Bipartite consensus for multi-agent networks of fractional diffusion PDEs via aperiodically intermittent boundary control.

In this paper, the exponential bipartite consensus issue is investigated for multi-agent networks, whose dynamic is characterized by fractional diffusion partial differential equations (PDEs). The main contribution is that a novel exponential convergence principle is proposed for networks of fractional PDEs via aperiodically intermittent control scheme. First, under the aperiodically intermittent control strategy, an exponential convergence principle is developed for continuously differentiable function. Second, on the basis of the proposed convergence principle and the designed intermittent boundary control protocol, the exponential bipartite consensus condition is addressed in the form of linear matrix inequalities (LMIs). Compared with the existing works, the result of the exponential intermittent consensus presented in this paper is applied to the networks of PDEs. Finally, the high-speed aerospace vehicle model is applied to verify the effectiveness of the control protocol.

Exponential synchronization for variable-order fractional discontinuous complex dynamical networks with short memory via impulsive control.

This paper considers the exponential synchronization issue for variable-order fractional complex dynamical networks (FCDNs) with short memory and derivative couplings via the impulsive control scheme, where dynamical nodes are modeled to be discontinuous. Firstly, the mathematics model with respect to variable-order fractional systems with short memory is established under the impulsive controller, in which the impulse strength is not only determined by the impulse control gain, but also the order of the control systems. Secondly, the exponential stability criterion for variable-order fractional systems with short memory is developed. Thirdly, the hybrid controller, which consists of the impulsive coupling controller and the discontinuous feedback controller, is designed to realize the synchronization objective. In addition, by constructing Lyapunov functional and applying inequality analysis techniques, the synchronization conditions are achieved in terms of linear matrix inequalities (LMIs). Finally, two simulation examples are performed to verify the effectiveness of the developed synchronization scheme and the theoretical outcomes.

Group Consensus in Finite Time for Fractional Multiagent Systems With Discontinuous Inherent Dynamics Subject to Hölder Growth.

This article is concerned with the global Mittag-Leffler group consensus and group consensus in finite time for fractional multiagent systems (FMASs), where the inherent dynamics is modeled to be discontinuous, and subject to the local Hölder nonlinear growth in a neighborhood of continuous points. First, a fractional differential inequality on convex functions and a global convergence principle in finite time for absolutely continuous functions are developed, respectively. Second, two new distributed control protocols are designed to realize the consensus between the follower agents in each subgroup and respective leaders. In addition, under the fractional Filippov differential inclusion framework, by applying the Lur'e Postnikov-type convex Lyapunov functional approach and Clarke's nonsmooth analysis technique, some sufficient conditions with respect to the global Mittag-Leffler group consensus and group consensus in finite time are addressed in terms of linear matrix inequalities (LMIs), respectively. Moreover, the settling time for the group consensus in finite time is estimated accurately. Finally, two simulation examples are provided to illustrate the validity of the proposed scheme and theoretical results.

Synchronization in finite time for variable-order fractional complex dynamic networks with multi-weights and discontinuous nodes based on sliding mode control strategy.

This paper is concerned with the global synchronization in finite time for variable-order fractional complex dynamic networks with multi-weights, where the dynamic nodes are modeled to be discontinuous, and subject to the local Hölder nonlinear growth in a neighborhood of continuous points. Firstly, an inequality with respect to variable-order fractional derivative for convex functions is proposed. On the basis of the proposed inequality, a global convergence principle in finite time for absolutely continuous functions is developed. Secondly, based on proposed convergence principle in finite time, a new sliding mode surface is presented, and an appropriate sliding mode control law is designed to drive the trajectory of the error system to the prescribed sliding mode surface in finite time and remain on it forever. In addition, on the basis of differential inclusions theory and Lur'e Postnikov-type convex Lyapunov function approach, the sufficient conditions with respect to the global stability in finite time are established in terms of linear matrix inequalities for the error system on designed sliding mode surface. Moreover, the upper bound of the settling time is explicitly evaluated. Finally, the effectiveness and correction of synchronization strategies are illustrated through two simulation experiments.

Global Nonfragile Synchronization in Finite Time for Fractional-Order Discontinuous Neural Networks With Nonlinear Growth Activations.

This paper is concerned with the global nonfragile Mittag-Leffler synchronization and the global synchronization in finite time for fractional-order discontinuous neural networks, where activation functions are discontinuous at 0, or modeled as a local Hölder functions with the nonlinear growth property in a neighborhood of 0. First, two lemmas concerned with the convergence with respect to an absolutely continuous function are developed. Second, a new property, which introduces an inequality of the fractional derivative for the variable upper limit integral with respect to the nonsmooth integrable function, is presented and applied in the synchronization results' analysis. In addition, under the fractional Filippov differential inclusion framework, by utilizing the Lur'e Postnikov-type Lyapunov functional, nonsmooth analysis method, and the convergence properties developed in this paper, the synchronization conditions are derived in the form of linear matrix inequalities. Moreover, the upper bound of the setting time for the global nonfragile synchronization in finite time is calculated accurately. Finally, two illustrations are presented to verify the correctness of the theoretical results.

Global synchronization in finite time for fractional-order neural networks with discontinuous activations and time delays.

This paper is concerned with the global Mittag-Leffler synchronization and the synchronization in finite time for fractional-order neural networks (FNNs) with discontinuous activations and time delays. Firstly, the properties with respect to Mittag-Leffler convergence and convergence in finite time, which play a critical role in the investigation of the global synchronization of FNNs, are developed, respectively. Secondly, the novel state-feedback controller, which includes time delays and discontinuous factors, is designed to realize the synchronization goal. By applying the fractional differential inclusion theory, inequality analysis technique and the proposed convergence properties, the sufficient conditions to achieve the global Mittag-Leffler synchronization and the synchronization in finite time are addressed in terms of linear matrix inequalities (LMIs). In addition, the upper bound of the setting time of the global synchronization in finite time is explicitly evaluated. Finally, two examples are given to demonstrate the validity of the proposed design method and theoretical results.

Implementing DBS methodology for the determination of Compound A in monkey blood: GLP method validation and investigation of the impact of blood spreading on performance.

BACKGROUND: This article describes validation work for analysis of an Abbott investigational drug (Compound A) in monkey whole blood with dried blood spots (DBS). The impact of DBS spotting volume on analyte concentration was investigated. RESULTS: The quantitation range was between 30.5 and 10,200 ng/ml. Accuracy and precision of quality controls, linearity of calibration curves, matrix effect, selectivity, dilution, recovery and multiple stabilities were evaluated in the validation, and all demonstrated acceptable results. Incurred sample reanalysis was performed with 57 out of 58 samples having a percentage difference (versus the mean value) less than 20%. A linear relationship between the spotting volume and the spot area was drawn. The influence of spotting volume on concentration was discussed. CONCLUSION: All validation results met good laboratory practice acceptance requirements. Radial spreading of blood on DBS cards can be a factor in DBS concentrations at smaller spotting volumes.

Effect of sample collection tubing type used in a clinical study on quantitation of pharmaceutical compounds in CSF by LC-MS/MS.

BACKGROUND: plasma/cerebrospinal fluid (CSF) ratio of compound K was determined to be lower than predicted during the conduct of clinical study. This triggered the evaluation of nonspecific binding of drug K and an additional ten compounds in CSF to collection tubing. Physiochemical properties such as pKa and log D values were correlated to the quantified results. RESULTS: mean recoveries of compound K quality controls sampled within 24 h, as compared with spiked quality control, were 12.9, 44.4 and 77.7% from silicone, Tygon and Pharmed collection tubing, respectively. Eight out of ten compounds showed significant loss into silicone and seven out of ten compounds showed no significant loss into Pharmed. CONCLUSION: silicone tubing is not recommended and Pharmed appears to be most appropriate. CSF sample collection tubing must be evaluated prior to starting clinical studies.

High-throughput salting-out assisted liquid/liquid extraction with acetonitrile for the simultaneous determination of simvastatin and simvastatin acid in human plasma with liquid chromatography.

Simvastatin (SS) is an effective cholesterol-lowering medicine, and is hydrolyzed to simvastatin acid (SSA) after oral administration. Due to SS and SSA inter-conversion and its pH and temperature dependence, SS and SSA quantitation is analytically challenging. Here we report a high-throughput salting-out assisted liquid/liquid extraction (SALLE) method with acetonitrile and mass spectrometry compatible salts for simultaneous LC-MS/MS analysis of SS and SSA. The sample preparation of a 96-well plate using SALLE was completed within 20 min, and the SALLE extract was diluted and injected into an LC-MS/MS system with a cycle time of 2.0 min/sample. The seamless interface of SALLE and LC-MS eliminated drying down step and thus potential sample exposure to room or higher temperature. The stability of SS and SSA in various concentration ratios in plasma was evaluated at room and low (4 degrees C) temperature and the low temperature (4 degrees C) was found necessary to maintain sample integrity. The short sample preparation time along with controlled temperature (2-4 degrees C) and acidity (pH 4.5) throughout sample preparation minimized the conversion of SS-->SSA to < or = 0.10% and the conversion of SSA-->SS to 0.00% The method was validated with a lower limit of quantitation (LLOQ) of 0.094 ng mL(-1) for both SS and SSA and a sample volume of 100 microL. The method was used for a bioequivalence study with 4048 samples. Incurred sample reproducibility (ISR) analysis of 362 samples from the study exceeded ISR requirement with 99% re-analysis results within 100+/-20% of the original analysis results.

Rapid, simultaneous determination of lopinavir and ritonavir in human plasma by stacking protein precipitations and salting-out assisted liquid/liquid extraction, and ultrafast LC-MS/MS.

Lopinavir and ritonavir are co-formulated in Kaletra approved for the treatment of human immunodeficiency virus infection. A validated analytical method is mandatory for clinical development and therapeutic drug monitoring. Here we are reporting a method for rapid, simultaneous determination of lopinavir and ritonavir in human plasma with stacked protein precipitations and salting-out assisted extraction (SALLE), and ultrafast LC-MS/MS detection. With stacked protein precipitations and SALLE, the sample preparation for a 96-well plate can be completed within 20 min by an automated pipette. Due to the unique cleanliness of SALLE extracts post double protein precipitations, the extracts were injected into an ultrafast liquid chromatography and tandem mass spectrometry system (LC-MS/MS) after simple dilution. An Agilent Zobax Extend-C18 Rapid resolution HT column (1.8 microm, 2.1 mm x 30 mm) was used for the separation. A mixture of acetonitrile:water (55:45, v/v) with 0.1% formic acid was used as the mobile phase. LC ran for approximately 48 s at a flow rate of 0.5 mL min(-1), tandem mass spectrometric data collection started at 15 s and lasts for 30 s. The method was validated with reference to Industry Guidance for Bioanalytical Method Validation and then used for clinical samples. The method is ultrafast, and robust. Results of incurred samples demonstrated excellent method of reproducibility. This ultrafast analysis speed did not compromise with the data quality. To our knowledge, this is the fastest analytical method for simultaneous determination of lopinavir and ritonavir.

Salting-out assisted liquid/liquid extraction with acetonitrile: a new high throughput sample preparation technique for good laboratory practice bioanalysis using liquid chromatography-mass spectrometry.

Acetonitrile, an organic solvent miscible with aqueous phase, has seen thousands of publications in the literature as an efficient deproteinization reagent. The use of acetonitrile for liquid-liquid extraction (LLE), however, has seen very limited application due to its miscibility with aqueous phase. The interest in LLE with acetonitrile has been pursued and reported in the literature by significantly lowering the temperature of the mixture or increasing the salt concentration in the mixture of acetonitrile and aqueous phase, resulting in the separation of the acetonitrile phase from aqueous phase, as observed in conventional LLE. However, very limited application of these methods has been reported. The throughput was limited. In this report, we report a new sample preparation technique, salting-out assisted liquid-liquid extraction with acetonitrile, for high-throughput good laboratory practice sample analysis using LCMS, Two compounds from an approved drug, Kaletra, were used to demonstrate the extractability of drugs from human plasma matrix. Magnesium sulfate was used as the salting-out reagent. Extracts were diluted and then injected into a reversed phase LC-MS/MS system directly. One 96-well plate was extracted with this new approach to evaluate multiple parameters of a good laboratory practice analytical method. Results indicate that the method is rapid, reliable and suitable for regulated bioanalysis. With minimal modification, this approach has been used for high-throughput good laboratory practice analysis of a number of compounds under development at Abbott.

High-throughput salting-out assisted liquid/liquid extraction and ultrafast LC for same-day delivery of first-in-human bioanalytical data.

BACKGROUND: With the need of fast-paced drug development, rapid delivery of bioanalytical data becomes a trend. Here, we present a strategy to demonstrate same-day data delivery. RESULTS: A novel salting-out assisted liquid/liquid extraction (SALLE) with acetonitrile and a MS-friendly salt was used to extract analyte from the first-in-human study plasma samples and the extract was successfully injected into ultrafast chromatography. The strategic combination of SALLE and ultrafast chromatography minimizes the turnaround time and allows the same-day delivery of bioanalytical data. The time saving from both extraction and injection was translated to a fast delivery of bioanalytical data. CONCLUSION: The first-in-human pharmacokinetic data of an investigational new drug candidate was delivered in approximately 4.5 work h after receiving the samples of each dose group using high-throughput SALLE and ultrafast LC. Incurred sample reassay results proved uncompromised data quality with the high-speed bioanalysis.

Simultaneous determination of a hydrophobic drug candidate and its metabolite in human plasma with salting-out assisted liquid/liquid extraction using a mass spectrometry friendly salt.

In previously reported applications of salting-out assisted liquid/liquid extraction (SALLE) with acetonitrile, only inorganic salts were evaluated and implemented as the salting-out reagents. A potential concern of the method for the subsequent LC-MS analysis of biological samples was that a portion of the added salt (typically of high concentration) might be extracted and affect the chromatography separation and ionization of chromatography effluents in a mass spectrometer. Here we report, for the first time, the use of a mass spectrometry friendly organic salt, ammonium acetate, as a salting-out reagent in SALLE with acetonitrile for the simultaneous quantitation of an Abbott investigational new drug ABT-869 and its hydrophilic metabolite in human plasma. The performance of SALLE with ammonium acetate was compared with that of a previously reported method with a conventional liquid/liquid extraction technique using a set of pooled incurred samples. The % differences of the measured concentrations for 24 samples from these two methods were found to be within acceptance criteria, demonstrating SALLE with ammonium acetate as a reliable sample preparation technique. The SALLE method is simple, fast (25 min/plate), easy for automation, free of drying down step, and environmentally friendly. SALLE with mass spectrometry friendly salts has been applied to regulated sample analysis of both hydrophilic and hydrophobic compounds. It is envisioned that SALLE with acetonitrile and ammonium acetate be a universal method for high throughput automated sample preparation for bioanalytical chemistry.

HPLC-MS/MS determination of a hardly soluble drug in human urine through drug-albumin binding assisted dissolution.

ABT-263 is under development for treatment of cancer. In order to support clinical trials, an analytical method for ABT-263 quantification in human urine became necessary. Due to the extremely poor solubility of ABT-263 in aqueous and most common organic solvents, a critical step was to dissolve the drug into urine matrix. Although other potential approaches could be used, addition of powder albumin was found to be the most advantageous. Albumin powder does not significantly alter urine sample volume (< or = 2.8%) and a range of albumin to urine sample volume ratios can be allowed for full recovery of drug and thus accurate quantification. The procedure is fairly simple and can potentially be a universal approach for compounds with low solubility in urine, but strong protein binding. The method has been validated to support clinical trials.

Interactions of two monoclonal antibodies with BNP: high resolution epitope mapping using fluorescence correlation spectroscopy.

Structure-function studies of antibody-antigen systems include the identification of amino acid residues in the antigen that interact with an antibody and elucidation of their individual contributions to binding affinity. We used fluorescence correlation spectroscopy (FCS) and alanine-scanning mutagenesis to characterize the interactions of brain natriuretic peptide (BNP) with two monoclonal antibodies. Human BNP is a 32 amino acid residue long cyclic polypeptide with the ring structure confined between cysteines in positions 10 and 26. It is an important cardiovascular hormone and a valuable diagnostic cardiac marker. We compare the binding strength of the N-terminus Alexa488-labeled BNP, native cyclic BNP, BNP alanine-substituted mutants, linear BNP, and its short fragments to determine the individual contributions of amino acid residues included in the continuous antigenic epitopes that are recognized by two different monoclonal antibodies raised toward BNP. Implementation of FCS for these studies offers all of the advantages of solution phase measurements, including high sensitivity, simplicity of manipulation with reagents, and elimination of solid phase interferences or separation steps. Significant differences in the molecular masses of the free and antibody bound BNP results in a substantial ( approximately 2.5-times) increase in the diffusion rates. Determination of the binding constants and inhibition effects by measuring the diffusion rates of the ligand at the single molecule level introduces the ultimate opportunity for researching systems where the fluorescence intensity and/or fluorescence anisotropy do not change upon interaction of the ligand with the protein. Monoclonal antibodies 106.3 and BC203 demonstrate high affinities to BNP and bind two distant epitopes forming robust antibody sandwiches. Both antibodies are used in Abbott diagnostic assays on AxSYM, IMx, and Architect platforms.

Quantification of sodium dodecyl sulfate in microliter biochemical samples by gas chromatography.

A novel gas chromatography (GC) method has been developed to accurately quantitate sodium dodecyl sulfate (SDS) in aqueous biochemical samples. This method is based on the quantitative conversion of SDS to 1-dodecanol in the GC injection port at elevated temperature, and the thermal degradation product 1-dodecanol was analyzed to determine SDS concentration. It was found that the addition of guanidinium chloride (GnHCl) to SDS samples (via direct dilution with GnHCl/MeOH solution) is necessary to ensure accurate quantitation. The presence of GnHCl enables quantitative conversion of SDS to 1-dodecanol, improves sensitivity, and virtually eliminates interference from proteins and other chemicals commonly present in biochemical samples. The method features direct analysis of diluted SDS samples, is free from interference, and is capable of quantifying less than 1 ng SDS in biochemical samples. It is also suitable for samples with limited volume, with as little as 1 microl sample being sufficient for quantitation.