development of a more intractable disease pattern or loss of responsiveness to previous regimens (e.g., lithium). Our open pilot findings add to the growing literature (4) that supports the safety and efficacy of extended-release divalproex sodium in psychiatric patient populations, and we hope that it stimulates more rigorous controlled clinical trials.

Phase I and Pharmacokinetic Study of LY293111, an Orally Bioavailable LTB4 Receptor Antagonist, in Patients With Advanced Solid Tumors

LY293111, a novel diaryl ether carboxylic acid derivative, is a potent and selective inhibitor of the lipoxygenase pathway either directly through 5'-lipoxygenase or via antagonism of the leukotriene B4 (LTB4) receptor. More recently it has been determined to have peroxisome proliferator activated receptor-gamma agonist (PPARgamma) activity. LY293111 has antineoplastic activity in a variety of preclinical models. The tolerability and pharmacokinetics of LY293111 administered continuously, by mouth, BID for repeat cycles of 21 days was evaluated. Thirty-eight patients with advanced solid tumors were treated at five dose levels (200 to 800 mg BID) for a total of 102 cycles. The most common toxicity was diarrhea (76%). One patient at 600 mg BID (n = 11) and two at 800 mg BID (n = 8), experienced dose-limiting grade 3 diarrhea. Dose reductions and/or delays were infrequent. Increases in steady-state maximum plasma concentration (Cmax,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUCtau,ss) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in Cmax,ss and AUCtau,ss was estimated to be 65% and 71% respectively. There was a small increase in AUC (1.37; 90% CI, 0.85 to 2.21) between single and multiple doses. Two patients with progressive chondrosarcoma and melanoma had stable disease lasting approximately 336 and 168 days, respectively. LY293111 can be administered safely by continuous oral therapy with mild toxicities. Diarrhea is dose-limiting. The recommended phase II dose will be 600 mg BID. The steady-state concentrations in humans exceed relevant levels observed in preclinical models.

Steady‐state nicotine plasma levels following use of four different types of Swedish snus compared with 2‐mg Nicorette chewing gum: A crossover study

The present study evaluated nicotine plasma levels achieved following 1 day's regular use of four commonly used brands of Swedish portion snus and 2-mg Nicorette chewing gum. The study also estimated the amount of sodium chloride extracted from each snus sachet to identify potential risks for exacerbation of heart failure and hypertension with the use of Swedish snus. Extracted dose of nicotine, area under the venous plasma concentration-time curve (AUC), maximum plasma nicotine concentration (Cmax) of the last (12th) dosing interval, and the Cmax and AUC ratios versus Nicorette were calculated. Relative bioavailable dose was calculated using AUC of 2-mg Nicorette gum as the reference. The mean extracted nicotine doses were 2.74+/-0.80, 1.55+/-0.68, 2.00+/-0.56, and 1.08+/-0.94 mg/sachet for General, Catch Licorice, Catch Mini, and Catch Dry Mini snus, respectively. The approximate bioavailable dose of nicotine from snus was 40%-60% of the extracted dose. The steady-state nicotine plasma concentration-time curve for the weakest brand, Catch Dry Mini portion snus, did not differ significantly from that of the 2-mg Nicorette gum. The AUC and Cmax for Catch Licorice 1 g and Catch Mini 0.5 g portion snus were twice those for the 2-mg Nicorette gum; for the strongest brand, General, these values were 2(1/2) times those for Nicorette gum. The differences in AUC and Cmax versus the 2-mg Nicorette gum were statistically significant (p=.020). Nicotine plasma levels with General portion snus were sustained at higher levels than current nicotine replacement therapy products, peaking at 29.0+/-8.5 ng/ml, and more closely mimicking cigarette smokers' nicotine plasma levels. The risks of aggravation of heart failure and hypertension with respect to increased salt load from the use of snus appeared to be negligible.

Parameter estimation of induction motor at standstill with magnetic flux monitoring

The paper presents a new method for the estimation of the electric parameters of induction motors (IMs). During the identification process the rotor flux is also estimated. The procedure relies on standstill tests performed with a standard drive architecture, hence, it is suitable for self-commissioning drives. The identification scheme is based on the model reference adaptive system (MRAS) approach. A novel parallel adaptive observer (PAO) has been designed, starting from the series-parallel Kreisselmeier observer. The most interesting features of the proposed method are the following: 1) rapidity and accuracy of the identification process; 2) low-computational burden; 3)excellent noise rejection, thanks to the adopted parallel structure; 4) avoidance of incorrect parameter estimation due to magnetic saturation phenomena, thanks to recursive rotor flux monitoring. The performances of the new scheme are shown by means of simulation and experimental tests. The estimation results are validated by comparison with a powerful batch nonlinear least square (NLS) method and by evaluating the steady-state mechanical curve of the IM used in the tests.

Evaluation technique of kinetic parameters for irreversible charge transfer reactions from steady-state voltammograms at microdisk electrodes

An explicit approximate expression for half-wave potentials of irreversible steady-state current-voltage curves at a microdisk electrode was derived from the diffusion equation and the Butler–Volmer equation on the basis of the previous analytical method [K. Aoki, K. Tokuda, H. Matsuda, J. Electroanal. Chem. 235 (1987) 87]. The plot of the half-wave potential, E 1/2 against ln(1− exp(−( E 1/2− E 0)) F/RT) showed a linear relation with the slope of RT/ αF, irrespective of the values of the kinetic parameters, where a is the radius of the electrode and α is the transfer coefficient. Values on the both axis in this plot are readily accessible from the voltammograms. The intercept gave the rate constant. Values of kinetic parameters obtained from the disk model were very close to those from the hemisphere model although there is big difference in current distribution on the two model electrodes.

Differential Role of the α1C Subunit Tails in Regulation of the Cav1.2 Channel by Membrane Potential, β Subunits, and Ca2+ Ions

Voltage-gated Ca(v)1.2 channels are composed of the pore-forming alpha1C and auxiliary beta and alpha2delta subunits. Voltage-dependent conformational rearrangements of the alpha1C subunit C-tail have been implicated in Ca2+ signal transduction. In contrast, the alpha1C N-tail demonstrates limited voltage-gated mobility. We have asked whether these properties are critical for the channel function. Here we report that transient anchoring of the alpha1C subunit C-tail in the plasma membrane inhibits Ca2+-dependent and slow voltage-dependent inactivation. Both alpha2delta and beta subunits remain essential for the functional channel. In contrast, if alpha1C subunits with are expressed alpha2delta but in the absence of a beta subunit, plasma membrane anchoring of the alpha1C N terminus or its deletion inhibit both voltage- and Ca2+-dependent inactivation of the current. The following findings all corroborate the importance of the alpha1C N-tail/beta interaction: (i) co-expression of beta restores inactivation properties, (ii) release of the alpha1C N terminus inhibits the beta-deficient channel, and (iii) voltage-gated mobility of the alpha1C N-tail vis a vis the plasma membrane is increased in the beta-deficient (silent) channel. Together, these data argue that both the alpha1C N- and C-tails have important but different roles in the voltage- and Ca2+-dependent inactivation, as well as beta subunit modulation of the channel. The alpha1C N-tail may have a role in the channel trafficking and is a target of the beta subunit modulation. The beta subunit facilitates voltage gating by competing with the N-tail and constraining its voltage-dependent rearrangements. Thus, cross-talk between the alpha1C C and N termini, beta subunit, and the cytoplasmic pore region confers the multifactorial regulation of Ca(v)1.2 channels.

A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene

Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG (I(Kr)) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (I(Ks)) channel. Here we identify a new variant, "SQT3", which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I(K1) than the wild-type (P<0.05) at potentials between -75 mV and -45 mV, with the peak current being shifted in the former with respect to the latter (WT, -75 mV; D172N, -65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I(K1) greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients' consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias.

Viscometric characterization of cobalt nanoparticle-based magnetorheological fluids using genetic algorithms

The rheological flow curves (shear stress vs. shear rate) of a nanoparticle cobalt-based magnetorheological fluid can be modeled using Bingham-plastic and Herschel–Bulkley constitutive models. Steady-state rheological flow curves were measured using a parallel disk rheometer for constant shear rates as a function of applied magnetic field. Genetic algorithms were used to identify constitutive model parameters from the flow curve data.

V102862 (Co 102862): a potent, broad‐spectrum state‐dependent blocker of mammalian voltage‐gated sodium channels

1. 4-(4-Fluorophenoxy)benzaldehyde semicarbazone (V102862) was initially described as an orally active anticonvulsant with robust activity in a variety of rodent models of epilepsy. The mechanism of action was not known. We used whole-cell patch-clamp techniques to study the effects of V102862 on native and recombinant mammalian voltage-gated Na+ channels. 2. V102862 blocked Na+ currents (I(Na)) in acutely dissociated cultured rat hippocampal neurons. Potency increased with membrane depolarization, suggesting a state-dependent mechanism of inhibition. There was no significant effect on the voltage dependence of activation of I(Na). 3. The dissociation constant for the inactivated state (K(I)) was approximately 0.6 microM, whereas the dissociation constant for the resting state (K(R)) was >15 microM. 4. The binding to inactivated channels was slow, requiring a few seconds to reach steady state at -80 mV. 5. The mechanism of inhibition was characterized in more detail using human embryonic kidney-293 cells stably expressing rat brain type IIA Na+ (rNa(v)1.2) channels, a major Na+ channel alpha subunit in rat hippocampal neurons. Similar to hippocampal neurons, V102862 was a potent state-dependent blocker of rNa(v)1.2 channels with a K(I) of approximately 0.4 microM and K(R) approximately 30 microM. V102862 binding to inactivated channels was relatively slow (k(+) approximately = 1.7 microM(-1) s(-1)). V102862 shifted the steady-state availability curve in the hyperpolarizing direction and significantly retarded recovery of Na+ channels from inactivation. 6. These results suggest that inhibition of voltage-gated Na+ channels is a major mechanism underlying the anticonvulsant properties of V102862. Moreover, understanding the biophysics of the interaction may prove to be useful in designing a new generation of potent Na+ channel blocker therapeutics.

Electrochemical Studies of Guanosine in DMF and Detection of Its Radical Cation in a Scanning Electrochemical Microscopy Nanogap Experiment

This communication reports the findings of the investigation of the electrochemical (EC) oxidation of the important bimolecular guanosine (Gs) by scanning electrochemical microscopy (SECM) using carbon fiber ultramicroelectrodes (CF-UMEs) as the probe and substrate. The first attempt is to try to gain a steady-state voltammogram for EC oxidation of Gs at the CF-UME probe in aqueous buffer solutions with three different pH values. Experimental results indicate that due to serious adsorption of Gs on the CF-UME surface, an "S-shaped" steady-state voltammetric curve, which is required for SECM studies, cannot be obtained in aqueous solutions. To solve this adsorption problem, a series of experiments for studying the EC behavior of Gs in DMF are carried out. A well-defined "S-shaped" steady-state cyclic voltammogram (CV) could be achieved at the CF-UME in DMF containing 0.1M TBAPF6 as the supporting electrolyte. By combining several EC techniques, including cyclic voltammetry at glassy carbon (GC) macroelectrode and CF-UMEs, and chronoamperometry, the general chemical characteristics and EC behavior of Gs in DMF solution are studied. Furthermore, SECM detection of Gs*+, the radical cation of Gs electrogenerated in its first oxidation, is carried out by using feedback and tip generation/substrate collection modes in a nanogap configuration. Gs*+ has been electrochemically detected for the first time, with an estimated lifetime of </=40 mus and E degrees = 1.55 V versus NHE for the Gs/Gs*+ couple.

Measurement and modeling of the flow behavior of aqueous foams using a recirculating pipe rheometer

A recirculating pipe rheometer associated with a foam generation system is described. In addition to the measurement of the volumetric flow rate and the pressure drop through straight pipes, the system allows simultaneous online measurement of the foam texture, foam density, temperature and inline static pressure. With this equipment, we measured steady-state flow curves of foams, stabilized by addition of a surfactant, over a shear rate range of ∼10 to 10 3 s −1. The data have been corrected for the apparent slip of the foam at the pipe wall. The flow behavior of foams is examined as a function of the gas volume fraction ϕ (or foam quality) ranging from 20 to 85%, at different static pressures and for various concentrations of the added surfactant. Foams at volume fractions up to ϕ = 50% contain isolated spherical bubbles. Their viscosity is Newtonian and governed by the volume fraction and not by the bubble size distribution, as shown by the good agreement with the predictions of the Taylor–Mooney viscosity model for moderately concentrated emulsions. For high volume fraction foams ( ϕ ≥ 60%), the bubbles are separated by a thin liquid film. The viscosity/shear stress curves of these foams show a severe shear-thinning behavior beyond an apparent dynamic yield stress and a tendency to a high shear stress asymptote. Their shear stress/shear rate equivalent curves are adequately fitted by the Herschel–Bulkley model. The predictions of empirical foam and emulsion models, which incorporate physical parameters, are also analyzed. The volume equalization method, proposed by Valko and Economides, which assumes that a suitable parameter is the expansion ratio related to the foam compressibility, fails to reduce the steady-state flow curves to a master curve, whatever the type of flow curve. On the other hand, the model of Princen and Kiss, which describes the shear viscosity as a function of the capillary number, is found adequate to describe the behavior of foams having a yield stress, but only for volume fractions up to 75%. Finally, the scaling analysis proposed by Prud’homme and Otsubo for highly concentrated emulsions is considered. We demonstrate that, at a fixed high volume fraction, the shear viscosities obtained for various concentrations of added surfactant scale with the ratio of the interfacial tension to the Sauter diameter, reflecting the importance of the total interfacial area.

Glass transitions and shear thickening suspension rheology

We introduce a class of simple models for shear thickening and/ or `jamming' in colloidal suspensions. These are based on schematic mode coupling theory (MCT) of the glass transition, having a memory term that depends on a density variable, and on both the shear stress and the shear rate. (Tensorial aspects of the rheology, such as normal stresses, are ignored for simplicity.) We calculate steady-state flow curves and correlation functions. Depending on model parameters, we find a range of rheological behaviours, including `S-shaped' flow curves, indicating discontinuous shear thickening, and stress-induced transitions from a fluid to a nonergodic (jammed) state, showing zero flow rate in an interval of applied stress. The shear thickening and jamming scenarios that we explore appear broadly consistent with experiments on dense colloids close to the glass transition, despite the fact that we ignore hydrodynamic interactions. In particular, the jamming transition we propose is conceptually quite different from various hydrodynamic mechanisms of shear thickening in the literature, although the latter might remain pertinent at lower colloid densities. Our jammed state is a stress-induced glass, but its nonergodicity transitions have an analytical structure distinct from that of the conventional MCT glass transition.

Individual Single-Walled Carbon Nanotubes as Nanoelectrodes for Electrochemistry

We demonstrate the use of individual single-walled carbon nanotubes (SWNTs) as nanoelectrodes for electrochemistry. SWNTs were contacted by nanolithography, and cyclic voltammetry was performed in aqueous solutions. Interestingly, metallic and semiconducting SWNTs yielded similar steady-state voltammetric curves. We clarify this behavior through a model that considers the electronic structure of the SWNTs. Interfacial electron transfer to the SWNTs is observed to be very fast but can nonetheless be resolved due to the nanometer critical dimension of SWNTs. These studies demonstrate the potential of using a SWNT as a model carbon nanoelectrode for electrochemistry.

A comparative tool for the validity of rate kinetics in ion channels by Onsager reciprocity theorem

The precise form of the rate constant functions of ion channels is very crucial for reproducing the electrophysiological behavior. Therefore, how well they account for experimental data plays an important role in the behavior of the model. In this study, we derive kinetic coefficients of activation and inactivation gates in ion channels by Onsager reciprocity theorem for an ensemble of gating particles, and propose that the obtained kinetic coefficients can be used as a comparative tool for the empirical validity of fitted rate constant functions to experimental data. We also illustrate its applicability based on the activation and inactivation kinetics of T-type calcium channel in thalamic relay neurons. We show that the shape of the steady-state curve by itself seems to be a poor indicator of the functional form of the rate functions, but the time constant curves reflect considerable variation depending on the particular form of the rate functions, and that the kinetic coefficients related to the time constants provide a powerful tool to determine the empirical validity of the fitted rate constants.

Protective effect of carvedilol on abnormality of L-type calcium current induced by oxygen free radical in cardiomyocytes.

The protective effect of carvedilol on abnormality of L-type calcium current induced by oxygen free radical in single guinea pig ventricular myocytes was studied. Whole-cell patch clamp technique was used to study the effect of H2O2 (0.5 mmol/L) on L-type calcium current in single guinea pig ventricular myocytes and the action of pretreatment with carvedilol (0.5 micromol/L). 0.5 micromol/L carvedilol had no significant effect on ICa,L and its channel dynamics. In the presence of 0.5 mmol/L H2O2, peak current of ICa,L was reduced significantly (P<0.001), the I-V curve of ICa,L was shifted upward, steady-state activation curve and steady-state deactivation curve of ICa,L were shifted left and recovery time of ICa,L was delayed significantly (P<0.001). 0.5 micromol/L carvedilol significantly alleviated the inhibitory effect of H2O2 on ICa,L as compared with that in H2O2 group (P<0.01). In addition, carvedilol reversed the changes of dynamics of ICa,L induced by H2O2. It was concluded that carvedilol could alleviate the abnormality of L-type calcium current induced by oxygen free radical in cardiomyocytes. It shows partly the possible mechanism of the special availability of carvedilol in chronic heart failure.

CO Tolerance of Commercial Pt and PtRu Gas Diffusion Electrodes in Polymer Electrolyte Fuel Cells

AbstractThe CO tolerance of commercial Pt and PtRu anode electrodes from different suppliers (E‐Tek and Tanaka) has been examined in polymer electrolyte fuel cells (PEFC) using AC‐impedance spectroscopy along steady‐state current‐voltage curves. A simple mathematical model has been derived in order to extract important kinetic parameters for CO poisoning on different anode electrodes. The Tanaka PtRu (40:60) electrode demonstrated the best CO tolerance under the selected operating conditions.Inductive behavior in the low frequency region of the impedance spectra for the E‐Tek Pt and PtRu electrode proved to be characteristic for CO poisoning. However, the impedance spectra of the Tanaka PtRu electrode did not show any inductive behavior and its CO surface coverage, extracted by fitting the experimental data to the model, was lower than the surface CO coverage of the E‐Tek electrodes.

A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model.

Sodium channel blockers are used clinically to treat a number of neuropathic pain conditions, but more potent and selective agents should improve on the therapeutic index of currently used drugs. In a high-throughput functional assay, a novel sodium channel (Na(V)) blocker, N-[[2'-(aminosulfonyl)biphenyl-4-yl]methyl]-N'-(2,2'-bithien-5-ylmethyl)succinamide (BPBTS), was discovered. BPBTS is 2 orders of magnitude more potent than anticonvulsant and antiarrhythmic sodium channel blockers currently used to treat neuropathic pain. Resembling block by these agents, block of Na(V)1.2, Na(V)1.5, and Na(V)1.7 by BPBTS was found to be voltage- and use-dependent. BPBTS appeared to bind preferentially to open and inactivated states and caused a dose-dependent hyperpolarizing shift in the steady-state availability curves for all sodium channel subtypes tested. The affinity of BPBTS for the resting and inactivated states of Na(V)1.2 was 1.2 and 0.14 microM, respectively. BPBTS blocked Na(V)1.7 and Na(V)1.2 with similar potency, whereas block of Na(V)1.5 was slightly more potent. The slow tetrodotoxin-resistant Na(+) current in small-diameter DRG neurons was also potently blocked by BPBTS. [(3)H]BPBTS bound with high affinity to a single class of sites present in rat brain synaptosomal membranes (K(d) = 6.1 nM), and in membranes derived from HEK cells stably expressing Na(V)1.5 (K(d) = 0.9 nM). BPBTS dose-dependently attenuated nociceptive behavior in the formalin test, a rat model of tonic pain. On the basis of these findings, BPBTS represents a structurally novel and potent sodium channel blocker that may be used as a template for the development of analgesic agents.

Effect of Orifice Location on Heat Transfer in a Duct Filled With Pressurized He II

Steady-state and transient heat transfer on a flat plate at one end of a rectangular duct with an orifice were measured in He II for bath temperatures of 1.8 K to 2.14 K at atmospheric pressure. The steady-state critical heat flux (CHF) was slightly affected by the orifice location. The transient heat transfer for a stepwise heat input with a magnitude larger than the CHF showed a quasi steady-state with a certain lifetime on the extrapolation of steady-state Kapitza conductance curve. The relation between the lifetime and step heat flux was significantly affected by the orifice location. Numerical analysis was performed for the steady-state and the transient heat transfer in the duct with the orifice by using the two-dimensional computer code named SUPER-2D based on the two-fluid model and the theory of mutual friction. The solutions of CHF and lifetime agreed well with the experimental data. The heat transport mechanism was clarified by the analysis.

Role of auxiliary β1-, β2-, and β3-subunits and their interaction with Nav1.8 voltage-gated sodium channel

The nociceptive C-fibers of the dorsal root ganglion express several sodium channel isoforms that associate with one or more regulatory β-subunits (β1–β4). To determine the effects of individual and combinations of the β-subunit isoforms, we co-expressed Nav1.8 in combination with these β-subunits in Xenopus oocytes. Whole-cell inward sodium currents were recorded using the two-microelectrode voltage clamp method. Our studies revealed that the co-expression β1 alone or in combination with other β-subunits enhanced current amplitudes, accelerated current decay kinetics, and negatively shifted the steady-state curves. In contrast, β2 alone and in combination with β1 altered steady-state inactivation of Nav1.8 to more depolarized potentials. Co-expression of β3 shifted steady-state inactivation to more depolarized potentials; however, combined β1β3 expression caused no shift in channel availability. The results in this study suggest that the functional behavior of Nav1.8 will vary depending on the type of β-subunit that expressed under normal and disease states.

Asymptotic-preserving &amp; well-balanced schemes for radiative transfer and the Rosseland approximation

We are concerned with efficient numerical simulation of the radiative transfer equations. To this end, we follow the Well-Balanced approach's canvas and reformulate the relaxation term as a nonconservative product regularized by steady-state curves while keeping the velocity variable continuous. These steady-state equations are of Fredholm type. The resulting upwind schemes are proved to be stable under a reasonable parabolic CFL condition of the type Δt≤O(Δx2) among other desirable properties. Some numerical results demonstrate the realizability and the efficiency of this process.