Pharmacokinetic-Pharmacodynamic Modeling: Time-Dependent Protein Binding—An Alternative Interpretation of Clockwise and Counterclockwise Hysteresis

1992 ◽  
Vol 81 (3) ◽  
pp. 232-236 ◽  
Author(s):  
Jose Luis Pedraz ◽  
Begona Calvo ◽  
Jacquelyn A. Smithers ◽  
Gary A. Thompson
Keyword(s):  
Protein Binding ◽  
Alternative Interpretation ◽  
Time Dependent ◽  
Pharmacodynamic Modeling ◽  
Dependent Protein

scholarly journals Single-Nucleotide Polymorphisms Sequencing Identifies Candidate Functional Variants at Prostate Cancer Risk Loci

Genes ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 547 ◽  
Author(s):  
Peng Zhang ◽  
Lori S. Tillmans ◽  
Stephen N. Thibodeau ◽  
Liang Wang
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Single Nucleotide Polymorphisms ◽  
Protein Binding ◽  
Prostate Cancer Risk ◽  
Sequencing Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Functional Variants ◽  
Dependent Protein

Genome-wide association studies have identified over 150 risk loci that increase prostate cancer risk. However, few causal variants and their regulatory mechanisms have been characterized. In this study, we utilized our previously developed single-nucleotide polymorphisms sequencing (SNPs-seq) technology to test allele-dependent protein binding at 903 SNP sites covering 28 genomic regions. All selected SNPs have shown significant cis-association with at least one nearby gene. After preparing nuclear extract using LNCaP cell line, we first mixed the extract with dsDNA oligo pool for protein–DNA binding incubation. We then performed sequencing analysis on protein-bound oligos. SNPs-seq analysis showed protein-binding differences (>1.5-fold) between reference and variant alleles in 380 (42%) of 903 SNPs with androgen treatment and 403 (45%) of 903 SNPs without treatment. From these significant SNPs, we performed a database search and further narrowed down to 74 promising SNPs. To validate this initial finding, we performed electrophoretic mobility shift assay in two SNPs (rs12246440 and rs7077275) at CTBP2 locus and one SNP (rs113082846) at NCOA4 locus. This analysis showed that all three SNPs demonstrated allele-dependent protein-binding differences that were consistent with the SNPs-seq. Finally, clinical association analysis of the two candidate genes showed that CTBP2 was upregulated, while NCOA4 was downregulated in prostate cancer (p < 0.02). Lower expression of CTBP2 was associated with poor recurrence-free survival in prostate cancer. Utilizing our experimental data along with bioinformatic tools provides a strategy for identifying candidate functional elements at prostate cancer susceptibility loci to help guide subsequent laboratory studies.

Abstract 391: Sterol Efflux Function and Protein Composition of HDL Associates With Recovery From Stroke

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Deanna Plubell ◽  
Alexandra Fenton ◽  
Clark Wayne ◽  
Neil A Zakai ◽  
Joseph F Quinn ◽  
...  
Keyword(s):  
Stroke Risk ◽  
Protein Composition ◽  
Hdl Cholesterol ◽  
Time Dependent ◽  
Stroke Recovery ◽  
Control Group ◽  
Post Stroke ◽  
Dependent Protein ◽  
Meta Analyses ◽  
The Relationship

Background: Prospective cohort studies and meta-analyses examining the relationship between HDL-cholesterol (C) and stroke are discordant and question the value of HDL-C as a marker for stroke risk prediction. Other properties of HDL-C such as cholesterol efflux capacity (CEC) and proteome, are less studied. Methods: We investigated the changes in HDL CEC and proteome to determine if they are associated with improved stroke recovery. Plasma from age- and lipid profile-matched healthy controls (N = 35) and stroke patients were collected at 24 (early, N = 35) and 96 hour (late, N = 20) post stroke, and analyzed with three independent assays to measure macrophage-mediated, ABCA1 and ABCG1-specific sterol efflux, and HDL proteome. Stroke recovery was assessed at 3 months using the Modified Rankin Scores (MRS) and the NIH Stroke Scale (NIHSS). Results: Both macrophage- and ABCG1-mediated CEC were reduced by 50% ( P <0.0001) and 20% ( P <0.038) in early and late post stroke samples, respectively, compared to the control group. Patients who had comparable or increased CEC between the two-time points exhibited lower NIHSS and MRS indicating better recovery. Proteomic analysis of HDL indicated a distinct time-dependent remodeling post stroke. Coagulation complement cascade proteins (FGB, FGA, A2M, C3) significantly increased (FDR>0.01) early and returned to control levels later, inflammation proteins (SAA1, SAA2, PON1, C4B) increased early and continued to increase. Interestingly, platelet adhesion proteins (DSG1, JUP, ITGB1, ITGA2, TUBB, DNAH3, PF4) were abundantly present in only later samples. Conclusion: 1) patients who maintain or improve HDL CEC post stroke exhibit better recovery scores, 2) post stroke HDL proteome remodeling is dynamic with distinct time-dependent protein signatures that may associate with stroke recovery.

scholarly journals Population Pharmacokinetic and Pharmacodynamic Modeling of Acetazolamide in Peritoneal Dialysis Patients and Healthy Volunteers

2013 ◽  
Vol 16 (1) ◽  
pp. 89 ◽  
Author(s):  
Corinne Seng Yue ◽  
Huu Hung Huynh ◽  
Catherine Raymond ◽  
Louise Charbonneau ◽  
Louise Roy
Keyword(s):  
Peritoneal Dialysis ◽  
Protein Binding ◽  
Free Fraction ◽  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic ◽  
Dialysis Patients ◽  
Elimination Half ◽  
Ocular Pressure ◽  
Total Body ◽  
Body Clearance

Purpose. To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). Methods. Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected. Results. As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4±1.4 vs 7.4±2.8 mmHg. Conclusion. Both PK and PD are significantly altered in dialysis patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Apparent Valproic Acid Neurotoxicity in a Hypoalbuminemic Patient

1993 ◽  
Vol 27 (1) ◽  
pp. 32-35 ◽  
Author(s):  
Barry E. Gidal ◽  
D. Michael Collins ◽  
Brad R. Beinlich
Keyword(s):  
Valproic Acid ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Plasma Concentrations ◽  
Free Fraction ◽  
Laboratory Evaluation ◽  
Neurologic Symptoms ◽  
Drug Concentrations ◽  
Dependent Protein

OBJECTIVE: To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations. CASE SUMMARY: A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 μg/mL, which was only slightly above the recommended therapeutic range (50–100 μg/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 μg/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction. DISCUSSION: VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed. CONCLUSIONS: It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.

Phenobarbital-dependent protein binding to Barbie box-like sequences in the coding region of cytochrome P450BM-3 gene from Bacillus megaterium

Gene ◽  
1996 ◽  
Vol 183 (1-2) ◽  
pp. 97-101 ◽  
Author(s):  
Elena K. Gaidamakova ◽  
Oleg V. Alpatov ◽  
Igor V. Ischenko ◽  
Sergei P. Kovalenko ◽  
Vyacheslav V. Lyakhovich
Keyword(s):  
Protein Binding ◽  
Bacillus Megaterium ◽  
Coding Region ◽  
Dependent Protein

Time-dependent, protein-directed growth of gold nanoparticles within a single crystal of lysozyme

2011 ◽  
Vol 6 (2) ◽  
pp. 93-97 ◽  
Author(s):  
Hui Wei ◽  
Zidong Wang ◽  
Jiong Zhang ◽  
Stephen House ◽  
Yi-Gui Gao ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Single Crystal ◽  
Time Dependent ◽  
Dependent Protein ◽  
Directed Growth

scholarly journals Activation and phosphorylation of the ‘dense-vesicle’ high-affinity cyclic AMP phosphodiesterase by cyclic AMP-dependent protein kinase

1989 ◽  
Vol 260 (1) ◽  
pp. 27-36 ◽  
Author(s):  
E Kilgour ◽  
N G Anderson ◽  
M D Houslay
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Time Dependent ◽  
Dependent Protein Kinase ◽  
High Affinity ◽  
Catalytic Unit ◽  
Dependent Protein ◽  
Membrane Extract ◽  
Pre Treatment ◽  
Vesicle Cycle

Incubation of a hepatocyte particulate fraction with ATP and the isolated catalytic unit of cyclic AMP-dependent protein kinase (A-kinase) selectively activated the high-affinity ‘dense-vesicle’ cycle AMP phosphodiesterase. Such activation only occurred if the membranes had been pre-treated with Mg2+. Mg2+ pre-treatment appeared to function by stimulating endogenous phosphatases and did not affect phosphodiesterase activity. Using the antiserum DV4, which specifically immunoprecipitated the 51 and 57 kDa components of the ‘dense-vesicle’ phosphodiesterase from a detergent-solubilized membrane extract, we isolated a 32P-labelled phosphoprotein from 32P-labelled hepatocytes. MgCl2 treatment of such labelled membranes removed 32P from the immunoprecipitated protein. Incubation of the Mg2+-pre-treated membranes with [32P]ATP and A-kinase led to the time-dependent incorporation of label into the ‘dense-vesicle’ phosphodiesterase, as detected by specific immunoprecipitation with the antiserum DV4. The time-dependences of phosphodiesterase activation and incorporation of label were similar. It is suggested (i) that phosphorylation of the ‘dense-vesicle’ phosphodiesterase by A-kinase leads to its activation, and that such a process accounts for the ability of glucagon and other hormones, which increase intracellular cyclic AMP concentrations, to activate this enzyme, and (ii) that an as yet unidentified kinase can phosphorylate this enzyme without causing any significant change in enzyme activity but which prevents activation and phosphorylation of the phosphodiesterase by A-kinase.

Morphogenetic disturbances from timed inhibitions of protein synthesis in Fundulus

Development ◽  
1973 ◽  
Vol 29 (2) ◽  
pp. 363-382
Author(s):  
Richard B. Crawford ◽  
Charles E. Wilde ◽  
Murk H. Heinemann ◽  
F. J. Hendler
Keyword(s):  
Protein Synthesis ◽  
Serial Order ◽  
Time Dependent ◽  
Amino Acid Incorporation ◽  
Active Expression ◽  
Dependent Protein ◽  
Early Zygote ◽  
The Times ◽  
Cleavage Failure ◽  
Ribosomal Complex

The reversible inhibition of protein synthesis at the 75–95% level in the early zygote of Fundulus results in a specific series of developmental failures dependent upon the times of inhibitor pulse initiation. The severity of the morphogenetic failure is inversely related to the time of initiation and directly to the length of the pulse. The defects reflect the time dependent serial order of events in morphogenesis. The defects range from failure of cleavage through disorders of blastulation, failure of axiation, anencephaly to microcephaly and are entirely predictable. With the exception of cleavage failure the pattern is identical with that found using pulses of actinomycin D in a similar manner. The agent used was pactamycin, an antibiotic which reversibly inhibits amino acid incorporation into protein by disturbing the assembly of the functional ribosomal complex. The significance of time dependent protein synthesis as an active expression in morphogenesis of similarly time dependent information flow via RNA synthesis is discussed.

Sign in / Sign up

Export Citation Format

Share Document