N-aralkylated Derivatives Of 1-aminobenzotriazole: Isozyme-selective Mechanism-based Inhibitors Of Guinea Pig Cytochrome P-450

1-Aminobenzotriazole (ABT) and its N-benzyl (BBT), N-{dollar}\alpha{dollar}-methylbenzyl ({dollar}\alpha{dollar}MB), and N-{dollar}\alpha{dollar}-ethylbenzyl ({dollar}\alpha{dollar}EB) derivatives were compared for their potency and isozyme-selectivity for mechanism-based inactivation of guinea pig hepatic and pulmonary cytochrome P450 (P450) in vitro, through the use of isozyme selective substrates for the guinea pig orthologs of rabbit P450 2B4, 1A1, and 4B1 (P450 2Bx, 1A1, 4Bx, respectively). {dollar}\alpha{dollar}MB, {dollar}\alpha{dollar}EB, and to a lesser extent, BBT, selectively inactivated P450 2Bx in pulmonary microsomes from untreated or {dollar}\beta{dollar}-naphthoflavone ({dollar}\beta{dollar}NF)-induced, and hepatic microsomes from phenobarbital (PB)-induced, guinea pigs. P450 loss caused by ABT paralleled the inhibition of enzyme activity in hepatic and pulmonary microsomes; however, P450 loss caused by BBT, {dollar}\alpha{dollar}MB or {dollar}\alpha{dollar}EB was never greater than 45% even when monooxygenase activity was inhibited by virtually 100%. BBT, {dollar}\alpha{dollar}MB and {dollar}\alpha{dollar}EB were more potent inhibitors of P450 activity in hepatic and pulmonary microsomes from untreated compared to induced guinea pigs.;The NADPH-dependent metabolism, and covalent binding to protein, of ({dollar}\sp{lcub}14{rcub}{dollar}C) ABT,N-benzyl-1-amino- ({dollar}\sp{lcub}14{rcub}{dollar}C) 2,3-benzotriazole( ({dollar}\sp{lcub}14{rcub}{dollar}C) 2,3-BBT), and N- ({dollar}\sp{lcub}14{rcub}{dollar}C) 7-benzyl-1-aminobenzotriazole ( ({dollar}\sp{lcub}14{rcub}{dollar}C) 7-BBT), were examined in guinea pig hepatic or pulmonary microsomes. Hepatic microsomes from {dollar}\beta{dollar}NF (vs PB) treated guinea pigs metabolized ({dollar}\sp{lcub}14{rcub}{dollar}C) ABT, ({dollar}\sp{lcub}14{rcub}{dollar}C) 2,3-BBT or ({dollar}\sp{lcub}14{rcub}{dollar}C) 7-BBT more extensively and to more products. NADPH-dependent covalent binding to microsomal protein of ({dollar}\sp{lcub}14{rcub}{dollar}C) 2,3-BBT or ({dollar}\sp{lcub}14{rcub}{dollar}C) 7-BBT was greater than that of ({dollar}\sp{lcub}14{rcub}{dollar}C) ABT in hepatic microsomes, especially those from PB-induced animals, and the covalently modified proteins co-migrated with P450 2Bx on Western blots. Covalent binding per nmol P450 in pulmonary microsomes was 3- to 4-fold higher with ({dollar}\sp{lcub}14{rcub}{dollar}C) 2,3-BBT than with ({dollar}\sp{lcub}14{rcub}{dollar}C) 7-BBT or ({dollar}\sp{lcub}14{rcub}{dollar}C) ABT.; ({dollar}\sp{lcub}14{rcub}{dollar}C) BBT, at a dose which effectively inhibited pulmonary P450 2Bx, was rapidly metabolized and excreted by guinea pigs following i.v. administration, with 75% of the radiolabel excreted in the urine within 12 hr. By 48 hr, {dollar}\u3c{dollar}1% of the radiolabel was present in liver, lungs, or kidneys of these animals.;In summary, BBT, {dollar}\alpha{dollar}MB, and {dollar}\alpha{dollar}EB are potent isozyme selective (P450 2Bx) inhibitors of guinea pig hepatic and pulmonary microsomal P450. BBT is metabolized in vitro to at least two reactive species capable of covalent modification of protein, and is rapidly ({dollar}\u3c{dollar}12 hr) metabolized and excreted in vivo

Progression of C-reactive protein from birth through preadolescence varies by mode of delivery

INTRODUCTION: Delivery via caesarean section (C-section) has been associated with an increased risk of childhood chronic diseases such as obesity and asthma, which may be due to underlying systemic inflammation. However, the impact of specific C-section types may be differential, as emergency C-sections typically involve partial labor and/or membrane rupture. Our objectives were to determine if mode of delivery associates with longitudinal profiles of high sensitivity CRP (hs-CRP) -a marker of systemic inflammation-from birth through preadolescence, and to examine if CRP mediates the association between mode of delivery and preadolescent body mass index (BMI). METHODS: Data from the WHEALS birth cohort (N = 1,258) were analyzed; 564 of the 1,258 children in the cohort had data available for analysis. Longitudinal plasma samples (birth through 10-years of age) from 564 children from were assayed for hs-CRP levels. Maternal medical records were abstracted to obtain mode of delivery. Growth mixture models (GMMs) were used to determine classes of hs-CRP trajectories. Poisson regression with robust error variance was used to calculate risk ratios (RRs). RESULTS: Two hs-CRP trajectory classes were identified: class 1 (76% of children) was characterized by low hs-CRP, while class 2 (24% of children) was characterized by high and steadily increasing hs-CRP. In multivariable models, children delivered via planned C-section had 1.15 times higher risk of being in hs-CRP class 2, compared to vaginal deliveries (p = 0.028), while no association was found for unplanned C-section deliveries [RR (95% CI) = 0.96 (0.84, 1.09); p = 0.49]. Further, the effect of planned C-section on BMI z-score at age 10 was significantly mediated by hs-CRP class (percent mediated = 43.4%). CONCLUSIONS: These findings suggest potentially beneficial effects of experiencing partial or full labor, leading to a lower trajectory of systemic inflammation throughout childhood and decreased BMI during preadolescence. These findings may have implications for chronic disease development later in life

Database analysis of venous thromboembolism treatment patterns in inpatient vs outpatient settings

Background: The standard of care for patients with venous thromboembolism (VTE) has been treatment with parenteral anticoagulation therapy, such as low-molecular weight heparin (LMWH), followed by long-term treatment with an oral vitamin K antagonist, such as warfarin. In recent years, novel oral anticoagulants have been approved for treatment and prevention of recurrent venous thromboembolism. There is little in the literature regarding real-world treatment patterns following outpatient diagnosis of VTE. Objectives: To describe the characteristics of outpatient-diagnosed patients treated for VTE in inpatient and outpatient settings, and characterize treatment patterns for initial treatment and secondary prevention of VTE. Methods: This study was a non-interventional retrospective observational cohort study conducted within an integrated health care system. Patients were identified using an algorithm comprised of VTE ICD-9 codes in combination with imaging procedures and treatments consistent with VTE. VTEs were verified by medical record review. Results: Inpatient-treated subjects had a mean age at Index (date of VTE diagnosis) of 65.7 (±15.1) years while outpatient-treated had a mean age of 61.6 (±16.3) years (p = 0.026). Eighty percent of all patients experienced an isolated deep vein thrombosis (DVT), 10% experienced isolated pulmonary embolism (PE) and 10% experienced PE with DVT. A significantly greater proportion of subjects with PE, alone or with DVT, were treated as inpatient (90%) and a greater proportion of subjects with isolated DVT were treated as outpatient (75%) (p \u3c 0.001). Initial anticoagulant therapy consisted of LMWH, warfarin and/or heparin for 90%, 29% or 2% of outpatient-treated and 74%, 88% or 82% of inpatient-treated patients, respectively. Extended anticoagulation consisted primarily of warfarin and/or LMWH for 87% and 81% of outpatient-treated and 76% and 58% of inpatient-treated patients, respectively. Conclusions: Patients with DVT were more likely to be treated as outpatients and those with any PE were more likely to be hospitalized. Hospitalized patients were older and had more comorbidities and risk factors. Patients treated as outpatients received LMWH as initial treatment but 30% of them also received warfarin. Outpatient-treated patients received LMWH and warfarin as extended therapy. Patients who were hospitalized received LMWH and/or warfarin and/or heparin as initial treatment and received warfarin, and to a lesser extent, LMWH as extended therapy

Assessment of cognitive impairment, treatment adherence, and healthcare resource utilization among treated schizophrenia patients

Background: Cognitive impairment associated with schizophrenia (CIAS) is common and can impact health outcomes (1). Information on the use of cognitive testing in clinical practice is lacking, and the relationship between cognitive impairment and healthcare resource utilization (HCRU) is poorly understood. This study assessed the measurement of CIAS and the associa-tion between CIAS, treatment adherence, and HCRU. Methods: Claims data from the Henry Ford Health System, a vertically integrated healthcare system serving metropolitan Detroit, Michigan, were used to identify patients aged 18 to 64 years with schizophrenia and use of antipsychotics from January 01, 2009, to June 30, 2014. Patients had ≥12 months of continuous enrollment preindex and ≥6 months postindex. The index date was the date of frst diagnosis of schizophrenia. Patients with cognitive decline independent of CIAS or schizoaf-fective disorder were excluded. Electronic medical records (EMR) were used to confrm diagnosis of schizophrenia and to assess measures of CIAS. Due to the lack of standardized measures of CIAS, 2 independent expert reviewers assessed mental status exam (MSE) records for evidence of CIAS and classifed patients as “clearly impaired” or “not impaired” during the assessment period. Administrative claims were used to assess treatment adherence during the study period and HCRU in the 12 months following index among patients with ≥12 months of follow-up. Descriptive statistics were performed as the study was exploratory in nature. Results: Following application of the inclusion/exclusion criteria and EMR assessment, 65 subjects were confrmed schizophrenia patients. The sample was 59% male with average age at index date of 43 years; 22% of patients were white, 62% black, and the remaining were unclassifed. Only 8% of patients had evidence of a standardized cognitive assessment. However, all patients had ≥1 MSE records; 60% (N = 39) of patients were classifed with CIAS through MSE review. The average medication possession ratio (MPR) for antipsychotic medica-tions was 0.4 ± 0.3 for cognitively impaired patients (N = 29) and 0.6 ± 0.4 for nonimpaired patients (N = 25). CIAS patients had 0.5 ± 0.4 outpatient visits, 0.08 ± 0.0 hospitalizations, and 0.15 ± 0.08 emergency department visits per patient per month (PPPM), whereas nonimpaired patients had 0.7 ± 0.7, 0 ± 0.0, and 0.08 ± 0.0 visits, respectively. Conclusion: Although cognitive impairment is prevalent in schizophrenia patients, the results suggest that CIAS is not formally assessed in clinical practice. Additional research is needed to understand the relationship between CIAS, HCRU, and outcomes

Birth Mode, Breastfeeding, Pet Exposure, and Antibiotic Use: Associations With the Gut Microbiome and Sensitization in Children

PURPOSE OF REVIEW: The infant gut microbiota has become a focus of multiple epidemiologic and cohort studies. This microbiome is derived from the mother (via the vaginal canal, maternal skin contact, breastfeeding, and possibly in utero microbial transfer) and is likely influenced by multiple external factors. It is now believed by some experts that colonization and formation of the newborn and alterations of gut microbiota in children are dependent on earlier alterations of the microbiota of mothers during or perhaps even before pregnancy. This review will focus on specific factors (pet keeping, breastfeeding, antibiotic use, and mode of delivery) that influence the infant gut microbiome and atopy. RECENT FINDINGS: This is a review of recent literature describing how pet keeping, breastfeeding, antibiotic use, and mode of delivery influences and changes the infant gut microbiome and atopy. General trends in gut microbiota differences have emerged in different birth cohorts when each external factor is analyzed, but consistency between studies is difficult to replicate. The aforementioned factors do not seem to confer an overwhelming risk for development of atopy alone. This review provides a comprehensive review of early life environmental factors and their influence on the infant gut microbiome and atopy

Can valid cases of schizophrenia be identified in administrative claims data?

Background: Large data sources, such as administrative claims, can be used to better understand the natural history, treatment and outcomes of schizophrenia provided that valid cases can be identified. International Classification of Diseases (ICD) codes or a combination of ICD codes and prescription claims have been used to identify schizophrenia patients, but validation studies of these methods for schizophrenia are limited. Objectives: To determine if valid cases of patients with schizophrenia can be identified using administrative claims data. Methods: Claims data from the Henry Ford Health System, an integrated healthcare system serving metropolitan Detroit, Michigan, were used to identify patients aged 18-64 years with schizophrenia from 01/ 01/2009 to 06/30/2014. Potential cases had ≥2 ICD-9 codes (295.x) for schizophrenia disorder in any position, ≥2 claims for an antipsychotic medication, ≥12 months of continuous enrollment pre-index, and ≥6 months of continuous enrollment post-index. Index date was defined as the first 295.x ICD-9 code. Patients with organic cognitive decline or schizoaffective disorder independent of schizophrenia were excluded. Trained medical records abstractors performed a structured review of all relevant fields including inpatient and outpatient records of the electronic medical record (EMR) (e.g. diagnosis fields; free text) to verify the schizophrenia diagnosis ±12 months from the index date. Results: Of the 145 patients who met inclusion/exclusion criteria, EMR review was completed on a random sample of 111 patients. Of these, 65 had an EMR-confirmed diagnosis of schizophrenia for a positive predictive value (PPV) of 59% (95% confidence interval: 52-64%). Unconfirmed patients had diagnoses of bipolar disorder (N = 25; 54%), major depressive disorder (N = 28; 61%), and/or schizoaffective disorder (N = 3; 7%). These diagnoses may be comorbid with a schizophrenia diagnosis, but no schizophrenia diagnosis was recorded. Conclusions: Identifying valid cases of schizophrenia in administrative claims data is challenging. There are few published studies of validated claims-based algorithms that identify cases of treated schizophrenia. This study, requiring ≥2 ICD-9 codes and ≥2 prescription claims, did not yield a high PPV for schizophrenia. Reasons may include diagnostic challenges in differentiating psychiatric conditions or comorbid diagnoses where only 1 diagnosis is recorded. Future studies of validated algorithms to identify schizophrenia patients are warranted

Developing a multiphase claims-based algorithm for non-live pregnancy outcomes research

Background: Non-live outcomes occur in about 30% of pregnancies and may be mediated by exposure to medication during pregnancy, depending on various factors including drug type, length, of exposure and/or time of exposure (eg, foetus age/proximity to conception). Understanding the safety of medication exposure during pregnancy is critical but presents methodological challenges. Registries are common, but often yield few cases. Administrative claims data can be used to study large numbers of women if the claims data accurately identify/estimate non-live outcomes, gestational age (GA) at non-live outcome, and medication exposure during pregnancy ending in non-live outcome. Objectives: To develop a multiphase claims-based algorithm that identifies non-live outcomes (Phase [Ph]1), estimates GA at non-live outcome (Ph2) and estimates medication exposure during pregnancy ending in non-live outcome (Ph3). Methods: A multiphase algorithm is being developed in stages among women aged ≥15 and ≤50 years with ≥1 end of pregnancy (EOP) ICD-9 code and enrolment and prescription coverage 340 days prior to EOP in the Henry Ford Health System in the United States between January 1, 2013, and September 30, 2015. Algorithms have been (Ph1) or will be (Ph2-3) developed, applied to claims data, and validated against electronic medical records using estimated positive predictive value (PPV), sensitivity, and corresponding 95% confidence interval (CI). The best-performing algorithm in each phase is used in the next phase. Based on previous work for live outcomes presented at ICPE 2017 (abstract 154), Ph1 Algorithm 1 (≥1 definitive ICD-9 EOP code) validation was modified to ascertain events ±30 days from the EOP date (vs 0-7 days). Work is ongoing to assess algorithms that estimate GA at non-live outcome by assigning an estimated GA to 3 or 5 categories of non-live outcomes (Ph2) and to assess drug exposure during pregnancy to long-term (eg, antidepressants) and short-term (antibiotics) medications based on estimated GA (Ph3). Results: A total of 698 women met the inclusion criteria, and 145 had non-live EOP codes. When validating EOP codes within 0-7 days of the EOP date, the Ph1 Algorithm 1 PPV was 79% (95% CI: 71, 85), and the sensitivity was 97% (95% CI: 96, 99). When validating EOP codes ±30 days from the EOP date, the PPV was 85% (95% CI: 78, 90), and the sensitivity was 100% (95% CI: 97, 100). Conclusions: Non-live EOP outcomes can be identified in claims data with high PPV and sensitivity. Further analyses are underway to validate algorithms for Ph2 and Ph3