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1.
Eur J Med Chem ; 191: 112118, 2020 Apr 01.
Article in English | MEDLINE | ID: mdl-32113126

ABSTRACT

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Cytoskeletal Proteins/antagonists & inhibitors , Drug Discovery , NIMA-Related Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cytoskeletal Proteins/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , K562 Cells , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/metabolism , Liver Neoplasms, Experimental/pathology , Mice , Mice, SCID , Molecular Docking Simulation , Molecular Structure , NIMA-Related Kinases/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Tissue Distribution
2.
Bioanalysis ; 5(4): 423-35, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23414376

ABSTRACT

BACKGROUND: To develop and validate an ultrasensitive bioanalytical assay for quantitation of fluticasone propionate in human plasma, aliquots of 0.6 ml of K(3)EDTA human plasma were treated with zinc sulfate solution and loaded onto a preconditioned SPE plate. The sample solutions were washed, eluted, dried and reconstituted. The extracted sample was injected onto a LC-MS/MS system and separated by a reverse-phase HPLC column with a 5 min gradient program, and detected by MS/MS for fluticasone propionate quantitation. RESULTS: Linearity was from 1 to 200 pg/ml. The intra- and inter-day accuracy and precision of the assay met validation acceptance criteria. Various stabilities were established and interference drug assessment was evaluated. The assay has been used for clinical studies. CONCLUSION: This ultrasensitive method has been successfully validated using LC-MS/MS for determination of fluticasone propionate in human plasma at low pg/ml level.


Subject(s)
Androstadienes/blood , Chromatography, Liquid/methods , Solid Phase Extraction/methods , Tandem Mass Spectrometry/methods , Fluticasone , Humans , Reproducibility of Results
3.
J Chem Phys ; 132(15): 155101, 2010 Apr 21.
Article in English | MEDLINE | ID: mdl-20423198

ABSTRACT

The study of fluctuations in gene regulatory networks is extended to the case of Gaussian colored noise. First, the solution of the corresponding Langevin equation with colored noise is expressed in terms of an Ito integral. Then, two important lemmas concerning the variance of an Ito integral and the covariance of two Ito integrals are shown. Based on the lemmas, we give the general formulas for the variances and covariance of molecular concentrations for a regulatory network near a stable equilibrium explicitly. Two examples, the gene autoregulatory network and the toggle switch, are presented in details. In general, it is found that the finite correlation time of noise reduces the fluctuations and enhances the correlation between the fluctuations of the molecular components.


Subject(s)
Models, Genetic , Stochastic Processes
4.
Am J Ther ; 14(3): 280-90, 2007.
Article in English | MEDLINE | ID: mdl-17515705

ABSTRACT

The in vitro metabolism of ciclesonide, a novel inhaled nonhalogenated glucocorticoid for the treatment of asthma, was compared in cryopreserved hepatocytes from mice, rats, rabbits, dogs, and humans. Incubations of C-ciclesonide with individual hepatocyte suspensions revealed similar metabolite profiles in all 5 in vitro systems used. Ciclesonide was rapidly converted to its active metabolite, desisobutyryl-ciclesonide (des-CIC). Des-CIC was then extensively metabolized to pharmacologically inactive metabolites through oxidation and reduction, followed by glucuronidation. A total of 12 groups of metabolites derived from des-CIC were characterized and identified by liquid chromatography/radioactivity monitor/mass spectrometry. Oxidation occurred on both the cyclohexane ring and the steroid moiety. Hippuric acid formation by cleavage of the cyclohexylmethyl moiety of ciclesonide, followed by aromatization of the cyclohexane ring through multiple steps of hydroxylation, dehydration, and conjugation with glycine, was found in rat, rabbit, and human hepatocyte incubations. The results indicated that ciclesonide and its active metabolite, des-CIC, were extensively metabolized in vitro in animal and human hepatocytes and that the metabolite profiles in mouse, rat, rabbit, and dog hepatocytes were similar to the profiles in human hepatocytes.


Subject(s)
Anti-Allergic Agents/metabolism , Hepatocytes/metabolism , Pregnenediones/metabolism , Animals , Dogs , Humans , In Vitro Techniques , Male , Mice , Mice, Inbred ICR , Rabbits , Rats , Rats, Sprague-Dawley , Species Specificity
5.
J Chem Phys ; 126(13): 134907, 2007 Apr 07.
Article in English | MEDLINE | ID: mdl-17430067

ABSTRACT

Based on the master equation with the inherent structure of conformation network, the authors investigate some important issues in the folding kinetics of lattice polymers. First, the topologies of conformation networks are discussed. Moreover, a new scheme of implementing Metropolis algorithm, which fulfills the condition of detailed balance, is proposed. Then, upon incorporating this new scheme into the geometric structure of conformation network the authors provide a theorem which can be used to place an upper bound on relaxation time. To effectively identify the kinetic traps of folding, the authors also introduce a new quantity, which is employed from the continuous time Monte Carlo method, called rigidity factor. Throughout the discussions, the authors analyze the results for different move sets to demonstrate the methods and to study the features of the kinetics of folding.


Subject(s)
Chemistry, Physical/methods , Polymers/chemistry , Algorithms , Kinetics , Models, Chemical , Models, Statistical , Models, Theoretical , Molecular Conformation , Monte Carlo Method , Protein Conformation , Protein Folding , Temperature , Thermodynamics , Time Factors
6.
Int J Neural Syst ; 17(1): 53-60, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17393563

ABSTRACT

The main purpose of this paper is to investigate the case that neurons can not be considered as individuals in the system, so they need to be treated as a continuum. In this paper, we have proved that if the interconnection of neural field is symmetric, then every trajectory of the system converges to an equilibrium. For the case that the interconnection is asymmetric, we give a sufficient condition which can guarantee that the equilibria of the neural field is unique and it also a global attractor.


Subject(s)
Models, Neurological , Neural Networks, Computer , Neural Pathways/physiology , Neurons/physiology , Algorithms , Nonlinear Dynamics
7.
IEEE Trans Neural Netw ; 17(6): 1639-41, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17131677

ABSTRACT

A new continuum model complementary to traditional cellular neural networks is introduced in this note. We consider a cellular neural field formed by infinitely many cellular neurons and modelled by an integrodifferential equation. Then, using LaSalle's invariance principle on Banach space, we show that the field quantity will asymptotically converge to an equilibrium state under the condition that all equilibria of the system are isolated. From the practical sense, the convergence indicates the essential capability of retrieving message from original raw data.


Subject(s)
Algorithms , Information Storage and Retrieval/methods , Neural Networks, Computer , Pattern Recognition, Automated/methods , Signal Processing, Computer-Assisted
8.
Am J Ther ; 13(6): 490-501, 2006.
Article in English | MEDLINE | ID: mdl-17122529

ABSTRACT

The pharmacokinetics, metabolism, and excretion of ciclesonide, a novel and effective inhaled glucocorticoid for the treatment of asthma, were investigated after intravenous and oral administration of 14C-ciclesonide in the mouse, rat, rabbit, and dog. The pharmacokinetics of ciclesonide in all animal species were characterized by a low oral bioavailability (approximately 6% or less), a high clearance, and a large volume of distribution. The apparent terminal half-life of ciclesonide was short; the apparent terminal half-life of the active desisobutyryl-ciclesonide metabolite (des-CIC or M1) was longer and ranged from 2.4 to 6.9 hours in the 4 species. Metabolites derived from ciclesonide in serum (or plasma) and excreta samples from the 4 animal species were profiled and identified by LC/RAM/MS (liquid chromatography/radioactivity monitor/mass spectrometry). Ciclesonide was extensively metabolized to yield des-CIC, which was further metabolized to primarily yield hippuric acid and hydroxylated metabolites, namely, isomers of cyclohexane-monohydroxylated des-CIC and B-ring-monohydroxylated des-CIC. Greater than 90% of intravenous and oral 14C-ciclesonide doses were recovered in all species; the main elimination route was fecal/biliary. A comparison of in vitro and in vivo metabolite profiles between mice, rats, rabbits, and dogs with those from humans indicated that metabolic pathways for ciclesonide were qualitatively similar in humans and in the 4 animal species.


Subject(s)
Anti-Asthmatic Agents/pharmacokinetics , Pregnenediones/pharmacokinetics , Administration, Oral , Animals , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/blood , Anti-Asthmatic Agents/urine , Area Under Curve , Biological Availability , Biotransformation , Chromatography, Liquid , Dogs , Feces/chemistry , Female , Half-Life , Humans , Injections, Intravenous , Male , Metabolic Clearance Rate , Mice , Pregnenediones/administration & dosage , Pregnenediones/blood , Pregnenediones/urine , Rabbits , Rats , Rats, Wistar , Tandem Mass Spectrometry
9.
Rapid Commun Mass Spectrom ; 20(19): 2969-72, 2006.
Article in English | MEDLINE | ID: mdl-16952212

ABSTRACT

Some compounds readily form [M+46]+ adduct ions during positive ion electrospray ionization mass spectrometry ((+)ESI-MS) analysis. These [M+46]+ ions were characterized as [M+CH3CH2NH2+H]+ by accurate mass determination. Ethylamine involved in the adduct was proposed to be the reduction product of acetonitrile and this was confirmed using deuterated acetonitrile. Other nitrile-containing compounds tested, including isobutyronitrile and benzonitrile, also formed the adduct ions of the respective amine forms under (+)ESI-MS conditions. Hydrogen/deuterium exchange experiments demonstrated that the reductive hydrogen originated from water. Reduction of nitriles (R-CN) to their respective amines (R-CH2NH2) under (+)ESI-MS conditions expands the ability to identify nitrile-containing chemical unknowns.


Subject(s)
Amines/chemistry , Nitriles/chemistry , Spectrometry, Mass, Electrospray Ionization/methods , Acetonitriles/chemistry , Deuterium/chemistry , Ethylamines/chemistry , Isotope Labeling , Oxidation-Reduction
10.
J Agric Food Chem ; 52(7): 2108-18, 2004 Apr 07.
Article in English | MEDLINE | ID: mdl-15053560

ABSTRACT

Atlantic salmon (approximately 1.3 kg) maintained in tanks of seawater at 5 +/- 1 degrees C were dosed with [3H]emamectin B1 benzoate in feed at a nominal rate of 50 microg of emamectin benzoate/kg/day for 7 consecutive days. Tissues, blood, and bile were collected from 10 fish each at 3 and 12 h and at 1, 3, 7, 15, 30, 45, 60, and 90 days post final dose. Feces were collected daily from the tanks beginning just prior to dosing to 90 days post final dose. The total radioactive residues (TRR) of the daily feces samples during dosing were 0.25 ppm maximal, and >97% of the TRR in pooled feces covering the dosing period was emamectin B1a. Feces TRR then rapidly declined to approximately 0.05 ppm by 1 day post final dose. The ranges of mean TRR for tissues over the 90 days post dose period were as follows: kidney, 1.4-3 ppm; liver, 1.0-2.3 ppm; skin, 0.04-0.09 ppm; muscle, 0.02-0.06 ppm; and bone, <0.01 ppm. The residue components of liver, kidney, muscle, and skin samples pooled by post dose interval were emamectin B1a (81-100% TRR) and desmethylemamectin B1a (0-17% TRR) with N-formylemamectin B1a seen in trace amounts (<2%) in some muscle samples. The marker residue selected for regulatory surveillance of emamectin residues was emamectin B1a. The emamectin B1a level was quantified in individual samples of skin and muscle using HPLC-fluorometry and was below 85 ppb in all samples analyzed (3 h to 30 days post dose).


Subject(s)
Drug Residues/pharmacokinetics , Ivermectin/analogs & derivatives , Ivermectin/administration & dosage , Ivermectin/pharmacokinetics , Salmo salar/metabolism , Animals , Drug Residues/analysis , Feces/chemistry , Intestines/chemistry , Kinetics , Tissue Distribution , Tritium
11.
Clin Imaging ; 28(1): 69-76, 2004.
Article in English | MEDLINE | ID: mdl-14996453

ABSTRACT

The purpose of the study is to correlate the sonographic signs of rotator cuff tears (RCTs) with surgical findings, with emphasis on partial-thickness tear. We prospectively performed ultrasonography (US) on 50 patients with suspected RCTs and comparison with operative findings. Six US signs, which included "nonvisualization", "focal depression", "focal thinning", "focal hypoechoic cleft", "floating bright spots" and "focal heterogeneous hypoechogenicity" in rotator cuffs (RCs), were emphasized, but only "focal heterogeneous hypoechogenicity" favored partial-thickness tear (10/14, 71%). All the other five signs, including "floating bright spots" (not pointed out in literatures), were suggestive of full-thickness tear. The overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy for US to detect RCTs were 95%, 90%, 97%, 82% and 94%, respectively. US is effective to detect RCTs and differentiate full- from partial-thickness tear.


Subject(s)
Rotator Cuff Injuries , Rotator Cuff/diagnostic imaging , Tendon Injuries/diagnostic imaging , Tendon Injuries/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Rotator Cuff/pathology , Rotator Cuff/surgery , Sensitivity and Specificity , Statistics as Topic , Tendon Injuries/pathology , Ultrasonography
12.
J Agric Food Chem ; 51(26): 7555-9, 2003 Dec 17.
Article in English | MEDLINE | ID: mdl-14664506

ABSTRACT

An accurate, reliable, and reproducible assay was developed and validated to determine flunixin in bovine liver, kidney, muscle, and fat. The overall recovery and percent coefficient of variation (%CV) of twenty-eight determinations in each tissue for flunixin free acid were 85.9% (5.9% CV) for liver, 94.6% (9.9% CV) for kidney, 87.4% (4.7% CV) for muscle, and 87.6% (4.4% CV) for fat. The theoretical limit of detection was 0.1 microg/kg (ppb, ng/g) for liver and kidney, and 0.2 ppb for muscle and fat. The theoretical limit of quantitation was 0.3, 0.2, 0.6, and 0.4 ppb for liver, kidney, muscle, and fat, respectively. The validated lower limit of quantitation was 1 ppb for edible tissues with the upper limit of 400 ppb for liver and kidney, 100 ppb for fat, and 40 ppb for muscle. Accuracy, precision, linearity, specificity, ruggedness, and storage stability were demonstrated. Briefly, the method involves an initial acid hydrolysis, followed by pH adjustment ( approximately 9.5) and partitioning with ethyl acetate. A portion of the ethyl acetate extract was purified by solid-phase extraction using a strong cation exchange cartridge. The eluate was then evaporated to dryness, reconstituted, and analyzed using LC/MS/MS. The validated method is sensitive and specific for flunixin in edible bovine tissue.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/analysis , Chromatography, High Pressure Liquid/methods , Clonixin/analogs & derivatives , Clonixin/analysis , Food Contamination/analysis , Mass Spectrometry/methods , Meat/analysis , Adipose Tissue/chemistry , Animals , Cattle , Drug Stability , Kidney/chemistry , Liver/chemistry , Muscle, Skeletal/chemistry , Reproducibility of Results , Sensitivity and Specificity
13.
J Agric Food Chem ; 51(13): 3753-9, 2003 Jun 18.
Article in English | MEDLINE | ID: mdl-12797739

ABSTRACT

A method was developed and validated to determine 5-hydroxyflunixin in raw bovine milk using liquid chromatography tandem mass spectrometry (LC/MS/MS). The mean recovery and percentage coefficient of variation (%CV) of 35 determinations for 5-hydroxyflunixin was 101% (5% CV). The theoretical limit of detection was 0.2 ppb with a validated lower limit of quantitation of 1 ppb and an upper limit of 150 ppb. Accuracy, precision, linearity, specificity, ruggedness, and storage stability were demonstrated. A LC/MS/MS confirmatory method using the extraction steps of the determinative method was developed and validated for 5-hydroxyflunixin in milk from cattle. Briefly, the determinative and confirmatory methods were based on an initial solvent (acetone/ethyl acetate) precipitation/extraction of acidified whole milk. The solvent precipitation/extraction effectively removed incurred ((14)C) residues from milk samples. The organic extract was then purified by solid phase extraction (SPE) using a strong cation exchange cartridge (sulfonic acid). The final SPE-purified sample was analyzed using LC/MS/MS. The methods are rapid, sensitive, and selective and provide for the determination and confirmation of 5-hydroxyflunixin at the 1 and 2 ppb levels, respectively.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/analysis , Chromatography, High Pressure Liquid/methods , Clonixin/analogs & derivatives , Clonixin/analysis , Drug Residues/analysis , Mass Spectrometry/methods , Milk/chemistry , Animals , Cattle , Drug Stability , Female , Hydroxylation , Quality Control , Sensitivity and Specificity
14.
J Ultrasound Med ; 21(3): 289-95; quiz 296-7, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11883540

ABSTRACT

OBJECTIVE: To use color Doppler ultrasonography to evaluate the morphology and vascularity of calcific tendonitis and to predict the formative and resorptive phases of the calcification. METHODS: Ninety-four patients with shoulder calcification on plain radiographs were enrolled in this study. Ultrasonography of the shoulder was focused on the rotator cuff. Color Doppler ultrasonography was applied in the calcific region. Patient symptoms were graded as painless, mild, moderate, and severe. The calcific plaques were classified as arc-shaped, fragmented or punctate, nodular, and cystic types. Color Doppler ultrasonographic signals were graded 0 to 3. The formative and resorptive phases of calcification were categorized by patient symptoms; acute onset of moderate or severe pain indicated the resorptive phase. RESULTS: The calcific plaques appeared arc shaped in 59 patients (20 painless, 19 mild, and 20 moderate), fragmented or punctate in 27 (2 painless, 3 mild, 20 moderate, and 2 severe), nodular in 6 (1 moderate and 5 severe), and cystic in 2 (severe). There was a significant difference between the morphology of the calcific plaques and clinical symptoms (P < .01). On color Doppler ultrasonography, grade 0 signals were found in 28 patients (22 painless and 6 with mild pain); grade 1 in 18 (16 mild and 2 severe); grade 2 in 41 (all moderate); and grade 3 in 7 (all severe). The correspondence between color Doppler ultrasonographic findings and clinical symptoms was excellent (P < .01). CONCLUSIONS: High-resolution ultrasonography with color Doppler imaging could differentiate the formative and resorptive phases of the calcification and could be used as a follow-up modality in calcific tendonitis of the shoulder.


Subject(s)
Calcinosis/diagnostic imaging , Rotator Cuff , Tendinopathy/diagnostic imaging , Ultrasonography, Doppler, Color , Female , Humans , Male , Middle Aged , Shoulder Pain/diagnosis
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