Steady-state Attainment Research Articles

Continuous process for the epoxidation of terpenes using mesoscale oscillatory baffled reactors

Continuous epoxidation of terpenes with H2O2 was carried out using mesoscale oscillatory baffled reactors (meso-OBRs) in a solvent-free environment. The performance of the new 3D-printed single, tri- and multi-orifice baffles was compared with helical and integral baffles. The performance investigated includes mixing intensity, induction period, steady-state attainment, and heat removal capability of the meso-OBR. Moreover, passive isothermalisation was also investigated using meso-OBR in a heat pipe assembly. The tri- and multi-orifice baffles were able to overcome mixing limitations and achieved a comparable rate of reaction to batch at mixing conditions of Reo > 850 and Reo > 500, respectively. Both baffles exhibited rapid steady-state attainment, shorter induction period (t = 1.5τ) and better reproducibility with product variation of ∼1.3%. The meso-OBR designs demonstrated effective heat transfer capability, allowing the reaction to being operated isothermally with ±1 °C temperature variation in solvent-free conditions. This removes the need for a solvent, thus reducing reaction volume by a 5-fold. The timescale for the reaction was reduced from ∼8 h in a conventional process to 30 min in the multi-orifice meso-OBR, a 16-fold reduction. A better process has been developed for a continuous epoxidation of terpenes with H2O2 using multi-orifice meso-OBRs, with a potential intensification factor of ∼80.

THU0219 FIRST-INHUMAN STUDY OF SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF IRAK1/4 INHIBITOR R835 IN HEALTHY SUBJECTS

Background:Toll-Like Receptors (TLR) and Interleukin-1 Receptors (IL-1R) play a critical role in the innate immune response as microbial and tissue damage sensors, providing a bridge between the innate and adaptive immunity. Interleukin receptor associated kinases (IRAK) 1 and 4 are serine/threonine kinases that are essential for signaling downstream of most TLRs and IL-1Rs and the resulting production of pro-inflammatory cytokines. Suppression of TLR and IL-1R signaling through inhibition of IRAK1/4 kinases is a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. We have identified a potent and selective IRAK1/4 inhibitor (R835) that showed dose-dependent inhibition of lipopolysaccharide (LPS, a TLR4 agonist), and IL-1β induced serum cytokines in mice. R835 prevented disease onset and progression in multiple rodent models of inflammatory diseases, including arthritis and lupus models.Objectives:The aim of this FIH study was to characterize the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of R835 after single or multiple dose oral administrations.Methods:This study was a randomized, placebo-controlled, double-blind Phase 1 study in healthy subjects in three parts: single ascending doses (20 mg-1920 mg, Part A) with food effect in a separate cohort (480 mg), multiple ascending doses (120 mg and 960 mg, BID, Part B) with a caffeine interaction (960 mg cohort), and an intravenous LPS challenge test at 240 mg oral dose of R835 (Part C).Results:Single doses of up to 480 mg R835 in organic solution, single doses of up to 1920 mg R835 as capsule, multiple doses of 120 mg R835 Q12H (organic solution), and 960 mg R835 Q12H (capsule) were safe and well tolerated. All R835 related adverse events (AEs) were mild in intensity and reversible, and mostly associated with the higher doses of R835 in the organic solution. The most common AEs were headache and gastrointestinal disturbance. The PK of R835 was linear and dose proportional in exposure over the dose range studied. A nominal level of accumulation in plasma achieved rapidly upon repeated BID administrations with steady-state essentially attained in 2 days. A high-fat meal with the capsule formulation resulted in slow rate of absorption but had no effect on the extent of absorption. There was no effect of R835 on metabolism of caffeine (P450 CYP1A2 prototype substrate). In the LPS challenge test, R835 profoundly inhibited the acute release of cytokines, including TNF-α, IL-6, IL-8, MIP1α and MIP1β, but had no impact on CRP release.Conclusion:R835 was well tolerated after single or multiple dose administrations. The most common AEs were headache and gastrointestinal disturbance. For both of the formulations tested, the PK of R835 was linear and exposure was dose proportional with rapid steady-state attainment following BID administration. There was no drug-drug interaction by use of caffeine as the protype substrate. R835 inhibited the LPS induced release of cytokines in the serum, including TNF-α, IL-6, IL-8, MIP1α and MIP1β, mirroring preclinical data in mice. The desirable PK and safety profile combined with proof of mechanism, as demonstrated by inhibition of cytokine release, support progression of R835 into Phase II clinical development as an agent for the treatment of inflammatory and autoimmune diseases.Disclosure of Interests: :Lucy Yan Shareholder of: Amgen, Rigel, Employee of: Amgen, Rigel, Sandra Tong Shareholder of: Rigel, Employee of: Rigel, Anthony Absalom: None declared, Izaak den Daas: None declared, Gary Park Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Vanessa Taylor Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Donna Chow Shareholder of: Rigel, Employee of: Rigel, Meng Lee Shareholder of: Rigel, Employee of: Rigel, Hanzhe Zheng Shareholder of: Rigel, Employee of: Rigel, Andrew Chow Shareholder of: Rigel, Employee of: Rigel

Practical considerations for managing breakthrough psychosis and symptomatic worsening in patients with schizophrenia on long-acting injectable antipsychotics.

With more long-acting injectable (LAI) antipsychotics available for treating schizophrenia, each with variable durations of action (2 weeks to 3 months), it is important to have clear management strategies for patients developing breakthrough psychotic symptoms or experiencing symptomatic worsening on LAIs. However, no treatment guidelines or clinical practice pathways exist; health-care providers must rely on their own clinical judgment to manage these patients. This article provides practical recommendations-based on a framework of clinical, pharmacokinetic, and dosing considerations-to guide clinicians' decisions regarding management of breakthrough psychotic symptoms. Management options include ruling out/addressing medical illness or substance abuse/misuse as a contributing factor, addressing stressors, optimizing nonpharmacologic treatments, treating medical/psychiatric comorbidities, ensuring proper LAI administration technique, addressing missed LAI doses or lack of steady-state attainment, and increasing LAI dose directly or indirectly by shortening the injection interval (off-label). If these strategies do not work sufficiently with frequent monitoring, the LAI could be supplemented with a low dose of the corresponding oral formulation for fast symptom control (off-label). However, caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and oral antipsychotics (OAPs) are limited, especially over extended periods. If symptoms abate, therapy optimization could be continued and slow discontinuation of the OAP could be considered. For persistent/worsening symptoms, the OAP should be increased to optimum effective dose while intensifying the initial steps used before it was added. If this fails, switching the OAP or LAI could be considered. We believe that these strategies will help clinicians manage breakthrough psychotic symptoms during LAI treatment and improve overall outcomes among those who can benefit from LAIs.

Steady-State Attainment Period for Fischer–Tropsch Products

In studying the mechanism of the Fischer–Tropsch (FT) reaction, deuterium tracer techniques have been widely used and several important conclusions have been reported. A novel combination of experiment and modelling to quantify the residence times of long chain hydrocarbons using deuterium tracing has been devised. In this study, the effect of variation of residence time with carbon number on the olefin to paraffin ratio is investigated and also the time required for each hydrocarbon to reach steady state is determined. The results show that the olefin to paraffin ratio decreases with increasing carbon number which is consistent with olefin readsorption but not necessarily diffusion enhanced olefin readsorption. Therefore, chain length-dependent solubility in the liquid phase should be the predominant cause for chain length-dependencies of secondary olefin reactions in FT synthesis. Furthermore, the results show that it takes around 100 h for the overall/total mole fractions to reach steady state. Therefore, actual compositions (mole fractions) equilibrate faster even though actual flows (moles/h) might still be changing. Hence, for practical purposes the total mole fraction can be used as a guide to establish steady state.

Experimental investigation of convective flows in a plane horizontal fluid layer heated from below and rotating about the vertical axis

The convective coherent structures in a plane horizontal fluid layer, heated from below and capable of rotation about the vertical axis, are experimentally investigated. It is shown that with increase in the supercriticality the time it takes for the convective structures to be formed decreases sharply. Rotation and an increase in the layer thickness-to-diameter ratio lead to an increase in the steady-state attainment time.

VOC destruction by water diluted hydrogen mild combustion

This study represents a preliminary numerical evaluation of the effect of steam dilution and hydrogen addition on the oxidation of formaldehyde and benzene, chosen as representative of the volatile organic compounds (VOC), in mild condition by evaluating the autoignition time and the steady state attainment. These parameters are important in the design of thermal VOC destruction plants since they influence the abatement efficiency and, therefore, the plant dimension. It has come out that, in comparison with the system diluted in nitrogen, steam induces lower autoignition times and, on the other hand, longer times for the attainment of the steady state. In contrast, for very high water content the autoignition time slightly increases. In particular results have shown that is possible to identify an optimum value of steam content that allows for the attainment of the steady state condition by the lowest residence time. Hydrogen addition to systems diluted in nitrogen promotes the oxidation reactions and anticipates the steady state condition. In steam diluted systems hydrogen delays the autoignition of the mixtures even though anticipates the attainment of the complete destruction of the VOC. The rate of production analysis has showed that the H(2)/O(2) reactions, that promote the ignition and the destruction of VOC, are sensibly modified by the presence of water and hydrogen.

Destruction of EDTA by mediated electrochemical oxidation process: Monitoring by continuous CO 2 measurements

The mediated electrochemical oxidation (MEO) process with cerium(IV) in nitric acid as the oxidizing medium was employed for the destruction of ethylenediaminetetraacetic acid (EDTA) in batch and continuous feeding modes. A complete mineralization of EDTA to CO 2 and water was achieved. The system parameters studied were the temperature (343, 353 and 368 K), concentration of nitric acid (2, 3 and 4 M), Ce(IV) concentration (0.7–0.95 M), aqueous EDTA concentration (67–268 mM) , flow rate of EDTA addition (3.0–7.5 ml/min), and feeding time (30 min and 2 h). The batch process CO 2 pattern clearly showed two distinct kinetic regimes. Accordingly the overall CO 2 formation rate constants were evaluated for fast and slow processes using pseudo first-order kinetics. In case of continuous organic feeding, the CO 2 formation rate constant was obtained using a new proposed mathematical procedure based on geometrical progression. The only parameter in the calculations was the first-order rate constant. The theoretical CO 2 evolution pattern was fitted on to the experimental data to obtain the formation rate constants. The activation energy was calculated based on the CO 2 formation constants and presented. The application of mathematical procedure predicted a steady-state attainment of CO 2 evolution for the destruction process during a long-term organic feeding and observed experimentally.

A phase I and pharmacokinetic (PK) study of high dose selenomethionine (SLM) in combination with irinotecan (IRI) in patients with advanced solid tumors

2080 Background: SLM, an organic selenium (Se) compound, potentiates IRI activity, protects against toxicity, and allows dose-escalation of IRI in pre-clinical models. IRI dose-escalation in mice models was possible only in association with serum Se concentrations > 1200ng/ml. We initiated a phase I study of daily SLM with weekly IRI to investigate: 1) the maximum tolerated dose (MTD) of IRI when combined with high dose SLM; 2) the pharmacokinetics (PK) of both compounds. Methods: IRI was escalated in a standard 3+3 design. SLM was administered at a fixed dose of 2200 μg/day starting 1 week before the 1st dose of IRI. IRI was administered intravenously weekly x 4 repeated every 6 weeks (1cycle). Dose level (DL) 1 and DL2 consisted of IRI 125mg/m2 and 160mg/m2 respectively. Blood for Se was drawn on days 1, 2, 8, 15, 29 and 50 (and later where possible). Results: 10 evaluable pts were treated on study (M/F: 6/4; median age: 59; ECOG 0/1: 3/7; prior chemo: 10). At DL2, 3 out of 4 pts had G3 diarrhea (DLT). None of the 6 DL1 pts had a DLT (declared MTD). Diarrhea was ≤ G2 (1 pt with G2) and neutropenia ≤ G2 at DL1 except for 1 pt with G4 neutropenia. SLM was associated with mild intermittent garlic-like breath. Se PK showed a suboptimal concentration <1000 ng/ml on day 1 of IRI. The mean Se (SD) serum half-life was 183 (94) h, and CLt/F 0.10 (0.04) L/h. Modeling of data suggests steady state attainment after ∼30 days, with a median Se steady state level of 844 (range 585 -1300) ng/ml. Responses were evaluable in 8 patients: 1 pt with prior IRI-refractory colon cancer had a partial response that is ongoing (11 months +). This patient had complete reversal of total alopecia upon built up of Se concentrations > 1200 ng/ml. 4pts had prolonged stable disease (Colon, NSCL, pancreatic, and gastric cancer). Conclusions: The administration of SLM at 2200 μg PO QD is safe but does not allow IRI escalation > 125mg/m2/week. Unexpected responses and disease stabilizations were noted at the MTD suggesting possible synergy between SLM and IRI. The inability to escalate IRI may be related to suboptimal concentrations of Se on D1 of IRI. SLM escalation in combination with fixed dose IRI is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sabinsa Sabinsa

Nonlinear mixed effects modelling for estimation of steady state attainment

Assessment of the time needed to attain steady state is a key pharmacokinetic objective during drug development. Traditional approaches for assessing steady state include ANOVA-based methods for comparing mean plasma concentration values from each sampling day, with either a difference or equivalence test. However, hypothesis-testing approaches are ill suited for assessment of steady state. This paper presents a nonlinear mixed effects modelling approach for estimation of steady state attainment, based on fitting a simple nonlinear mixed model to observed trough plasma concentrations. The simple nonlinear mixed model is developed and proposed for use under certain pharmacokinetic assumptions. The nonlinear mixed modelling estimation approach is described and illustrated by application to trough data from a multiple dose trial in healthy subjects. The performance of the nonlinear mixed modelling approach is compared to ANOVA-based approaches by means of simulation techniques. Copyright © 2005 John Wiley & Sons, Ltd.

Biased polymers in the origin of life

We delve into the study of a Markov chain formalism applied to the thermal prebiotic oligomerization of amino acids. We find for the case of only two types of electromagnetic interactions, that the steady state attainment by the Markov chain is a built in mechanism limiting the expected variability in sequences in a population of polymers. Such result may be of importance as it makes more accessible the replication of a minimal chemical machinery compatible with life.

RF breakdown by toroidal helicons

Bounded whistlers are well-known for their efficient plasma production capabilities in thin cylindrical tubes. In this paper we shall present their radio frequency (RF) breakdown and discharge sustaining capabilities in toroidal systems. Pulsed RF power in the electronmagnetohydrodynamic (EMHD) frequency regime is fed to the neutral background medium. After the breakdown stage, discharge is sustained by toroidal bounded whistlers. In these pulsed experiments the behaviour of the time evolution of the discharge could be studied in four distinct phases of RF breakdown, steady state attainment, decay and afterglow. In the steady state average electron density of ≈1012 per cc and average electron temperature of ≈20 eV are obtained at 10−3 mbar of argon filling pressure. Experimental results on toroidal mode structure, background effects and time evolution of the electron distribution function will be presented and their implications in understanding the breakdown mechanism are discussed.

Effect of shear schedule on particle size, density, and structure during flocculation in stirred tanks

The effect of shear history on the evolution of the polystyrene—alum floc size, density, and structure is investigated by small-angle light scattering during cycled-shear and tapered-shear flocculation in a stirred tank using a Rushton impeller. First, various sampling schemes are experimentally evaluated. The floc structure is characterized by the mass fractal dimension, D f , and the relative floc density. During turbulent shear flocculation, small floc structures are shown to be more open ( D f = 2.1) than larger floc structures ( D f = 2.5) as a result of shear-induced restructuring during steady state attainment. Flocs produced by cycled-shear flocculation are grown at shear rate G-50 s −1 for 30 min, are fragmented at G b = 100, 300, or 500 s −1 for one minute, and then are regrown at G = 50 s −1. This shear schedule decreases the floc size but compacts the floc structure. When flocs are produced by gradual reduction of the shear rate from G-300 to 50 s −1 (tapered-shear flocculation), smaller though equally dense flocs are produced compared with cycled-shear flocculation. The cycled-shear flocculation method produces the largest flocs with the highest potential for sedimentation when the fragmentation shear rate is G b = 300 s −1.

Morphology and electrophysiology of guinea pig gastric mucosal repair in vitro.

Guinea pig gastric mucosae stripped of their outer muscle layers were studied in Ussing chambers for up to 14 h. Ten minutes after the mucosae were mounted in the chamber, the electrical parameters were low but continued to rise over 90 min until steady-state potential difference (PD), resistance (R), and short-circuit current (Isc) were recorded. Morphological analysis during the first 10 min of the tissue in the chamber revealed gaps in the epithelium due to damaged cells. However, tissues examined after 20 min in the chamber showed little evidence of epithelial discontinuity. Thereafter, the initial rise in the electrical parameters was noted. After steady-state attainment, the lumen was exposed to 1.25 M NaCl for 5 min and then changed back to 150 mM NaCl. Ten minutes after washout and return to control solutions, the PD, R, and Isc had fallen to low values. At 30 min after washout of the NaCl, the PD, R, and Isc began to increase and after 2 h were back to control values. Morphological analysis of mucosae fixed up to 10 min after exposure to 1.25 M NaCl showed extensive damage and exfoliation of surface cells. However, by 30 min the epithelium was restored and had very few discontinuities, which was then followed by the return of the electrical parameters. The conclusions from these studies are 1) guinea pig gastric mucosae exposed to hypertonic NaCl on the luminal side will primarily result in surface epithelial cell destruction with an immediate drop in the transepithelial electrical values; 2) after return to isotonic saline the damaged mucosa can repair itself within minutes, which then allows the reestablishment of the transepithelial electrical parameters by 2 h; and 3) the good viability and reproducibility of this preparation present a suitable mammalian model system for the study of factors of mucosal repair.

Respiratory responses to intermittent and prolonged exercise in a hot-dry environment

Ventilatory gas exchange ratio (R), V̇O 2, ventilation (V̇ E), respiration rate (RR), rectal temperature (T re), and heart rate (HR) were determined for four acclimatized subjects during intermittent and prolonged exercise on a treadmill at 24° and 45°C (dry) as follows: 1) 8 cycles (10 min. exercise and 5 min. rest), and 2) prolonged exercise lasting for 90 min. While during intermittent and prolonged exercise, V̇O 2 and V̇ E did not differ in the heat, RR, T re, HR and the respiratory dead space were higher in the hot ambient environment. After steady-state attainment, exercise R was higher in the initial as compared to the last cycles with higher values in neutral as compared to the hot ambient condition. It was concluded that heat was more effective than time in lowering the R, probably with a greater dependence on fat oxidation in the latter exercise cycles which seemed to be more pronounced in the heat.