L'AUrelle A. Johnson

This study aims to examine the current wellbeing among pharmacy students in underrepresented groups (URGs) and investigate the impact on having access to affinity groups. A survey was distributed to students in April and May 2023, at a Midwestern College of Pharmacy, centering around diversity, equity, inclusion, and accessibility (DEIA) efforts and their impact on student wellbeing and experiences with the college-supported affinity groups. Student responses were analyzed using descriptive statistics. Sixty-five (75%) of the eighty-six students who completed the survey identified with at least one URG. First-generation students (n = 36), underrepresented racial/ethnic groups (n = 24), and LGBTQ+ (n = 13) were the three most prominent groups. Twenty-seven percent (n = 23) of students belonged to multiple URGs. Among the students in URGs, three out of four experienced distress. The students in URGs experienced distress at a higher rate compared to their peers in all categories. Twenty percent (n = 16) of students did not agree that there was equitable treatment on campus. This rate was higher among students in URGs compared to their peers. Eighty-three percent (n = 52) of individuals who did not participate in an affinity group recognized there was a need. Among individuals who did not participate, nearly half identified with a URG. Pharmacy students, especially those in URGs, may benefit from additional interventions by pharmacy schools to improve the offering and visibility of supportive services. Providing URG-centered resources addresses the gap between the wellbeing and academic experience of pharmacy students in URGs compared to their peers.

Background: Increased xanthine oxidase (XO) activity and uric acid levels are known to be associated with obesity and hypertension; however, it is not known if obesity is directly responsible for these associations in youth. This study investigated the effect of weight loss on XO activity, uric acid, and their relationship to blood pressure change in obese youth to provide greater insight on how obesity increases cardiovascular risk. Methods: This was an ancillary study in which 16 adolescents (mean age 15 ± 2 years) received meal replacement therapy over a period of four weeks. Outcomes measured at baseline and after intervention included weight, blood pressure, XO activity, plasma uric acid, uric acid clearance, and creatinine clearance. Results: After the meal replacement intervention, participants experienced reductions in body weight (109.2 ± 16 kg vs. 105.2 ± 14 kg, p < 0.0001) and BMI (38.7 ± 4 kg vs. 37.4 ± 3 kg, p < 0.0001). Plasma XO activity was reduced by 9.8% (p = 0.016). Uric acid clearance was decreased by 39% (p = 0.006). SBP (systolic blood pressure) and plasma uric acid concentrations were reduced but did not achieve statistical significance (p = 0.34 and 0.38, respectively). DBP (diastolic blood pressure) was unchanged (p = 0.86). No significant relationships were found between changes in blood pressure and changes in either XO activity or plasma uric acid levels. Conclusion: Weight loss led to decreases in uric acid production by lowering XO activity and decreases in uric acid clearance by reducing glomerular filtration (GF) and increasing reabsorption. Changes in XO activity and uric acid levels did not correlate with changes in blood pressure.

Background: Pathological mechanisms of how childhood obesity leads to increased risk of cardiovascular disease (CVD) are not fully characterized. Oxidative-stress–related enzymes, such as xanthine oxidase (XO), have been linked to obesity, endothelial dysfunction, and CVD in adults, but little is known about this pathway in children. The aim of this study was to determine whether differential XO activity is associated with endothelial dysfunction, CVD risk factors, or cytokine levels. Methods: Fasting plasma samples were obtained from obese (BMI ≥95th percentile; n=20) and age- and gender-matched healthy weight (BMI >5th and n=22) children and adolescents (mean age, 12±3 years) to quantify XO activity. In addition, fasting cholesterol, insulin, glucose, blood pressure, endothelial function, and cytokine levels were assessed. Results: We observed a 3.8-fold increase in plasma XO activity in obese, compared to healthy weight, children (118±21 vs. 31±9 nU/mg of protein; pz-score (r=0.41), waist circumference (r=0.41), high-density lipoprotein cholesterol (r=−0.32), oxidized low-density lipoprotein (r=0.57), adiponectin (r=−0.53), and monocyte chemotactic protein-1 (r=−0.59). Conclusion: XO activity is highly elevated in obese children and correlates with CVD risk factors, suggesting that XO may play a role in increasing cardiovascular risk early in life in the context of obesity.

Background: Cyclophosphamide, an alkylating agent, is metabolically activated to phosphoramide mustard, to form toxic DNA DNA (G-NOR-G) crosslinks. Increased exposure to cyclophosphamide metabolites has been associated with treatment-related toxicity. The effect of obesity on exposure to cyclophosphamide-induced G-NOR-G crosslinks is not known. Therefore we sought to determine whether obesity affects the formation of cyclophosphamide-specific G-NOR-G crosslinks. Patients and Methods: Plasma cyclophosphamide concentrations and blood cell G-NOR-G amounts were measured. Results: Overweight/obese patients received a significantly higher daily cyclophosphamide dose (median 3000 vs. 4450 mg, p<0.01). Despite the higher doses, overweight/obese patients had lower exposure to cyclophosphamide compared to lean patients with an area under the curve (AUC(0-infinity)) = 529.24 vs. 867.99 mu cg/ml*h respectively, p<0.01. G-NOR-G amounts were similar in overweight/obese and lean subjects, AUC(0-infinity)=142.8 vs. 147.0 adducts/10(6) nucleotides*h, respectively, p=0.59. Conclusion: Overweight/obese patients have altered metabolism and disposition of cyclophosphamide. This altered exposure may be an important determinant of efficacy and may play a role in treatment-related mortality.

Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A₁, A_2A, or A₃ receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A_2B receptors. Clofarabine and cladribine both bound to the A_2A receptor with a K _i of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A₃ receptor with a K _i of 10 μM, and none of these compounds bound to the A_2B receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A₁ receptor. In addition, clofarabine, cladribine, and fludarabine were A₁ agonists (IC₅₀ 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K _i > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• It has been well established that obese adults exhibit differences in expression and regulation of drug metabolizing enzymes as compared with healthy‐weight adults. However, as obesity is becoming a more prevalent problem in children, little, if any, information is available that specifically addresses the consequences of obesity on drug metabolism in this population.WHAT THIS STUDY ADDS• This is the first study that provides evidence for elevated levels of xanthine oxidase and N‐acetyltransferase 2 enzyme activity in children who are obese. This new knowledge may provide insight into improving dosing strategies in obese children with concomitant diseases who are treated with therapeutic agents that are metabolized by these enzymes.AIMSIt is well established that oxidative and conjugative enzyme activity differs between obese and healthy‐weight adults. However, the effect of obesity on drug metabolism in children has not been studied extensively. This study examined whether obese and healthy‐weight children vary with respect to oxidative enzyme activity of CYP1A2, xanthine oxidase (XO) and conjugative enzyme activity of N‐acetyltransferase 2 (NAT2).METHODSIn vivoCYP1A2, XO and NAT2 activity was assessed in obese (n= 9) and lean (n= 16) children between the ages of 6–10 years using caffeine (118.3 ml Coca Cola®) as probe. Urine samples were collected in 2‐h increments over 8 h. Caffeine and metabolites were measured using LC/MS, and urinary metabolic ratios were determined based on reported methods.RESULTSSixteen healthy‐weight and nine obese children were evaluated. XO activity was elevated in paediatric obese volunteers compared with non‐obese paediatric volunteers (XO metabolic ratio of 0.7 ± 0.06vs.0.6 ± 0.06, respectively, 95% CI 0.046, 0.154,P< 0.001). NAT2 activity was fivefold higher in the obese (1 ± 0.4) as compared with non‐obese children (0.2 ± 0.1), 95% CI 0.26, 1.34,P< 0.05. However, no difference was observed in CYP1A2 activity between the groups (95% CI −2.72, 0.12,P> 0.05).CONCLUSIONSThis study provides evidence that obese children have elevated XO and NAT2 enzyme activity when compared with healthy‐weight controls. Further studies are needed to determine how this may impact the efficacy of therapeutic agents that may undergo metabolism by these enzymes.

The 5‐year survival rates for childhood ALL are approaching 80%, but therapy‐related toxicities are common. One of the challenges in this population is determining the most efficacious therapeutic regimens for these individuals. Factors such as drug metabolism, genetics, and concomitant disease affect drug efficacy and may be important in determining therapeutic outcomes in these patients. This review will focus on these factors in the treatment of childhood ALL. Pediatr Blood Cancer 2008;51:320–326.