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1.  Current clinical evidence on pioglitazone pharmacogenomics 
Pioglitazone is the most widely used thiazolidinedione and acts as an insulin-sensitizer through activation of the Peroxisome Proliferator-Activated Receptor-γ (PPARγ). Pioglitazone is approved for use in the management of type 2 diabetes mellitus (T2DM), but its use in other therapeutic areas is increasing due to pleiotropic effects. In this hypothesis article, the current clinical evidence on pioglitazone pharmacogenomics is summarized and related to variability in pioglitazone response. How genetic variation in the human genome affects the pharmacokinetics and pharmacodynamics of pioglitazone was examined. For pharmacodynamic effects, hypoglycemic and anti-atherosclerotic effects, risks of fracture or edema, and the increase in body mass index in response to pioglitazone based on genotype were examined. The genes CYP2C8 and PPARG are the most extensively studied to date and selected polymorphisms contribute to respective variability in pioglitazone pharmacokinetics and pharmacodynamics. We hypothesized that genetic variation in pioglitazone pathway genes contributes meaningfully to the clinically observed variability in drug response. To test the hypothesis that genetic variation in PPARG associates with variability in pioglitazone response, we conducted a meta-analysis to synthesize the currently available data on the PPARG p.Pro12Ala polymorphism. The results showed that PPARG 12Ala carriers had a more favorable change in fasting blood glucose from baseline as compared to patients with the wild-type Pro12Pro genotype (p = 0.018). Unfortunately, findings for many other genes lack replication in independent cohorts to confirm association; further studies are needed. Also, the biological functionality of these polymorphisms is unknown. Based on current evidence, we propose that pharmacogenomics may provide an important tool to individualize pioglitazone therapy and better optimize therapy in patients with T2DM or other conditions for which pioglitazone is being used.
doi:10.3389/fphar.2013.00147
PMCID: PMC3840328  PMID: 24324437
pioglitazone; thiazolidinedione; CYP2C8; cytochrome P450; PPAR; pharmacokinetics; pharmacodynamics
2.  A Preliminary Study on the Effects of Self-Reported Dietary Caffeine on Pain Experience and Postoperative Analgesia 
Journal of Caffeine Research  2012;2(4):159-166.
Background
Caffeine reduces the amount of analgesic medications necessary to provide postoperative pain (POP) relief and augments treatments for headaches and dental pain. Despite considerable evidence of its beneficial effects, little is understood about the role of dietary caffeine consumption on baseline pain sensitivity or POP following oral surgery.
Method
Baseline experimental pain testing (quantitative sensory testing [QST]) using four stimulus modalities was conducted on 30 healthy adults (53% females) before surgical extraction of four third molars. Self-reported caffeine ingestion was reported before QST, and on the day of surgery, preoperative and postoperative caffeine plasma concentrations (CPC) were measured by mass spectrometry. POP ratings were obtained at timed intervals.
Results
In QST, compared to subjects who self-reported no caffeine intake, those who self-reported caffeine ingestion demonstrated a higher pain sensitivity, particularly, on ramp and hold sustained heat at 44°C and 46°C, as well as a lower heat pain threshold and tolerance (p=0.05). Differences approached significance (p=0.06) in POP between subjects with CPC above 300 ng/mL and those with CPC below 300 ng/mL. Specifically, those with >300 ng/mL CPC had a slightly lower POP (mean 2.43, range 0–5) compared to those with <300 ng/mL CPC whose POP ratings were slightly higher (mean 2.89) with a greater variability (range 0–9.5).
Conclusions
Self-reported, dietary caffeine intake was associated with higher QST ratings with lower threshold and tolerance particularly on heat pain modalities. External factors (i.e., analgesic dosage) may have played a role in the analgesic effects of caffeine on POP in oral surgery, especially in individuals with CPC exceeding 300 ng/mL who reported lower pain.
doi:10.1089/jcr.2012.0016
PMCID: PMC3621341
3.  Simplified method for determination of clarithromycin in human plasma using protein precipitation in a 96-well format and liquid chromatography-tandem mass spectrometry 
A simplified method to determine clarithromycin concentrations in human plasma using protein precipitation in a 96-well plate and liquid chromatography tandem mass spectrometry was developed and validated. Plasma proteins were precipitated with acetonitrile and roxithromycin was used as the internal standard. After vortex-mixing and centrifugation, the supernatants were directly injected onto a Phenomenex Luna Phenyl-Hexyl column (50 × 2.0 mm I.D., 3μm). The mobile phase consisted of water and methanol (30:70; v/v) containing 0.1% formic acid and 5 mM ammonium acetate. The flow rate was 0.22 mL/min and the total run time (injection to injection) was less than 3 minutes. Detection of the analytes was achieved using positive ion electrospray tandem mass spectrometry in selected reaction monitoring (SRM) mode. The linear standard curve ranged from 100 to 5,000 ng/mL and the precision and accuracy (inter- and intrarun) were within 8.3% and 6.3%, respectively. The method was successfully used to determine clarithromycin concentrations in human plasma samples obtained from healthy subjects who were given clarithromycin 500 mg for three days. The method is rapid, simple, precise and directly applicable to clarithromycin pharmacokinetic studies.
doi:10.1016/j.jchromb.2008.06.050
PMCID: PMC3832059  PMID: 18639501
clarithromycin; roxithromycin; protein precipitation; LC-MS; human plasma
4.  Effect of Cytochrome P450 3A5 Genotype on Atorvastatin Pharmacokinetics and Its Interaction with Clarithromycin 
Pharmacotherapy  2011;31(10):942-950.
Study Objective
To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin.
Design
Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study.
Setting
Clinical research center at a teaching hospital.
Subjects
Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors).
Intervention
In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days.
Measurements and Main Results
Pharmacokinetic parameters of both forms of atorvastatin—atorvastatin acid and atorvastatin lactone—were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin’s muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8–64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6–42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC0−∞ of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049).
Conclusion
Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.
doi:10.1592/phco.31.10.942
PMCID: PMC3712822  PMID: 21950641
cytochrome P450; CYP; CYP3A5 genotype; pharmacogenetics; atorvastatin; clarithromycin; drug interaction
5.  Effects of high fructose corn syrup and sucrose on the pharmacokinetics of fructose and acute metabolic and hemodynamic responses in healthy subjects 
Metabolism  2011;61(5):641-651.
Objective
It is unclear whether high fructose corn syrup (HFCS), which contains a higher amount of fructose and provides an immediate source of free fructose, induces greater systemic concentrations of fructose as compared to sucrose. It is also unclear whether exposure to higher levels of fructose leads to increased fructose-induced adverse effects. The objective was to prospectively compare the effects of HFCS- versus sucrose-sweetened soft drinks on acute metabolic and hemodynamic effects.
Materials/Methods
Forty men and women consumed 24 oz of HFCS- or sucrose-sweetened beverages in a randomized crossover design study. Blood and urine samples were collected over 6 hr. Blood pressure, heart rate, fructose, and a variety of other metabolic biomarkers were measured.
Results
Fructose area under the curve and maximum concentration, dose normalized glucose area under the curve and maximum concentration, relative bioavailability of glucose, changes in postprandial concentrations of serum uric acid, and systolic blood pressure maximum levels were higher when HFCS-sweetened beverages were consumed as compared to sucrose-sweetened beverages.
Conclusions
Compared to sucrose, HFCS leads to greater fructose systemic exposure and significantly different acute metabolic effects.
doi:10.1016/j.metabol.2011.09.013
PMCID: PMC3306467  PMID: 22152650
soft drinks; sweetened beverages; adverse metabolic effects; carbohydrate metabolism
6.  Use of Enantiomeric Bupropion and Hydroxybupropion to Assess CYP2B6 Activity in Glomerular Kidney Diseases 
Journal of clinical pharmacology  2010;50(6):714-720.
doi:10.1177/0091270009353031
PMCID: PMC3614080  PMID: 20103693
glomerulonephritis; bupropion; hydroxybupropion; single-dose pharmacokinetics; CYP2B6; lupus nephritis; ANCA vasculitis
7.  Pharmacometabolomics Reveals Racial Differences in Response to Atenolol Treatment 
PLoS ONE  2013;8(3):e57639.
Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.
doi:10.1371/journal.pone.0057639
PMCID: PMC3594230  PMID: 23536766
8.  Nicotine as a Factor in Stress Responsiveness Among Detoxified Alcoholics 
Aims: The effect of transdermal nicotine on stress reactivity was investigated in currently smoking, detoxified, substance-dependent individuals (65% alcohol dependent, n = 51; 31 male) following a psychosocial stressor. Methods: Using a randomized, double-blind, placebo-controlled design, subjects were assigned to receive either active transdermal nicotine (low or high dose) or placebo. Six hours following nicotine administration, subjects performed a laboratory psychosocial stressor consisting of two 4-min public-speaking sessions. Results: Consistent with prior reports, substance-dependent individuals displayed a blunted stress response. However, a review of the cortisol distribution data encouraged additional analyses. Notably, a significant minority of the substance-dependent individuals (33%) demonstrated elevated poststress cortisol levels. This group of responders was more likely to be alcohol dependent and to have received the high dose of nicotine [χ2(2) = 32, P < 0.0001], [χ2(2) = 18.66, P < 0.0001]. Differences in salivary cortisol responses between responders and nonresponders could not be accounted for by the length of sobriety, nicotine withdrawal levels, anxiety or depressive symptomatology at the time of the psychosocial stressor. Conclusion: These results suggest that nicotine administration may support a normalization of the salivary cortisol response following psychosocial stress in subgroups of substance-dependent individuals, particularly those who are alcohol dependent. Given the association between blunted cortisol levels and relapse, and the complex actions of nicotine at central and peripheral sites, these findings support the systematic study of factors including nicotine, which may influence stress reactivity and the recovery process in alcohol-dependent individuals.
doi:10.1093/alcalc/agq070
PMCID: PMC3002844  PMID: 21045074
9.  Validation and application of a liquid chromatography-tandem mass spectrometric method for quantification of the drug transport probe fexofenadine in human plasma using 96-well filter plates 
A rapid method to determine fexofenadine concentrations in human plasma using protein precipitation in 96-well plates and liquid chromatography-tandem mass spectrometry was validated. Plasma proteins were precipitated with acetonitrile containing the internal standard fexofenadine-d6, mixed briefly, and then filtered into a collection plate. The resulting filtrate was diluted and injected onto a Phenomenex Gemini C18 (50 × 2.0 mm, 5 micron) analytical column. The mobile phase consisted of 0.1% formic acid, 5 mM ammonium acetate in deionized water and methanol (35:65, v/v). The flow rate was 0.2 ml/min and the total run time was 2 min. Detection of the analytes was achieved using positive ion electrospray ionization and high resolution multiple reaction monitoring mode (H-SRM). The linear standard curve ranged from 1 to 500 ng/ml and the precision and accuracy (intra- and inter-run) were within 4.3% and 8.0%, respectively. The method has been applied successfully to determine fexofenadine concentrations in human plasma samples obtained from subjects administered a single oral dose of fexofenadine. The method is rapid, sensitive, selective and directly applicable to human pharmacokinetic studies involving fexofenadine.
doi:10.1016/j.jchromb.2009.12.022
PMCID: PMC2818817  PMID: 20045385
Fexofenadine; fexofenadine-d6; protein precipitation; LC-MS; human plasma
10.  Atenolol Exposure and Risk for Development of Adverse Metabolic Effects: A Pilot Study 
Pharmacotherapy  2010;30(9):872-878.
Study Objective
To evaluate whether the level of systemic exposure to atenolol explains observed interindividual differences in adverse metabolic responses.
Design
Open-label, prospective, pharmacokinetic pilot substudy of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study.
Setting
General clinical research center.
Patients
Fifteen hypertensive adults (mean age 46 ± 8.9 yrs) who were enrolled in the PEAR study.
Intervention
Patients received atenolol therapy for at least 8 weeks, with 5 of those weeks at a dosage of 100 mg/day, and then underwent a 2-hour oral glucose tolerance test during a pharmacokinetic study visit.
Measurements and Main Results
Twenty-hour plasma atenolol concentrations were measured during the pharmacokinetic visit. Glucose and insulin levels were measured during the 2-hour oral glucose tolerance test, and fasting plasma lipid, glucose, and insulin levels were measured at baseline and after 8 weeks of atenolol treatment. A significant association was noted between atenolol area under the concentration-time curve (AUC) and change in fasting glucose level when adjusted for covariates (p=0.0025); the effect was strongest in women. No significant relationship was noted between plasma atenolol concentration and glucose AUC during oral glucose tolerance testing (r=0.08, p=0.78), nor between atenolol AUC and change in triglyceride levels (r=0.13, p=0.63).
Conclusion
Higher plasma atenolol exposure may be a risk factor for an increase in fasting plasma glucose level during atenolol treatment. These findings require confirmation in a larger sample.
doi:10.1592/phco.30.9.872
PMCID: PMC2999810  PMID: 20795842
hypertension; β-blockers; atenolol; adverse metabolic effect; oral glucose tolerance test; OGTT; plasma lipid levels; glucose
11.  Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation 
Objective
To examine the phenotypic expression of CYP2E1 in liver transplant patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1 activity over time after transplantation.
Methods
Thirty-three stable liver transplant patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations were determined by HPLC. Twenty-eight healthy control subjects, eight patients with moderate to severe liver disease, and four patients who had not received liver transplants were also studied for comparison. The chlorzoxazone metabolic ratio, calculated as the plasma concentration of 6-hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration, was used as the phenotypic index. In a subgroup of patients and control subjects, additional blood samples were obtained to allow for the calculation of chlorzoxazone pharmacokinetic parameters by noncompartmental methods.
Results
The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean ± SD, 6.4 ± 5.1) was significantly higher than that after 1 month after surgery (2.1 ± 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 ± 0.5). The chlorzoxazone metabolic ratios in the patients who had not received liver transplants (1.1 ± 0.7) were equivalent to those of healthy control subjects. The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 ± 1848 ng/ml in seven liver transplant patients in the first month after surgery compared with 1618 ± 320 ng/ml in 16 healthy control subjects (p < 0.05). The maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral clearance, and the formation clearance of 6-hydroxychlorzoxazone were also significantly different between the groups.
Conclusions
We conclude that significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic ratio, occurs in the first month after sugery in liver transplant patients and that drugs that are substrates for CYP2E1 may require dosage alteration during that period. Contrary to expectations, drug metabolism is not uniformly depressed after liver transplantation.
doi:10.1016/S0009-9236(98)90161-8
PMCID: PMC2978967  PMID: 9542473
12.  A Sensitive and Specific Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Intracellular and Extracellular Uric Acid 
Uric acid (UA) is known to be a major biological antioxidant in plasma. However, there is a strong correlation between UA levels and cardiovascular risk. Recent studies suggest that in the intracellular environment, UA can become a prooxidant that causes endothelial dysfunction. For conducting detailed studies of UA’s role in human pathogenesis, there is a critical need for a sensitive and specific method for the determination of intracellular UA levels. We therefore developed a simple, sensitive method for determination of trace amounts of intracellular UA, as well as comparatively large amounts of UA in plasma and urine (for the determination of extracellular concentrations of UA), based on liquid chromatography and tandem mass spectrometry (LC-MS/MS). UA was separated from interferences by HPLC and quantified by mass spectrometry in the negative ESI mode using single reaction monitoring (SRM). For the identification and quantification of UA, the parent ions selected were m/z 167.0, which corresponds to the urate anion, and m/z 169.0, which corresponds to the 1,3-15N–UA anion. 1,3-15N–UA is used as an internal standard to ensure accuracy of the measurement. After precipitation of proteins with 10% TCA solution, UA was subjected to LC-MS/MS analysis. The correlation coefficient was 0.9998 to 1.0000 based on the calibration curve. The intra- and inter-day precision (C.V. %) ranged from 0.01 to 3.07 and 0.01 to 3.68 in vivo and in vitro systems. Recovery tests of added standards have been successfully performed and the values ranged from 90.10 to 103.59 % and 98.74 to 106.12 % for in vivo and in vitro analyses, respectively. This study demonstrates that intracellular levels of UA can be measured using LC-MS/MS with isotope labeled UA as an internal standard.
doi:10.1016/j.jchromb.2009.05.037
PMCID: PMC2752364  PMID: 19520625
Uric acid; urine; plasma; cell lysate; cardiovascular disease; and LC-MS/MS
13.  Plasma Coenzyme Q10 Predicts Lipid-lowering Response to High-Dose Atorvastatin 
Journal of clinical lipidology  2008;2(4):289-297.
Background
Coenzyme Q10 (CoQ10) is a provitamin synthesized via the HMG-CoA reductase pathway, and thus may serve as a potential marker of intrinsic HMG-CoA reductase activity. HMG-CoA reductase inhibitors (statins) decrease CoQ10, although it is unclear whether this is due to reductions in lipoproteins, which transport CoQ10.
Objectives
We evaluated whether baseline plasma CoQ10 concentrations predict the lipid-lowering response to high-dose atorvastatin, and to what extent CoQ10 changes following atorvastatin therapy depend on lipoprotein changes.
Methods
Individuals without dyslipidemia or known cardiovascular disease (n=84) received atorvastatin 80 mg daily for 16 weeks. Blood samples collected at baseline and after 4, 8, and 16 weeks of treatment were assayed for CoQ10.
Results
Individuals with higher baseline CoQ10:LDL-C ratios displayed diminished absolute and percent LDL-C reductions at 8 and 16 weeks of atorvastatin treatment (P<0.001 to 0.01). After 16 weeks of atorvastatin, plasma CoQ10 decreased 45% from 762±301 ng/ml to 374±150 ng/ml (P<0.001). CoQ10 changes were correlated with LDL-C and apolipoprotein B changes (r=0.27-0.38, P=0.001-0.02), but remained significant when normalized to all lipoproteins. CoQ10 changes were not associated with adverse drug reactions.
Conclusion
Baseline CoQ10:LDL-C ratio was associated with the degree of LDL-C response to atorvastatin. Atorvastatin decreased CoQ10 concentrations in a manner that was not completely dependent on lipoprotein changes. The utility of CoQ10 as a predictor of atorvastatin response should be further explored in patients with dyslipidemia.
doi:10.1016/j.jacl.2008.05.001
PMCID: PMC2598393  PMID: 19649137
Coenzyme Q10; HMG CoA-reductase inhibitors; lipids; pharmacology; biomarkers
14.  Simultaneous determination of uric acid metabolites allantoin, 6-aminouracil, and triuret in human urine using liquid chromatography–mass spectrometry 
Uric acid (UA) can be directly converted to allantoin enzymatically by uricase in most mammals except humans or by reaction with superoxide. UA can react directly with nitric oxide to generate 6-aminouracil and with peroxynitrite to yield triuret; both of these metabolites have been identified in biological samples. We now report a validated high-performance liquid chromatography and tandem mass spectrometry method for the determination of these urinary UA metabolites. Urine samples were diluted 10-fold, filtered and directly injected onto HPLC for LC–MS/MS analysis. The urinary metabolites of UA were separated using gradient HPLC. Identification and quantification of UA urinary metabolites was performed with electrospray in positive ion mode by selected-reaction monitoring (SRM). Correlation coefficients were 0.991–0.999 from the calibration curve. The intra-and inter-day precision (R.S.D., %) of the metabolites ranged from 0.5% to 13.4% and 2.5–12.2%, respectively. In normal individuals (n = 21), urinary allantoin, 6-aminouracil and triuret, were 15.30 (±8.96), 0.22 (±0.12), and 0.12 (±0.10) μg/mg of urinary creatinine (mean (±S.D.)), respectively. The new method was used to show that smoking, which can induce oxidative stress, is associated with elevated triuret levels in urine. Thus, the method may be helpful in identifying pathways of oxidative stress in biological samples.
doi:10.1016/j.jchromb.2008.11.029
PMCID: PMC2684329  PMID: 19081307
Metabolites; Allantoin; 6-Aminouracil; Triuret; LC; MS/MS; Uric acid
15.  A Summer Research Training Program to Foster PharmD Students' Interest in Research 
Objectives
To establish and assess the effectiveness of a 10-week summer research program on increasing doctor of pharmacy (PharmD) students' interest in research, particularly as it related to future career choices.
Design
Survey instruments were sent to 25 participants who had completed the research program in the summer of 2004, 2005, or 2006 to assess their satisfaction with the program and its influence on their career choices after graduation.
Assessment
Respondents reported a high degree of satisfaction with the program, indicating that the program allowed them to determine their suitability for a career in research, and 55% reported their intention to pursue additional research training.
Conclusion
A brief introduction to the clinical research environment helped pharmacy students understand the clinical sciences and careers in research. The introduction increased the likelihood of students pursuing a research career path after obtaining their PharmD degree.
PMCID: PMC2384198  PMID: 18483591
research; career; students
16.  Effect of Ceftazidime on Systemic Cytokine Concentrations in Rats 
Antimicrobial Agents and Chemotherapy  2000;44(11):3217-3219.
The effect of a single dose of ceftazidime on circulating concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in a rat model of sepsis was studied. IL-6 concentrations were significantly elevated (100 to 200 times the baseline) 6 h after ceftazidime administration in both septic and nonseptic (control) rats. TNF-α concentrations increased significantly in nonseptic (∼40 times the baseline) rats but not septic (∼2 to 3 times the baseline) rats. Ceftazidime administration was not associated with an increase in endotoxin concentrations. These findings suggest that ceftazidime modulation of proinflammatory cytokine concentrations may be independent of its antimicrobial properties.
PMCID: PMC101638  PMID: 11036058
17.  Determinants of Ceftazidime Clearance by Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodialysis 
Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m2 acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m2 polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m2 polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CIdiffusion) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17% ± 7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (P < 0.0001) were observed between CIdiffusion of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.
PMCID: PMC89925  PMID: 10817721

Results 1-17 (17)