Purpose: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patientsExperimental Design: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6).Results: CYP3A activity (AUC 0 -40min ) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by ϳ50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, ␣-1 acid glycoprotein, explained ϳ18% of overall variation in CYP3A activity (P < 0.001).Conclusions: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.

Vancomycin-associated AKI occurs infrequently in the pediatric cardiac intensive care population and is strongly associated with patient critical illness.

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OBJECTIVESPatients supported on extracorporeal membrane oxygenation (ECMO) have an increased incidence of seizures. Phenobarbital (PB) and fosphenytoin (fos-PHT) are common antiepileptic drugs (AEDs) used to manage seizures in the pediatric population; however, it is unknown what effect ECMO has on the serum concentrations of AEDs. The purpose of this study is to evaluate the effect of ECMO on AED serum concentrations.METHODS A retrospective, matched-cohort study was performed in patients younger than 18 years who received ECMO and were treated with intravenous (IV) PB or fos-PHT at Texas Children's Hospital between 2004 and 2014. Patients receiving IV AED therapy and ECMO were matched, based on age, sex, and weight, with patients receiving IV AED therapy without ECMO. The 24-hour cumulative AED dose, serum concentrations, number of doses per serum concentration drawn ratio, volume of distribution, therapeutic serum concentrations, and time to therapeutic serum concentration were compared between both groups. The fos-PHT and PB groups were analyzed in all patients and in neonates only. CONCLUSION Pediatric patients receiving PB on ECMO and neonatal patients receiving fos-PHT on ECMO required larger doses, and in pediatric patients achieved lower serum concentrations, suggesting the necessity for alternative dosing strategies in these populations.

Purpose: Bortezomib (PS-341), a first-in-class proteasome inhibitor, is metabolized by deboronation involving cytochrome P4503A (CYP3A), which also metabolizes docetaxel. Preclinical studies have shown synergy between bortezomib and taxanes. We conducted a phase I study combining bortezomib and docetaxel in refractory solid tumor patients. Experimental Design: Patients received escalating doses of weekly docetaxel (days 1 and 8) and twice weekly bortezomib (days 2, 5, 9, and 12) in 3-week cycles.Two subjects were enrolled at each dose level, with cohort expansion to six for dose-limiting toxicity (DLT). Dose levels 1, 2, and 3 consisted of docetaxel/bortezomib 25/0.8, 25/1.0, and 30/1.0 mg/m 2 , respectively. CYP3A activity and docetaxel pharmacokinetic studies were conducted, and proteasome inhibition was assessed. Results: Fourteen patients received a total of 34 cycles of treatment. Dose level 2 was expanded for DLT that occurred in two of six patients consisting of febrile neutropenia in one patient and grade 3 thrombocytopenia in one patient. One patient received two cycles at dose level 3 with dose reduction to dose level 2, where grade 3 thrombocytopenia occurred at cycle 3. Both episodes of grade 3 thrombocytopenia were transient (<7 days). Dose level 1was then expanded to six patients where no DLTs occurred. CYP3A activity and docetaxel clearance did not change between weeks 1and 5. Conclusions: The maximum tolerated dose was docetaxel 25 mg/m 2 (days 1and 8) with bortezomib 0.8 mg/m 2 (days 2, 5, 9, and 12) given every 21days. Bortezomib treatment did not alter CYP3A activity and docetaxel clearance.

Angiotensin-converting enzyme inhibitors (ACEi) are commonly used for pediatric cardiology patients. However, studies examining their safety for neonates with cardiac disease are scarce. The current study aimed to test the hypothesis that ACEi-mediated nephrotoxicity occurs in neonates and may be underappreciated in this population. A retrospective review of 243 neonates with cardiac disease between 2007 and 2010 was performed. Demographic data, weight, length, captopril and enalapril dosing, serum [K⁺], serum creatinine, and concomitant medications during ACEi therapy were recorded and analyzed. Body surface area (BSA), creatinine clearance (CrCl), and change in [K⁺] were calculated. The age range of neonates at ACEi initiation was 15.9-18.1 days. The inclusion criteria was met by 206 neonates: 168 term (82%) and 38 preterm (18%) newborns. Of these neonates, 42% were female, and all the patients had a BSA smaller than 0.33 m² (a group known to have relative renal insufficiency). The mean dose of enalapril was 0.08 ± 0.007 mg/kg for the preterm neonates and 0.08 ± 0.003 mg/kg for the term neonates. The mean dose of captopril was 0.07 ± 0.009 mg/kg for the preterm neonates and 0.13 ± 0.019 mg/kg for the term neonates. A significant decrease in CrCl occurred for both the preterm (p < 0.01) and term (p < 0.001) neonates while they were receiving ACEi. However, the two groups did not differ significantly (p = 0.183). Nearly 42% of all the patients showed renal risk, with approximately 30% demonstrating renal failure by modified pRIFLE (pediatric risk, injury, failure, loss, and end-stage renal disease) criteria. Despite the lack of significantly different CrCl, the premature neonates were more likely to experience ACEi-related renal failure by pRIFLE (55%) than their term counterparts (23%; p < 0.001). Despite its common use for term neonates with cardiac disease, ACEi should be used cautiously and only when indications are clear. These results also raise the question whether ACEi should be used at all for preterm neonates.

Background: E-cigarette and vaping use-associated acute lung injury (EVALI) has been recently recognized as a complication in individuals who use vaping devices. Another consideration is that EVALI may have an adverse influence on the outcome of intercurrent respiratory infections. We document this deadly combination in the case of a young man who had EVALI and simultaneous Influenza-A infection leading to severe Acute Respiratory Distress Syndrome (ARDS). Case presentation: A 27-year-old male with a history of tobacco and vaping use was admitted to hospital after two weeks of flu-like symptoms, diarrhea and vomiting. A chest x-ray was consistent with multifocal pneumonia, and microbiological tests were positive for Influenza-A and methicillin-sensitive Staphalacoccus aureus (MSSA). Bronchoscopy provided evidence of acute inhalational injury. After admission, he acutely decompensated with severe hypoxia and hypotension; he required intubation, sedation and vasopressors. He developed sepsis with acute kidney failure, liver failure, biventricular systolic dysfunction and severe rhabdomyolysis. He was placed on veno-venous (VV) extracorporeal membrane oxygenation (ECMO) initially and later changed to Veno-Arterial (VA) ECMO. Nevertheless, the patient continued to deteriorate, and he expired two weeks after admission. Conclusion: This case documents that EVALI can act as a major factor leading a respiratory infection to progress into severe ARDS with a fatal outcome.

The Coronavirus Disease 2019 (COVID-19) pandemic has required rapid and effective protocol adjustments at every level of healthcare. The use of extracorporeal membrane oxygenation (ECMO) is pivotal to COVID-19 treatment in cases of refractory hypoxemic hypercapnic respiratory failure. As such, our large, metropolitan air ambulance system in conjunction with our experts in advanced cardiopulmonary therapies modified protocols to assist peripheral hospitals in evaluation, cannulation and initiation of ECMO for rescue and air transportation of patients with COVID-19 to our quaternary center. The detailed protocol is described alongside initial data of its use. To date, 14 patients have been placed on ECMO support at an outside facility and successfully transported via helicopter to our hub hospital using this protocol.