Upcycling the anthracyclines: New mechanisms of action, toxicology, and pharmacology.

The anthracyclines are a family of natural products isolated from soil bacteria with over 2000 chemical representatives. Since their discovery seventy years ago by Waksman and co-workers, anthracyclines have become one of the best-characterized anticancer chemotherapies in clinical use. The anthracyclines exhibit broad-spectrum antineoplastic activity for the treatment of a variety of solid and liquid tumors, however, their clinical use is limited by their dose-limiting cardiotoxicity. In this review article, we discuss the toxicity of the anthracyclines on several organ systems, including new insights into doxorubicin-induced cardiotoxicity. In addition, we discuss new medicinal chemistry developments in the biosynthesis of new anthracycline analogs and the synthesis of new anthracycline analogs with diminished cardiotoxicity. Lastly, we review new studies that describe the repurposing of the anthracyclines, or "upcycling" of the anthracyclines, as anti-infective agents, or drugs for niche indications. Altogether, the anthracyclines remain a mainstay in the clinic with a potential new "lease on life" due to deeper insight into the mechanism underlying their cardiotoxicity and new developments into potential new clinical indications for their use. Keywords: Anthracycline, chemotherapy, toxicology, medicinal chemistry, biosynthesis.

Etoposide and etoposide phosphate hypersensitivity in children: Incidence, risk factors, and prevention strategies.

INTRODUCTION: Etoposide is critical in treating pediatric cancers, although hypersensitivity can be severe and treatment-limiting. Reported rates of hypersensitivity range from 2% to 51%. Hypersensitivity data for etoposide phosphate, a newer product, are lacking. The primary objective of this study was to assess etoposide and etoposide phosphate hypersensitivity incidence. Secondary objectives included evaluation of potential risk factors for hypersensitivity and strategies to prevent recurrence. METHODS: This retrospective cohort study evaluated pediatric patients who received initial etoposide phosphate or etoposide dose between August 2012 and July 2017. The primary outcome was documentation of hypersensitivity within four months of initial dose. Potential risk factors evaluated included age, allergies, dose, infusion rate, infusion concentration, and premedication. RESULTS: Of 246 patients, hypersensitivity reactions occurred in five of 54 patients (9.3%) who received etoposide phosphate and 52 of 192 patients (27.1%) who received etoposide (p = 0.0061). For etoposide, the mean initial infusion rate was 64.6 ± 40.9 mg/m2/h for patients with hypersensitivity and 49.5 ± 33.4 mg/m2/h without hypersensitivity (p = 0.0886). Etoposide phosphate rate was not associated with hypersensitivity. Recurrent hypersensitivity occurred in one of nine patients (11.1%) who received etoposide desensitization and one of 38 patients (2.6%) who changed formulation to etoposide phosphate. CONCLUSIONS: Etoposide was associated with more hypersensitivity than etoposide phosphate in pediatric patients. Etoposide hypersensitivity was associated with higher infusion rates, but not etoposide phosphate. Differences in hypersensitivity incidence and infusion rate influence indicate a formulation-effect. Etoposide hypersensitivity recurrence may be prevented by changing to etoposide phosphate formulation. During etoposide phosphate shortages, etoposide desensitization may prevent recurrent hypersensitivity.

Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis.

BACKGROUND: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction. AIM: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates. METHODS: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines. RESULTS: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism. CONCLUSIONS: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.

Estimation of Glomerular Filtration Rate in Patients With Cirrhosis by Using New and Conventional Filtration Markers and Dimethylarginines.

BACKGROUND & AIMS: Equations used to estimate glomerular filtration rate (GFR) are not accurate in patients with cirrhosis. We aimed to develop a new equation to estimate the GFR in subjects with cirrhosis and compare its performance with chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C and creatinine-cystatin C equations, which were derived in populations without cirrhosis. METHODS: From 2010 through 2014, we measured GFR in 103 subjects with cirrhosis based on non-radiolabeled iothalamate plasma clearance. We measured blood levels of creatinine, cystatin C, ß-trace protein, ß2-microglobulin, L-arginine, and symmetric and asymmetric dimethylarginines simultaneously with GFR. Multivariate linear regression analysis was performed to develop models to estimate GFR. Overall accuracy, defined by the root mean square error (RMSE) of our newly developed model to estimate GFR, was compared with that of the CKD-EPI equations. To obtain an unbiased estimate of our new equation to estimate GFR, we used a leave-one-out cross-validation strategy. RESULTS: After we considered all the candidate variables and blood markers of GFR, the most accurate equation we identified to estimate GFR included serum levels of creatinine and cystatin C, as well as patients' age, sex, and race. Overall, the accuracy of this equation (RMSE = 22.92) was superior to that of the CKD-EPI cystatin C equation (RMSE = 27.27, P = .004). Among subjects with cirrhosis and diuretic-refractory ascites, the accuracy of the equation we developed to estimate GFR (RMSE = 19.36) was greater than that of the CKD-EPI cystatin C (RMSE = 27.30, P = .003) and CKD-EPI creatinine-cystatin C equations (RMSE = 23.37, P = .004). CONCLUSIONS: We developed an equation that estimates GFR in subjects with cirrhosis and diuretic-refractory ascites with greater accuracy than the CKD-EPI cystatin C equation or CKD-EPI creatinine-cystatin C equation.

Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis.

UNLABELLED: Conventional creatinine-based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD-EPI creatinine-cystatin C equation (2012) was superior to previous creatinine- or cystatin C-based GFR equations. To evaluate the performance of the CKD-EPI creatinine-cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by nonradiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the "bias," "precision," and "accuracy" of the new CKD-EPI creatinine-cystatin C equation to that of 24-hour urinary creatinine clearance (CrCl), Cockcroft-Gault (CG), and previously reported creatinine- and/or cystatin C-based GFR-estimating equations. Accuracy of CKD-EPI creatinine-cystatin C equation as quantified by root mean squared error of difference scores (differences between mGFR and estimated GFR [eGFR] or between mGFR and CrCl, or between mGFR and CG equation for each subject) (RMSE = 23.56) was significantly better than that of CrCl (37.69, P = 0.001), CG (RMSE = 36.12, P = 0.002), and GFR-estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P = 0.024), CG (P = 0.0001), 4-variable MDRD (P = 0.027), and CKD-EPI creatinine 2009 (P = 0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD-EPI creatinine-cystatin C equation differed from the mGFR by more than 30%. CONCLUSION: The diagnostic performance of CKD-EPI creatinine-cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis.

Performance of a divided-load intravenous vancomycin dosing strategy for obese patients.

BACKGROUND: Current guidelines recommend vancomycin trough concentrations of 15 to 20 µg/mL in complicated infections and all trough concentrations >10 µg/mL to avoid developing microbial resistance. To date, no published protocol reliably meets these recommendations for obese patients. OBJECTIVE: We assessed the performance of a novel, obese-specific, divided-load vancomycin protocol for attaining target trough concentrations within 12 to 24 hours of dosing initiation, and during maintenance dosing, in obese patients. METHODS: The protocol was evaluated through prospective medical record review in 54 consecutive obese patients. Vancomycin serum concentrations were drawn before the third and fifth dose after initiation. Steady-state concentrations were drawn after the third dose once maintenance dosing was achieved and periodically thereafter. RESULTS: Within 12 hours after dosing initiation, 48 (89%) study patients exhibited trough concentrations of 10 to 20 µg/mL averaging 14.5 ± 3.2 µg/mL; 51 (94%) study patients exhibited trough concentrations >10 µg/mL within 12 hours after dosing initiation, and 3 (6%) had trough concentrations >20 µg/mL. Thirty-one participants had second trough concentrations drawn within 24 hours of dosing initiation, averaging 15.0 ± 3.1 µg/mL; 24 patients had a total of 32 trough concentrations drawn during maintenance dosing, averaging 15.1 ± 2.5 µg/mL. CONCLUSION: Obese-specific, divided-load dosing achieved trough concentrations of 10 to 20 µg/mL for 89% of obese patients within 12 hours of initial dosing and 97% of obese patients within 24 hours of initial dosing while preventing doses given during supratherapeutic trough levels; 97% of troughs measured during steady state were within target range.

A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.

BACKGROUND: Renal hemodynamic measurements are complicated to perform in patients with cirrhosis, yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics. METHODS: In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic-sensitive and 2 diuretic-refractory ascites). RESULTS: Patients with diuretic-refractory ascites had the lowest mean GFR (36.5 ml/min/1.73 m(2)) and RPF (133.6 ml/min/1.73 m(2)) when compared to those without ascites (GFR 82.9 ml/min/1.73 m(2), RPF 229.9 ml/min/1.73 m(2)) and with diuretic-sensitive ascites (GFR 82.3 ml/min/1.73 m(2), RPF 344.1 ml/min/1.73 m(2)). A higher mean filtration fraction (FF) (GFR/RPF 0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF ~0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and ß2-microglobulin performed better compared to Cr in estimating RPF, ß-trace protein, ß2-microglobulin, and SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index. CONCLUSION: The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention and reduce mortality from kidney failure in cirrhosis.

Effect of uremic serum and uremic toxins on drug metabolism in human microsomes.

There is increasing evidence that renal impairment modifies nonrenal drug clearance through drug metabolizing cytochrome P450 (CYP) enzymes. In this study, the direct inhibitory effect of serum from chronic renal failure (CRF) patients receiving dialysis was evaluated in CYP3A4 (testosterone) and CYP2B6 (bupropion) metabolism assays. Human liver microsomes were incubated with ultrafiltered serum collected pre- and post-hemodialysis from ten CRF patients. Additionally, several uremic toxins were evaluated in the CYP3A4 assay. In only three patients was there a significant decrease or increase in testosterone or bupropion metabolism post-dialysis. Urea, mannitol, guanidine, homocysteine, uridine and creatinine had no effect on CYP3A4 metabolism. CMPF, hippuric acid and p-cresol had IC50 values that fell within CRF patient plasma concentrations. The IC50 values for indoxyl sulfate and indole-3-acetic acid were greater than CRF plasma concentrations. The lack of a consistent effect on CYP3A4 or CYP2B6 metabolism by uremic serum may be due in part to the frequency of hemodialysis in these patients which reduced the accumulation of uremic toxins. CMPF, hippuric acid and p-cresol have the ability to inhibit CYP3A4 metabolism at clinical concentrations which may correspond to reports of changes in hepatic metabolism in some CRF patients.

Performance of a divided-load intravenous vancomycin dosing strategy for critically ill patients.

BACKGROUND: Current guidelines recommend vancomycin trough concentrations 15 to 20 µg/mL in complicated infections and all trough concentrations above 10 µg/mL. OBJECTIVE: We assessed the performance of a novel divided-load protocol designed to attain target trough concentrations within 24 hours of initiation and prevent doses given at concentrations above the target range, in critically ill patients. METHODS: The protocol was evaluated in 79 critically ill patients through retrospective medical record review. Vancomycin serum concentrations were drawn before the third dose after initiation and after any dosing change. Steady-state concentrations were drawn before the fifth or sixth doses. Vancomycin concentrations before the second dose were predicted using a nonparametric expectation maximization algorithm. RESULTS: Sixty-nine of 79 patients received scheduled doses, and 62 (90%) of the scheduled-dose patients attained therapeutic target concentrations 12 to 24 hours after therapy initiation. Eight scheduled-dose patients weighed > 150% of ideal body weight (IBW) and were significantly more likely to exhibit supratherapeutic trough concentrations before the fifth or sixth doses (P = .0004) compared with patients weighing ≤150% of IBW. Ten of 79 patients (8 dialysis dependent and 2 experiencing acute kidney injury) were dosed in response to measured serum drug concentrations drawn according to the divided-load protocol. All the 8 dialysis-dependent patients (100%) attained therapeutic concentrations 12 hours after therapy initiation. CONCLUSION: The divided-load vancomycin dosing strategy achieved measured trough concentrations 15 to 20 µg/mL for most critically ill patients within 24 hours of initial dosing, without allowing doses given during supratherapeutic concentrations.

Impact of medication therapy management on underserved, primarily Hispanic patients with diabetes.

BACKGROUND: Diabetes-related complications are more pronounced in Hispanic patients versus patients of other ethnicities. It is documented that medication therapy management (MTM) can improve diabetes outcomes; however, data regarding Hispanic patients are limited. OBJECTIVE: To evaluate the impact of MTM on hemoglobin A1c (A1C), blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) in underserved, primarily Hispanic patients who use a safety-net clinic as their medical home. METHODS: A retrospective, observational study of uninsured, primarily Hispanic patients with diabetes who received MTM from October 2009 through March 2011. Patients were stratified into 2 cohorts: A1C less than 9% and A1C greater than or equal to 9%. Patients were also stratified by frequency of MTM visits and insulin use, regardless of A1C. A chart review was conducted to evaluate diabetes-related outcomes pre- and postimplementation of MTM. The primary study outcome was reduction of A1C. Secondary outcomes included reduction of BP and LDL-C and reduction of A1C based on MTM visit frequency or insulin use. RESULTS: Sixty-four patients with at least 1 MTM visit and pre- and postimplementation A1C data were included. In the cohort with A1C greater than or equal to 9%, mean (SD) A1C values decreased from 10.9% (1.4%) to 8.8% (1.5%) versus the cohort with A1C less than 9%, whose A1C changed minimally, from 7.2% (0.9%) to 7.4% (1.4%). Regardless of their A1C, patients who were using insulin at baseline had a change in A1C of -0.8% (1.5%) versus -0.1% (1.6%) in those who were not using insulin at baseline (p = 0.04); patients who participated in multiple MTM visits had a significant reduction in A1C, from 9% to 8.3% (95% CI -1.26 to -0.03; p = 0.02) compared with patients participating in only 1 MTM visit. CONCLUSIONS: Pharmacist-provided MTM can significantly improve diabetes control in uninsured, primarily Hispanic patients with poorly controlled diabetes and in those who are using insulin. Multiple MTM visits also yielded significant A1C reductions.

Performance of different body weights in the Cockcroft-Gault equation in critically ill patients with and without augmented renal clearance: A multicenter cohort.

STUDY OBJECTIVE: The primary objective was to evaluate the performance of the Cockcroft-Gault (CG) equation with different body weights (BWs) compared to a measured creatinine clearance (mCrCl) in an intensive care unit (ICU) population with and without augmented renal clearance (ARC). DESIGN: Multicenter, retrospective cohort. SETTING: Two ICUs in the United States and four ICUs from a previous international observational analysis. PATIENTS: Adult ICU patients admitted from January 1, 2010 to July 30, 2020 with at least one mCrCl collected within the initial 10 days of hospitalization were eligible for inclusion. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the performance of the CG equation in ARC (mCrCl≥130 ml/min/1.73 m2 ) and non-ARC (mCrCl<130 ml/min/1.73 m2 ) patients. Correlation was analyzed by Pearson's correlation coefficient, bias by mean difference, and accuracy by the percentage of patients within 30% of the mCrCl. A total of 383 patients were included, which provided 1708 mCrCl values. The majority were male (n = 239, 62%), median age of 55 years [IQR 40-65] with a surgical diagnosis (n = 239, 77%). ARC was identified in 229 (60%) patients. The ARC group had lower Scr values (0.6 [0.5-0.7] vs. 0.7 [0.6-0.9] mg/dl, p < 0.001) and higher mCrCl (172.8 (SD 39.1) vs. 89.9 mL/min/1.73 m2 (SD 25.4), p < 0.001) compared with the non-ARC group, respectively. Among non-ARC patients there was a moderate correlation (r = 0.33-0.39), moderate accuracy (range 48-58%), and low bias (range of -12.9 to 17.1) among the different BW estimations with the adjusted BW having the better performance. Among ARC patients there was low correlation (r = 0.24-0.28), low to moderate accuracy (range 38-70%), and high bias (range of -58.5 to -21.6). CONCLUSIONS: The CG-adjusted BW had the best performance in the non-ARC patients, while CG performed poorly with any BW in ARC patients. Although the CG equation remains the standard equation for estimating CrCl in the ICU setting, a new, validated equation is needed for patients with ARC.

Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1.

OBJECTIVES: Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90% of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24. METHODS: Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule. RESULTS: Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P<0.05) and week 72 (SVR) (36.6% vs 54.8%; P<0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P<0.05). Ribavirin exposures ≥4,065 and ≥4,480 ng/ml/day in the first week (AUC(0-7)) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC(0-7) level than CA (P<0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84%) and SVR (AA: 52 vs. CA: 60%) rates in patients who met the ribavirin AUC(0-7) thresholds. Ribavirin AUC(0-7) predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC(0-7) levels increased response rates primarily in AA with the less favorable non-C/C genotypes. CONCLUSIONS: Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1.

Dofetilide dose calculation errors in elderly associated with use of the modification of diet in renal disease equation.

OBJECTIVE: To report 2 cases of drug dosage calculation errors that occurred when the Modification of Diet in Renal Disease (MDRD) equation was used for initiating drug therapy with dofetilide in elderly patients with chronic kidney disease. CASE SUMMARY: An 83-year-old woman and a 92-year-old man were admitted for dofetilide treatment initiation and cardioversion for atrial fibrillation. The estimated glomerular filtration rate (eGFR) determined with use of the MDRD equation was significantly higher than the estimated creatinine clearance (eCrCl) determined with use of the Cockcroft-Gault equation for both cases (85 vs 43 mL/min for the man and 40 vs 24 mL/min for the woman). Initial dofetilide dosages calculated by the MDRD equation were 2-fold higher than those calculated by eCrCl in both cases. Initiation of dose based on the MDRD in the first patient led to a 32% increase in the QTc interval from baseline. Dofetilide therapy was adjusted for QTc interval prolongation based on eCrCl and reinitiated at a lower dose, and the patient did not develop further significant increases in the QTc interval. In the second patient, the lower dose based on eCrCl was initiated and the QTc interval remained within an acceptable range. DISCUSSION: The initial dosing of dofetilide is based on eCrCl as specified by the drug manufacturer. Recent widespread use and automated reporting of the eGFR by clinical laboratories has tempted some clinicians to consider using eGFR for calculating drug doses. However, recent data suggest that the eGFR, calculated by the MDRD equation, consistently overestimates eCrCl, leading to dose discrepancies, particularly in the elderly. The cases reported here illustrate the drug dose calculation errors that may occur when using the MDRD equation for initiating doses of dofetilide. CONCLUSIONS: Use of the eGFR or MDRD equation for calculation of doses in renal dysfunction has not been validated, and significant drug dose errors have been reported. The use of eGFR to calculate doses of dofetilide should be avoided.

Probenecid increases renal retention and antitumor activity of DFMO in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children. Interference with the polyamine biosynthesis pathway by inhibition of MYCN-activated ornithine decarboxylase (ODC) is a validated approach. The ODC inhibitor α-difluoromethylornithine (DFMO, or Eflornithine) has been FDA-approved for the treatment of trypanosomiasis and hirsutism and has advanced to clinical cancer trials including NB as well as cancer-unrelated human diseases. One key challenge of DFMO is its rapid renal clearance and the need for high and frequent drug dosing during treatment. METHODS: We performed in vivo pharmacokinetic (PK), antitumorigenic, and molecular studies with DFMO/probenecid using NB patient-derived xenografts (PDX) in mice. We used LC-MS/MS, HPLC, and immunoblotting to analyze blood, brain tissue, and PDX tumor tissue samples collected from mice. RESULTS: The organic anion transport 1/3 (OAT 1/3) inhibitor probenecid reduces the renal clearance of DFMO and significantly increases the antitumor activity of DFMO in PDX of NB (P < 0.02). Excised tumors revealed that DFMO/probenecid treatment decreases polyamines putrescine and spermidine, reduces MYCN protein levels and dephosphorylates retinoblastoma (Rb) protein (p-RbSer795), suggesting DFMO/probenecid-induced cell cycle arrest. CONCLUSION: Addition of probenecid as an adjuvant to DFMO therapy may be suitable to decrease overall dose and improve drug efficacy in vivo.

Stimulating and sustaining scholarly activity at teaching-intensive institutions.

INTRODUCTION: Research and scholarship are core elements of the academic mission. Yet fulfilling institutional and accreditation requirements for scholarly activity can be challenging, particularly for teaching-intensive institutions. This paper describes strategies for employing a teacher-scholar model to stimulate and sustain scholarly activity. METHODS: Metrics of scholarly productivity were programmatically assessed and reported for at least five years following implementation of sixteen different strategic initiatives at three teaching-intensive colleges of pharmacy. Data reported included publications (original peer-reviewed publications, case reports, review articles), presentations (posters, podiums, and continuing education sessions), peer-reviewed published abstracts, grants awarded, and total extramural funding per annum. Faculty and student engagement in scholarship was indicated by authorship on at least one scholarly work. RESULTS: Broad increases in metrics of scholarly productivity were observed, while the timing and degree of change varied (1.4-fold to 10.4-fold, across all institutions, all years). Notably, the most robust growth was observed in grantsmanship and the number of faculty and student contributors to scholarly works. A key observation was that increased scholarly output was sustained, as during the most recent three-year period publications increased 1.6-fold, grants and extramural funding increased 3.4- and 15.8-fold, respectively, and faculty and student contributors increased 1.8- and 4.5-fold, respectively. CONCLUSIONS: Overall, these data point to a substantive, detailed approach for increasing scholarship at diverse, teaching-intensive institutions by implementing cost-conscious strategies, including clear ties between scholarly effort/productivity and faculty performance/advancement, strong faculty development and mentoring, institutional commitments to infrastructure and research budgets, and student engagement in scholarly activities.

The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training.

OBJECTIVE: The purpose of this study was to examine the effects of aerobic exercise training (AEXT) on dipping status in pre-hypertensive and stage-1 hypertensive individuals. A secondary purpose was to evaluate whether AEXT alters oxidative stress and endothelial biomarkers correlated to dipping status. METHODS: Twenty-three subjects underwent 24-h ambulatory blood pressure monitoring at baseline and after 6 months of AEXT. AEXT consisted of training at 70% VO(2max) 3 days/week for 6 months. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)-cholesterol, oxidized LDL (ox-LDL), triglycerides, urinary and plasma nitric oxide end-products, superoxide dismutase and 8-iso-PGF(2alpha) were measured before and after AEXT. Statistically, ANOVA and linear regression were used. RESULTS: Before and after AEXT, there were no significant differences between dippers and non-dippers in any of the biomarkers except for total cholesterol following AEXT. In a sub-analysis following AEXT, 14 subjects retained their original dipping status, five subjects changed from dippers to non-dippers and four subjects changed from non-dippers to dippers. Significant differences existed between these groups in changes in total and LDL-cholesterol, ox-LDL, 8-iso-PGF(2alpha) and % Dip. CONCLUSIONS: Changes in cholesterol levels but not oxidative stress or endothelial biomarkers were related to changes in BP variables following AEXT in dippers and non-dippers.

Metabolomic biomarkers are associated with mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis.

AIM: To assess the ability of signature metabolites alone, or in combination with the model for end-stage liver disease-Na (MELD-Na) score to predict mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. MATERIALS & METHODS: Plasma metabolites were detected using ultrahigh-performance liquid chromatography/tandem mass spectrometry in 39 patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. Mortality was predicted using Cox proportional hazards regression and time-dependent receiver operating characteristic curve analyses. RESULTS: The top five metabolites with significantly greater accuracy than the MELD-Na score (area under the receiver operating characteristic curve [AUROC] = 0.7591) to predict 1-year mortality were myo-inositol (AUROC = 0.9537), N-acetylputrescine (AUROC = 0.9018), trans-aconitate (AUROC = 0.8880), erythronate (AUROC = 0.8345) and N6-carbamoylthreonyladenosine (AUROC = 0.8055). Several combined MELD-Na-metabolite models increased the accuracy of predicted 1-year mortality substantially (AUROC increased from 0.7591 up to 0.9392). CONCLUSION: Plasma metabolites have the potential to enhance the accuracy of mortality predictions, minimize underestimates of mortality in patients with cirrhosis and low MELD-Na scores, and promote equitable allocation of donor livers.

Peginterferon pharmacokinetics in African American and Caucasian American patients with hepatitis C virus genotype 1 infection.

BACKGROUND & AIMS: The relationship between serum peginterferon pharmacokinetics and pharmacodynamics and the early virologic response (EVR) to peginterferon and ribavirin therapy was assessed in patients with chronic hepatitis C virus (HCV) genotype 1 infection. METHODS: A total of 333 patients (160 African Americans [AA] and 173 Caucasian Americans [CA]) who received peginterferon alpha-2a (180 microg/wk) without a dose modification during the initial 4 weeks of therapy were analyzed. Peginterferon and 2,5-oligoadenylate synthetase (2,5-OAS) serum levels were measured on days 0, 1, 2, 3, 7, 14, 28, 56, 84, and 168 of treatment. The EVR (>or=2-log(10) decline in HCV RNA levels by week 12 of therapy) was the primary virologic end point. RESULTS: Peginterferon pharmacokinetics after the first dose were similar in AA and CA, but AA had greater peginterferon concentrations at days 1, 3, 14, and 28 (P < .05). AA had higher absolute serum 2,5-OAS levels on days 0, 1, 2, 3, 7, 14, 28, and 56 (P < .05), but the magnitude of 2,5-OAS induction during treatment were similar. AA patients showed a smaller decline in serum HCV RNA during the first 28 days of treatment (P < .001) and a lower EVR (65% vs 83%). AA and CA with EVR had significantly higher serum peginterferon concentrations and serum 2,5-OAS induction during the first 12 weeks than patients without an EVR. CONCLUSIONS: Peginterferon alpha-2a pharmacokinetic and pharmacodynamic variability is associated with EVR in both AA and CA with HCV infection, but do not explain the racial disparity in combination treatment efficacy.