Continuous Partial Oxidation of Methane to Methanol Catalyzed by Diffusion-Paired Copper Dimers in Copper-Exchanged Zeolites.

Copper-exchanged zeolites can continuously and selectively catalyze the partial oxidation of methane to methanol using only oxygen and water at low temperatures, but the genesis and nature of the active sites are currently unknown. Herein, we demonstrate that this reaction is catalyzed by a [Cu-O-Cu]2+ motif that forms via a hypothesized proton-aided diffusion of hydrated Cu ions within the cages of SSZ-13 zeolites. While various Cu configurations may be present and active for methane oxidation, a dimeric Cu motif is the primary active site for selective partial methane oxidation. Mechanistically, CH4 activation proceeds via rate-determining C-H scission to form a surface-bound C1 intermediate that can either be desorbed as methanol in the presence of H2O/H+ or completely oxidized to CO2 by gas-phase O2. High partial oxidation selectivity can be obtained with (i) high methane and water partial pressures and (ii) maximizing Cu dimer formation by using zeolites with high Al content and low Cu loadings.

Effect of Exogenous Antithrombin Administration on Anti-Xa Levels in Infants Treated With Enoxaparin.

OBJECTIVES: Determine the effect of exogenous antithrombin III administration on low molecular weight heparin anti-Xa levels in the context of enoxaparin dosing in infants. METHODS: A retrospective chart review of infants receiving concomitant antithrombin III and enoxaparin. The primary objective of this study was to determine the median change in anti-Xa level with antithrombin III supplementation. Secondary objectives were to analyze the median change in antithrombin III levels after administration of exogenous antithrombin III, the dosing of antithrombin III, and the dose of enoxaparin throughout therapy. For a safety analysis, any bleeding events were recorded. RESULTS: The study included 17 patients who received a total of 33 doses of antithrombin III. The median change in anti-Xa levels in infants receiving exogenous antithrombin III was 0.2 units/mL (p < 0.001). The median dose of antithrombin III was 50 units/kg and was administered when patients were receiving a median enoxaparin dose of 1.71 mg/kg. The median increase in antithrombin III levels was 16.5% (p < 0.001). CONCLUSIONS: These results demonstrated that administration of exogenous antithrombin III to infants who were being treated with enoxaparin results in a significant increase in anti-Xa levels. At this time, there is insufficient evidence to recommend routine administration of antithrombin III to infants on enoxaparin. However, antithrombin III supplementation could be considered a potential option for patients who are unable to adequately achieve therapeutic anti-Xa levels with enoxaparin alone.

Evaluation of the Effects of Extracorporeal Membrane Oxygenation on Antiepileptic Drug Serum Concentrations in Pediatric Patients.

OBJECTIVES: Patients 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. RESULTS: Fourteen patients met inclusion criteria. The fos-PHT neonatal (20.1 vs 11.3 mg/kg/day, p = 0.044), PB composite (33.9 vs 21.6 mg/kg/day, p = 0.012), and PB neonatal (40.3 vs 20 mg/kg/day, p = 0.04) had larger 24-hour cumulative doses compared with non-ECMO patients. Lower serum concentrations were observed in the PB composite ECMO group (19.1 vs 35.4 mg/L, p < 0.001) and the PB neonatal ECMO group (20.5 vs 27.8 mg/L, p = 0.01) compared with non-ECMO patients. 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.

Use of Vasopressin in Neonatal Intensive Care Unit Patients With Hypotension.

OBJECTIVE: To evaluate the safety and efficacy of vasopressin for the treatment of hypotension in patients admitted to neonatal intensive care units (NICUs). METHODS: Vasopressin use in 69 infants admitted to our NICU between 2011 and 2014 was examined. Data evaluated included demographics; serum creatinine, sodium, and lactate concentrations; urine output; and systolic, diastolic, and mean blood pressures (BPs). Parameters prior to vasopressin use were compared to those at maximum dose. RESULTS: Vasopressin use was associated with increased urine output (p < 0.05), and increased systolic (p < 0.0005), diastolic (p < 0.01), and mean (p < 0.001) BP. There were no differences in sodium or lactate concentrations before vs during infusion; vasopressin use was not associated with hyponatremia (sodium < 130 mEq/L) at the maximum dose. CONCLUSIONS: Vasopressin for the treatment of neonatal hypotension appears safe and was efficacious in raising BP. These data suggest that vasopressin could be considered a viable option in the treatment regimen in hypotensive infants in the NICU.

Evaluating the safety of intermittent intravenous sildenafil in infants with pulmonary hypertension.

OBJECTIVE: To compare the occurrence of hypotension following administration of intermittent intravenous (IV) and enteral sildenafil for treatment of pulmonary hypertension (PH) in infants. We hypothesized there may be more adverse effects associated with intermittent IV sildenafil compared with enteral sildenafil. METHODS: This was a retrospective matched-cohort study conducted in a tertiary care children's hospital. Patients were included if they were less than 1 year of age and received intermittent sildenafil for PH. Exclusion criteria consisted of concurrent extracorporeal membrane oxygenation during the initiation of sildenafil, the utilization of sildenafil as a one-time dose, continuation of home-dosing regimen, or inclusion in the other cohort. A total of 40 patients were matched 1:1 based on postmenstrual age and primary diagnosis. RESULTS: There was no statistically significant difference in the primary outcome, as 30% (6/20) of patients receiving IV sildenafil required a hypotension intervention compared with 10% (2/20) in the enteral cohort (P = 0.24). The majority of interventions occurred within 24 hr of the initiation of sildenafil with 4/6 patients (67%) in the IV group and 2/2 patients (100%) in the enteral group, respectively. Baseline mean arterial pressure was significantly lower in the IV patients that required an intervention compared with those that did not (44 ± 6.3 vs. 65 ± 13.4 mmHg, P = 0.0024). CONCLUSIONS: There were no statistically significant differences in safety outcomes between intermittent IV and enteral sildenafil in infants with PH. Hemodynamic parameters should be monitored closely upon sildenafil initiation. Limitations include the retrospective nature and small sample size. Pediatr Pulmonol. 2017;52:232-237. © 2016 Wiley Periodicals, Inc.

Stability and Sterility of Enoxaparin 8 mg/mL Subcutaneous Injectable Solution.

BACKGROUND: Enoxaparin is often diluted to accurately deliver doses to neonatal and infant patients. Current recommendations for dilutions may not be adequate for the smallest patients. METHODS: Review of dosing at our institution occurred, and an 8 mg/mL concentration of enoxaparin was chosen. A concentration of 8 mg/mL was compounded by diluting 0.4 mL of enoxaparin (100 mg/mL) into 4.6 mL of sterile water for injection into an empty sterile vial. Four syringes of the 8 mg/mL concentration were prepared by 5 technicians (20 total syringes). Stability and sterility testing occurred a 0, 7, 14, and 30 days. One-way repeated-measures analysis of variance was used to detect significant differences in Anti-Factor Xa concentrations at the testing time points. RESULTS: The dilution of enoxaparin was sterile at 30 days but exhibited significant degradation at the 30-day point (p < 0.05). CONCLUSION: A dilution of enoxaparin 8 mg/mL is stable and sterile for 14 days refrigerated but is not stable at 30 days.

Outcomes in Postoperative Pediatric Cardiac Surgical Patients Who Received an Antiepileptic Drug.

BACKGROUND: Advances in cardiac operations over the last few decades, including corrective operations in early life, have dramatically increased the survival of children with congenital heart disease. However, postoperative care has been associated with neurologic complications, with seizures being the most common manifestation. The primary objective of this study is to describe the outcomes in pediatric patients who received an antiepileptic drug (AED) post-cardiac surgery. METHOD: A retrospective cohort study was performed in all patients less than 18 years of age who received an AED in the cardiovascular intensive care unit at Texas Children's Hospital from June 2002 until June 2012. Cardiac surgical patients initiated on phenobarbital, phenytoin, and levetiracetam were queried. Patients were excluded if the AED was not initiated on the admission for surgery. Patients who received 1 AED were compared to patients who received 2 AED, and differences in outcomes examined between the 3 AEDs used were evaluated. RESULTS: A total of 37 patients met the study criteria. Patients were initiated on an AED a median of 4 days following surgery and became seizure free a median of 1 day after initiation, with 65% remaining seizure free after the first dose. Half of all patients required 2 AEDs for seizure control, with a higher proportion of adolescents requiring 2 AEDs (p = 0.04). No differences were found when comparing the collected outcomes between phenobarbital, fosphenytoin, or levetiracetam. CONCLUSION: No adverse events were reported with the AEDs reviewed. Further work is necessary to evaluate long-term neurodevelopmental outcomes in this population and whether outcomes are a result of the AED or of other clinical sequelae.

Catalytic Oxidation of Methane into Methanol over Copper-Exchanged Zeolites with Oxygen at Low Temperature.

The direct catalytic conversion of methane to liquid oxygenated compounds, such as methanol or dimethyl ether, at low temperature using molecular oxygen is a grand challenge in C-H activation that has never been met with synthetic, heterogeneous catalysts. We report the first demonstration of direct, catalytic oxidation of methane into methanol with molecular oxygen over copper-exchanged zeolites at low reaction temperatures (483-498 K). Reaction kinetics studies show sustained catalytic activity and high selectivity for a variety of commercially available zeolite topologies under mild conditions (e.g., 483 K and atmospheric pressure). Transient and steady state measurements with isotopically labeled molecules confirm catalytic turnover. The catalytic rates and apparent activation energies are affected by the zeolite topology, with caged-based zeolites (e.g., Cu-SSZ-13) showing the highest rates. Although the reaction rates are low, the discovery of catalytic sites in copper-exchanged zeolites will accelerate the development of strategies to directly oxidize methane into methanol under mild conditions.

Prostaglandin Availability and Association with Outcomes for Infants with Congenital Heart Disease.

Data regarding availability of prostaglandin E1 (PGE) and its impact on the stabilization, transport, critical care course, and surgical outcome of infants with ductal-dependent congenital heart disease in the current pediatric healthcare environment are unknown. We sought to determine the proportion of hospitals in Texas that stock PGE and to investigate associations between PGE availability and clinical outcomes. All birth institutions listed with the Texas Department of Health and Human Services were contacted to determine PGE availability as of 2011. Outcomes of all infants admitted to our institution from 2007 to 2012 who received PGE for ductal-dependent lesions were evaluated. PGE was stocked in 50 % (n = 139) of hospitals that performed deliveries in Texas in 2011 representing 79.1 % (303, 481) of births. Hospitals that did not stock PGE had less annual births and were located a further distance from a center that provided pediatric cardiac surgical services. Patients born at a hospital that did not stock PGE had significantly greater serum lactate and creatinine (p = 0.002) and serum lactate on admission (p < 0.001). The PGE availability was not associated with hospital length of stay, postoperative length of stay, or mortality. When stratifying in TGA and HLHS subgroups, lack of PGE availability remained associated with higher creatinine, higher lactate, lower glucose, and lower pH. PGE is not universally available in all healthcare institutions providing obstetrical services. Lack of availability of PGE at an outlying hospital was associated with increased morbidity, but was not associated with mortality or length of stay.

Vancomycin-associated acute kidney injury in pediatric cardiac intensive care patients.

OBJECTIVE: Acute kidney injury (AKI) is a significant source of morbidity among critically ill pediatric patients, including those that have undergone cardiac surgery. Vancomycin may contribute to AKI in pediatric patients admitted to a cardiac intensive care unit. DESIGN AND SETTING: Patients admitted to the cardiac intensive care unit at Texas Children's Hospital and received vancomycin over a 4-year period were included in a case-control study. Patients were excluded if they underwent renal replacement therapy during vancomycin therapy. Patient demographic and disease state variables, vancomycin therapy variables, and use of other nephrotoxic medications were collected. The overall incidence of AKI was calculated based on doubling of serum creatinine during or within 72 hours of vancomycin therapy (vancomycin-associated AKI [vAKI]). Patients who developed vAKI were matched with three patients who did not develop vAKI, and conditional logistic regression was used to determine independent risk factors for vAKI. RESULTS: A total of 418 patients met study criteria (males 57.8%) and infants (31 days to 2 years) were the most populous age group (48.6%). Vancomycin-associated AKI occurred in 30 patients (7.2%), which resulted in a total of 120 patients (30 cases; 90 controls). No significant differences were noted in vancomycin dosing between groups. Vancomycin-associated AKI patients were less likely to have undergone cardiac surgery (P < .05), more likely to have undergone extracorporeal membrane oxygenation (P < .05), and had greater exposure to nephrotoxic medications (P < .05). A conditional logistic regression model identified extracorporeal membrane oxygenation as associated with vAKI (odds ratio 14.4, 95% confidence interval 1.02-203, P = .048) and patients with prior cardiovascular surgery (odds ratio 0.10, 95% confidence interval 0.02-0.51, P < .01) or an elevated baseline serum creatinine (odds ratio 0.009, 95% confidence interval 0.0002-0.29, P < .01) as less likely to develop vAKI. CONCLUSIONS: Vancomycin-associated AKI occurs infrequently in the pediatric cardiac intensive care population and is strongly associated with patient critical illness.

Micronutrient requirements of high-risk infants.

Micronutrient requirements are well-established for healthy full-term infants. However, few such recommendations exist for high-risk infants, including full-term infants with a variety of medical disorders or very preterm infants. Key micronutrients considered in this review are calcium, phosphorus, magnesium, iron, and zinc. The ongoing unresolved shortages, especially of intravenous forms of these minerals, remain a major problem. Considered are some aspects of how the nutrient shortages may be managed, recognizing the complexity and changing nature of the supply.

Low cobalamin levels in African Americans with and without sickle cell disease.

About 7% of the adult population has subclinical cobalamin (B12) deficiency. Subjects with sickle cell disease (SCD) may be at higher risk of cobalamin deficiency because of increased demand, inadequate supply, coexisting folate deficiency or malabsorption. We compared the clinical and laboratory characteristics of low serum cobalamin levels in patients with SCD with those patients without this hemoglobinopathy (non-SCD). Between 1993 and 2003, 105 SCD patients and 112 non-SCD patients who had serum cobalamin measurements were identified at our institution. The mean cobalamin level in SCD patients was significantly lower (496 +/- 352 pg/ml) than that in patients without SCD (869 +/- 660 pg/ml, p<0.0001). The frequency of low cobalamin levels, defined by a serum cobalamin level of <200 pg/ml, was 18.1% (19/105) and 9.8% (11/112) in SCD and non-SCD patients, respectively (chi2=3.11, nonsignificant). The mean age of the low-cobalamin SCD and non-SCD patients was 28.1 and 62.9, respectively, and their male:female ratios were 11:8 in SCD patients and 2:9 in non-SCD patients. None of the SCD patients had neurological manifestations, but nine of the 11 non-SCD low-cobalamin level patients did. The proportion of SCD patients with unexplained low cobalamin levels (13/19) was higher than that in non-SCD patients (4/11, chi2=2.92, nonsignificant) Our data suggest that cobalamin levels are lower in SCD patients than in subjects without SCD, and low-cobalamin SCD patients are younger and more likely to be males.

Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors.

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 1 was then expanded to six patients where no DLTs occurred. CYP3A activity and docetaxel clearance did not change between weeks 1 and 5. CONCLUSIONS: The maximum tolerated dose was docetaxel 25 mg/m(2) (days 1 and 8) with bortezomib 0.8 mg/m(2) (days 2, 5, 9, and 12) given every 21 days. Bortezomib treatment did not alter CYP3A activity and docetaxel clearance.

Factors affecting cytochrome P-450 3A activity in cancer patients.

PURPOSE: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients. EXPERIMENTAL 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(0-40 min)) 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 approximately 50% 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, alpha-1 acid glycoprotein, explained approximately 18% 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.

Doxorubicin cardiotoxicity in African Americans.

PURPOSE: The African-American race was examined as a risk factor for cardiotoxicity from doxorubicin-based therapy for cancer. PATIENTS AND METHODS: Retrospective survey of the Howard University Hospital cancer registry during 1997-2001 identified 100 evaluable patients out of 120 African Americans who underwent doxorubicin-based combination chemotherapy (65% women, 35% men, median age 46 years, range 32-84 years). The fraction of patients who developed post-treatment cardiotoxicity, defined as congestive heart failure or a left-ventricular ejection fraction less than 45%, was compared with that from a retrospective study of 399 patients of unknown age and racial distribution. Cases were stratified by cumulative dose of doxorubicin. Statistical significance of the difference in incidence of cardiotoxicity was tested by chi-square analysis. RESULTS: Patients received multiple doses of doxorubicin (range 264 to 580 mg/m2 with median of 374) with the final echocardiographic assessment at a median of 1.3 years. Howard oncologists frequently used a 48-hour infusion rather than the conventional rapid bolus to reduce the cardiotoxicity of doxorubicin. The fraction with cardiotoxicity in our study versus Lefrak's review at four ranges of doxorubicin was 25% versus 18% at 551-600 mg/m2, 10% versus 4% at 501-550 mg/m2, 4% versus 1% at 451-500 mg/m2, and 0% versus <1% at <450 mg/m2. Seventy-two percent of the patients having depressed ejection fraction and/or heart failure were women. African Americans had a higher rate of cardiotoxicity after doxorubicin (7/100 cases) than that of Lefrak's (10/399) study population and were statistically significant at p<0.027 with an odds ratio of 2.93. CONCLUSION: We have shown for the first time that African Americans at our institution appear to suffer cardiotoxicity from doxorubicin three times more frequently than the previously noted study population. To better clarify this observation, a larger study in a multiracial setting is needed.

Hypopigmentation in an African patient treated with imatinib mesylate: a case report.

Imatinib mesylate (STI 571, Gleevec) is a potent bcr-abl tyrosine kinase inhibitor. It also inhibits c-kit tyrosine kinase. Imatinib mesylate is active in the treatment of cronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). It is considered by some authorities to be the standard of care in newly diagnosed CML as well as patients in chronic phase who do not have a related match. C-kit and its ligand stem-cell factor regulate melanocyte development and survival. Hypopigmentation in patients receiving imatinib mesylate for CML has been reported recently. In this article, we report a black Nigerian male with GIST, who developed hypopigmentation of distal parts of digits, as well as generalized lightening of skin on the body three months after receiving imatinib mesylate. We believe that this is the first case of hypopigmentation reported in a black patient with GIST.

Advanced gastrointestinal stromal tumors successfully treated with imatinib mesylate: a report of two cases.

Activation of kit-receptor tyrosine kinase occurs in all cases of gastrointestinal stromal tumors, regardless of the mutation status of kit. Imatinib mesylate (STI 571,Gleevec) is a selective inhibitor of certain protein tyrosine kinases. It has been shown in preclinical models and clinical studies to have activity against such tumors. The aim of the present study was to report the efficacy of imatinib mesylate in the treatment of advanced gastrointestinal stromal tumors. Two adults with histologically confirmed, unresectable, and metastatic gastrointestinal stromal tumors that expressed CD117 (a marker of kit-receptor tyrosine kinase) were identified at our institution during 2000-2002. As the diseases were advanced and not amenable to surgery, chemotherapy, or radiation therapy, imatinib mesylate was used, because this targeted inhibitor has been shown to be active against advanced gastrointestinal stromal tumors and has a mild toxicity profile. Imatinib mesylate induced a sustained response in both patients with advanced unresectable or metastatic gastrointestinal stromal tumors. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.