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Biomedical subjects

Charles R Yates

Publications and source records attributed to Charles R Yates.

11 recordsLinked to original sources
PubMed2006

Status of PharmD/PhD programs in colleges of pharmacy: the University of Tennessee dual PharmD/PhD program.

OBJECTIVES: To describe the University of Tennessee PharmD/PhD program and assess the prevalence and characteristics of PharmD/PhD programs in the United States. METHODS: Survey instruments were mailed in May 2004 to UT dual-degree program participants and deans of US colleges and schools of pharmacy. RESULTS: University of Tennessee PharmD/PhD students completed more than 30 hours of graduate credit before obtaining their PharmD and 72.2% agreed or strongly agreed that the program met their professional goals. More than 40% of US pharmacy colleges and schools have or plan to have PharmD/PhD programs. A wide variation exists in the level of integration, PhD concentrations offered, entrance requirements, and student benefits. Most schools with PharmD/PhD programs had few students enrolled in the program, but attrition rates were low (<20%) for 69% of the schools. CONCLUSIONS: Dual-degree programs attract and retain pharmacy students in research programs and 47.6% of graduates entered academia and industry.

Curriculum↗
PubMed2006

Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury.

The genetic basis of acute lung injury (ALI) is poorly understood. The myosin light chain kinase (MYLK) gene encodes the nonmuscle myosin light chain kinase isoform, a multifunctional protein involved in the inflammatory response (apoptosis, vascular permeability, leukocyte diapedesis). To examine MYLK as a novel candidate gene in sepsis-associated ALI, we sequenced exons, exon-intron boundaries, and 2 kb of 5' UTR of the MYLK, which revealed 51 single-nucleotide polymorphisms (SNPs). Potential association of 28 MYLK SNPs with sepsis-associated ALI were evaluated in a case-control sample of 288 European American subjects (EAs) with sepsis alone, subjects with sepsis-associated ALI, or healthy control subjects, and a sample population of 158 African American subjects (AAs) with sepsis and ALI. Significant single locus associations in EAs were observed between four MYLK SNPs and the sepsis phenotype (P<0.001), with an additional SNP associated with the ALI phenotype (P=0.03). A significant association of a single SNP (identical to the SNP identified in EAs) was observed in AAs with sepsis (P=0.002) and with ALI (P=0.01). Three sepsis risk-conferring haplotypes in EAs were defined downstream of start codon of smooth muscle MYLK isoform, a region containing putative regulatory elements (P<0.001). In contrast, multiple haplotypic analyses revealed an ALI-specific, risk-conferring haplotype at 5' of the MYLK gene in both European and African Americans and an additional 3' region haplotype only in African Americans. These data strongly implicate MYLK genetic variants to confer increased risk of sepsis and sepsis-associated ALI.

Adolescent↗
PubMed2004

Real-time PCR-based genotyping assay for CXCR2 polymorphisms.

BACKGROUND: The human chemokine receptor CXCR2 (IL8RB) is a high affinity receptor for interleukin-8 as well as other CXC chemokines, and is involved in the chemotaxis of immune cells. Genetic variants of CXCR2 have potential relevance in various inflammatory human disorders. We developed a real-time polymerase chain reaction (PCR)-based allelic discrimination assay for the detection of the CXCR2 single nucleotide polymorphisms (SNPs) C785T, T1208C and G1440A. METHODS: Polymorphisms were delineated using PCR amplification of specific alleles (PASA). Allele-specific primers were developed for both wild-type and mutant alleles. An additional nucleotide mismatch at the third position from the 3' end of each primer was used to improve amplification specificity and to prevent generation of nonspecific products. Genotypes were assigned based on PCR growth curves and melt curve analysis performed on a SmartCycler using SYBR Green I chemistry. RESULTS: Genotyping assignments were successfully performed in a set of 20 human DNA samples, and were validated by comparison with results from direct DNA sequencing and agarose gel electrophoresis of PCR products. CONCLUSIONS: Due to its rapid and relatively inexpensive performance and accuracy, the presented allelic discrimination assay for CXCR2 polymorphisms has wide applicability, especially for high-throughput sample analysis in large population genotyping studies.

Black or African American↗
PubMed2004

Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS.

Dysregulated systemic inflammation with excess activation of pro-inflammatory transcription factor nuclear factor-kappaB (NF-kappaB)-activated by inflammatory signals-compared to the anti-inflammatory transcription factor glucocorticoid receptor-alpha (GRalpha)-activated by endogenous or exogenous glucocorticoids (GCs)-is an important pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with acute respiratory distress syndrome (ARDS). Activation of one transcription factor in excess of the binding (inhibitory) capacity of the other shifts cellular responses toward increased (dysregulated) or decreased (regulated) transcription of inflammatory mediators over time. Recent data indicate that failure to improve in ARDS (unresolving ARDS) is frequently associated with failure of the activated GRs to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol, a condition defined as systemic inflammation-associated acquired GC resistance; it is potentially reversible with prolonged GC supplementation. In the first part of this paper, after a brief description of inflammation in ARDS and our model of translational research, we review the two cellular signaling pathways that are central to the regulation of inflammation-the stimulatory NF-alphaB and the inhibitory GRalpha. In the second part, we review findings of recent studies indicating that excessive inflammatory activity in patients with unresolving ARDS may induce noncompensated GC resistance in target organs. In the third part, we review factors affecting cellular response to GC and potential mechanisms involved in inflammation-associated GC resistance.

Biomarkers↗
PubMed2003

Structural determinants of P-glycoprotein-mediated transport of glucocorticoids.

PURPOSE: The aim of this study was to determine requisite structural features for P-glycoprotein-mediated transport of a series of structurally related glucocorticoids (GCs). METHODS: Transport experiments were conducted in wild-type and stably transfected MDRI LLC-PK cell line. Transport efficiency (Teff = Peff, B-->A / Peff, A-->B) in both cell lines was compared as a measure of passive diffusion and P-glycoprotein-mediated transepithelial transport for each steroid. Three-dimensional structure-activity relationships were built to determine how specific structural features within the steroids affect their P-gp-mediated efflux. RESULTS: Mean (+/- SD) Teff in LLC-PK cells was 1.1 +/- 0.17, indicating that differences in structure and partition coefficient did not affect drug flux in the absence of P-glycoprotein. Teff in L-MDRI cells ranged from 3.6 to 26.6, demonstrating the importance of glucocorticoid structure to P-glycoprotein transport. The rank order of Teff in MDR1 cells was: methylprednisolone> prednisolone > betamethasone > dexamethasone/prednisone > cortisol. There was no correlation between individual Teff values and partition coefficient. 3D-QSAR models were built using CoMFA and CoMSIA with a q2 (r2) of 0.48 (0.99) and 0.41 (0.95), respectively. CONCLUSIONS: Nonpolar bulky substituents around the C-6alpha position, as well as a hydrogen-bond donor at position C-11, enhance P-glycoprotein affinity and cellular efflux, whereas bulky substituents at C-16 diminish transporter affinity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients.

Variability in CYP3A (CYP3A4/5) and P-glycoprotein (human MDR1 gene product) activity underlies interindividual differences in oral cyclosporine (CsA) bioavailability. Racial differences in polymorphic expression of CYP3A5 and MDR1 may explain observed interracial variability in oral bioavailability. Our objective was to evaluate the effect of CYP3A5 and MDR1 polymorphic expression on CsA oral disposition. Steady-state plasma concentration profiles (n = 19) were sampled in renal transplant recipients receiving concentration-adjusted CsA maintenance therapy. CsA plasma concentrations were measured by fluorescence polarization immunoassay. CYP3A5 and MDR1 genotypes were determined by real-time polymerase chain reaction. Noncompartmental pharmacokinetic analysis and nonlinear mixed-effects modeling (NONMEM) were performed to assess the effect of genotype on CsA pharmacokinetics. MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. CsA oral clearance was significantly higher in subjects who carried at least one 3435T allele compared to homozygous wild-type individuals (40.0 +/- 2.2 vs. 26.4 +/- 3.1 L/h, p = 0.007). MDR1 C3435T genotype accounted for 43% of the interindividual variability of CsA oral clearance in the study population after accounting for interoccasion variability. The authors were unable to independently assess whether CYP3A5 correlated with any CsA pharmacokinetic parameter since all CYP3A5 nonexpressors were also 3435T allele carriers. MDR1 3435T allele carriers have enhanced oral clearance compared to individuals with the CC genotype. The frequency of the 3435T allele is lower in African Americans compared to Caucasians. Thus, the MDR1 C3435T genotype offers a potential mechanistic basis to explain interracial differences in CsA oral bioavailability. Further studies are needed to explore the relationship between CYP3A5 and MDR1 genotype and phenotype.

Adult↗
PubMed2002

Clinical pharmacokinetics of 5-aminolevulinic acid in healthy volunteers and patients at high risk for recurrent bladder cancer.

5-Aminolevulinic acid (ALA) is a precursor of protoporphyrin IX (PpIX) that is being evaluated for use in photodiagnosis and phototherapy of malignant and nonmalignant disorders. Previous clinical studies using topical, oral, and intravesical administration have been conducted in attempts to determine the optimal route of administration for ALA. The purpose of these studies was to examine the systemic pharmacokinetics and elimination of ALA, the bioavailability of ALA after oral and intravesical doses, and the factors that affect ALA concentrations in the bladder during intravesical treatment. The disposition of ALA was evaluated in six healthy volunteers receiving single intravenous and oral doses (100 mg) and eight patients at high risk for recurrent bladder cancer receiving an intravesical dose (1.328 g) of ALA. The mean (+/-S.D.) plasma area under the plasma concentration-time curve from time 0 to infinity of PpIX (0.20 +/- 0.11 microg small middle dot h/ml) after intravenous administration of ALA was not significantly different from that observed after oral administration of ALA (0.15 +/- 0.11 microg*h/ml; P = 0.49). ALA terminal half-life was approximately 45 min after intravenous or oral administration. The oral bioavailability of ALA was approximately 60%. After intravesical administration, urine production was largely responsible for decreases in ALA concentration in the bladder, with less than 1% being absorbed into the systemic circulation. In summary, oral and intravenous administration of ALA at these doses results in modest plasma levels of PpIX. Regional administration (i.e., intravesical) of ALA resulted in a significant pharmacokinetic advantage, with urinary bladder being exposed to concentrations approximately 20,000-fold higher than systemic circulation.

Administration, Intravesical↗
PubMed2002

Detection of MDR1 single nucleotide polymorphisms C3435T and G2677T using real-time polymerase chain reaction: MDR1 single nucleotide polymorphism genotyping assay.

The objective of this study was to develop a real-time polymerase chain reaction (PCR) method to detect MDR1 (human multidrug resistance gene) single nucleotide polymorphisms (SNPs) C3435T and G2677T. C3435T and G2677T are linked to MDR1*2, which is associated with enhanced efflux activity in vitro. Using the Smart Cycler, an allele-specific real-time PCR-based genotyping method was developed to detect C3435T and G2677T. The MDR1 genotype of human genomic DNA templates was determined by direct DNA sequencing. PCR reactions for genotyping C3435T and G2677T by using allele-specific primers were conducted in separate tubes. An additional nucleotide mismatch at the third position from the 3' end of each allele-specific primer was used to abrogate nonspecific PCR amplification. The fluorescence emitted by SYBR Green I was monitored to detect formation of specific PCR products. PCR growth curves exceeding the threshold cycle were considered positive. Fluorescence melt-curve analysis was used to corroborate results from PCR growth curves. Using PCR growth curves, our assay accurately determined hetero- and homozygosity for C3435T and G2677T. Genotype assignments based on PCR growth curve, melt-curve analysis, agarose gel electrophoresis, and direct DNA sequencing results of PCR products were in perfect agreement. We have developed a rapid MDR1 genotyping method that can be used to assess the contribution of MDR1*2 to pharmacokinetic and pharmacodynamic variability of P-glycoprotein substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗