New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types.

AP endonuclease-1/Redox factor-1 (APE1/Ref-1 or Ref-1) is a multifunctional protein that is overexpressed in most aggressive cancers and impacts various cancer cell signaling pathways. Ref-1's redox activity plays a significant role in activating transcription factors (TFs) such as NFκB, HIF1α, STAT3 and AP-1, which are crucial contributors to the development of tumors and metastatic growth. Therefore, development of potent, selective inhibitors to target Ref-1 redox function is an appealing approach for therapeutic intervention. A first-generation compound, APX3330 successfully completed phase I clinical trial in adults with progressing solid tumors with favorable response rate, pharmacokinetics (PK), and minimal toxicity. These positive results prompted us to develop more potent analogs of APX3330 to effectively target Ref-1 in solid tumors. In this study, we present structure-activity relationship (SAR) identification and validation of lead compounds that exhibit a greater potency and a similar or better safety profile to APX3330. In order to triage and characterize the most potent and on-target second-generation Ref-1 redox inhibitors, we assayed for PK, mouse and human S9 fraction metabolic stability, in silico ADMET properties, ligand-based WaterLOGSY NMR measurements, pharmacodynamic markers, cell viability in multiple cancer cell types, and two distinct 3-dimensional (3D) cell killing assays (Tumor-Microenvironment on a Chip and 3D spheroid). To characterize the effects of Ref-1 inhibition in vivo, global proteomics was used following treatment with the top four analogs. This study identified and characterized more potent inhibitors of Ref-1 redox function (that outperformed APX3330 by 5-10-fold) with PK studies demonstrating efficacious doses for translation to clinic.

Long-term childhood outcomes for babies born at term who were exposed to antenatal corticosteroids.

BACKGROUND: Antenatal corticosteroids improve neonatal outcomes when administered to infants who are at risk of preterm delivery. Many women who receive antenatal corticosteroids for threatened preterm labor proceed to deliver at term. Thus, long-term outcomes should be evaluated for term-born infants who were exposed to antenatal corticosteroids in utero. OBJECTIVE: This study aimed to compare long-term outcomes between term-born children aged ≥5 years who were born to women who received antenatal corticosteroids for threatened preterm labor and children whose mothers were also evaluated for threatened preterm labor but did not receive antenatal corticosteroids. STUDY DESIGN: We performed a retrospective cohort study of children born at ≥37 weeks' gestation, aged ≥5 years, and born to mothers diagnosed with threatened preterm labor during pregnancy. The primary exposure of interest was receiving antenatal corticosteroids. Among the collected childhood medical conditions, the primary outcome of interest was a diagnosis of asthma. RESULTS: Of the 3556 term-born children aged ≥5 years, 629 (17.6%) were exposed to antenatal corticosteroids (all betamethasone), and 2927 (82.3%) were controls whose mothers were evaluated for threatened preterm birth but did not get antenatal corticosteroid injections. Women receiving antenatal corticosteroids had higher rates of maternal comorbidities (diabetes mellitus, hypertension; P≤.01). Antenatal corticosteroid-exposed children had no difference in diagnosis of asthma (12.6% vs 11.6%), attention deficit disorder, or developmental delay (P=.47, .54, and .10, respectively). Controlling for maternal and neonatal characteristics, asthma was not different between those exposed to antenatal corticosteroids and controls (odds ratio, 1.05; 95% confidence interval, 0.79-1.39). The odds of the child's weight percentile being <10% were increased for antenatal corticosteroid-exposed children born at term (odds ratio, 2.00; 95% confidence interval, 1.22-3.25). CONCLUSION: Children born at term who were exposed to antenatal corticosteroids may have increased odds of being in a lower growth percentile than those not exposed. However, rates of diagnoses such as asthma, developmental delay, and attention deficit disorders were not different.

The Childhood Opportunity Index's Association with Adverse Pregnancy and Newborn Outcomes in Nulliparous Persons.

OBJECTIVE: The objective of the study was to determine if using a novel measure of social determinants of health, the Childhood Opportunity Index (COI), at the time of delivery was associated with development of adverse pregnancy outcomes (APO) in nulliparous pregnant persons. STUDY DESIGN: Data were extracted from the 779 participants from a single nuMoM2b (Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be) study site, a prospective cohort study designed to identify contributors to APOs. Residential address information at delivery was linked to the location's COI. The overall composite and component scores in education, health and environmental, and socioeconomic indices were recorded. APOs of interest included preterm birth, hypertensive disorders of pregnancy, small for gestational age at birth, stillbirth, and gestational diabetes. Participant characteristics were compared by COI category and the association of COI with APOs was analyzed by logistic regression, controlling for age and self-reported race/ethnicity. RESULTS: The overall COI distribution was very low (45%), low (17%), moderate (10%), high (15%), and very high (13%). A total of 329 (43.5%) participants experienced at least one APO. Overall COI was associated with developing an APO (p = 0.02). Each component score was also associated with developing APOs and with race/ethnicity (p < 0.05). Compared with higher COI categories, an overall low or very low categorized location was independently associated with developing an APO (odds ratio: 1.636, 95% confidence interval: 1.16-2.31). Adjusting for gestational age at birth, those in lower COI areas had newborns with lower birth weight, birth length, and head circumference (estimate [95% confidence interval] birth weight: -0.0005 g [-0.0008 to -0.0001]; length: -0.065 cm [-0.124 to -0.0091]; head circumference: -0.123 cm [-0.208 to -0.045]). COI was not associated with other newborn outcomes. CONCLUSION: COI, a marker for social determinants of health, is independently associated with APOs. The COI may be a tool for risk stratification for pregnant people to help with APO-reducing strategies. KEY POINTS: · The COI is a neighborhood-level marker for social determinants of health.. · The COI at time of delivery is associated with APO and newborn birth weight, length, and head circumference.. · The COI may be usable in pregnancy clinics to help identify resource needs to optimize outcomes for pregnant individuals and newborns..

STOP-AD portal: Selecting the optimal pharmaceutical for preclinical drug testing in Alzheimer's disease.

We propose an unbiased methodology to rank compounds for advancement into comprehensive preclinical testing for Alzheimer's disease (AD). Translation of compounds to the clinic in AD has been hampered by poor predictive validity of models, compounds with limited pharmaceutical properties, and studies that lack rigor. To overcome this, MODEL-AD's Preclinical Testing Core developed a standardized pipeline for assessing efficacy in AD mouse models. We hypothesize that rank-ordering compounds based upon pharmacokinetic, efficacy, and toxicity properties in preclinical models will enhance successful translation to the clinic. Previously compound selection was based solely on physiochemical properties, with arbitrary cutoff limits, making ranking challenging. Since no gold standard exists for systematic prioritization, validating a selection criteria has remained elusive. The STOP-AD framework evaluates the drug-like properties to rank compounds for in vivo studies, and uses an unbiased approach that overcomes the validation limitation by performing Monte-Carlo simulations. HIGHLIGHTS: Promising preclinical studies for AD drugs have not translated to clinical success. Systematic assessment of AD drug candidates may increase clinical translatability. We describe a well-defined framework for compound selection with clear selection metrics.

Physiologically based pharmacokinetic modelling in pregnancy: Model reproducibility and external validation.

AIMS: Physiologically based pharmacokinetic (PBPK) models have been previously developed for betamethasone and buprenorphine for pregnant women. The goal of this work was to replicate and reassess these models using data from recently completed studies. METHODS: Betamethasone and buprenorphine PBPK models were developed in Simcyp V19 based on prior publications using V17 and V15. Ability to replicate models was verified by comparing predictions in V19 to those previously published. Once replication was verified, models were reassessed by comparing predictions to observed data from additional studies in pregnant women. Model performance was based upon visual inspection of concentration vs. time profiles, and comparison of pharmacokinetic parameters. Models were deemed reproducible if parameter estimates were within 10% of previously reported values. External validations were considered acceptable if the predicted area under the concentration-time curve (AUC) and peak plasma concentration fell within 2-fold of the observed. RESULTS: The betamethasone model was successfully replicated using Simcyp V19, with ratios of reported (V17) to reproduced (V19) peak plasma concentration of 0.98-1.04 and AUC of 0.95-1.07. The model-predicted AUC ratios ranged from 0.98-1.79 compared to external data. The previously published buprenorphine PBPK model was not reproducible, as we predicted intravenous clearance of 70% that reported previously (both in Simcyp V15). CONCLUSION: While high interstudy variability was observed in the newly available clinical data, the PBPK model sufficiently predicted changes in betamethasone exposure across gestation. Model reproducibility and reassessment with external data are important for the advancement of the discipline. PBPK modelling publications should contain sufficient detail and clarity to enable reproducibility.

Does lack of exposure to individual antidepressants at different points during pregnancy associate with reduced risk of adverse newborn outcomes?

BACKGROUND: The objective of this study was to determine if the lack of exposure to individual antidepressants at certain times in pregnancy improved maternal and infant outcomes. METHODS: This was a retrospective cohort study of 2741 pregnant women prescribed antidepressant(s) before or during pregnancy. Data were obtained from electronic medical records. Analysis was limited to women prescribed one of five antidepressants (bupropion, citalopram, escitalopram, fluoxetine, sertraline). Period of exposure was determined using prescription order dates. Primary outcomes were neonatal intensive care unit (NICU) admission and adaptation syndrome in the newborn. Logistic regression, adjusted for maternal age, race, and insurance, compared consistent exposure throughout pregnancy versus (A) no exposure in the third trimester, (B) no exposure early in pregnancy, and (C) exposure in the midtrimester alone. RESULTS: Compared to women prescribed an antidepressant continually throughout pregnancy, NICU admission was less likely for women lacking exposure in the third trimester if they had been taking bupropion (aOR 0.43, 95% CI 0.21-0.90) or escitalopram (aOR 0.49, 95% CI 0.28-0.85). Women previously taking escitalopram but lacking third trimester exposure also had lower odds of adaptation syndrome (aOR 0.19, 95% CI 0.07-0.48). No differences were found in other outcomes for women taking other antidepressants or for any outcomes for women who lacked early pregnancy drug exposure compared to exposure throughout pregnancy. CONCLUSION: For the five antidepressants included in this study, lack of exposure early or late in pregnancy compared to consistent exposure throughout pregnancy generally did not change newborn outcomes. The exceptions were bupropion and escitalopram, where lack of exposure in the third trimester associated with lower rates of adaptation syndrome or NICU admission. These data may help pregnant women with depression in need of drug therapy to have informed discussions with providers about the potential risks and benefits to continuing or stopping drugs at different times during pregnancy.

Improving natural product research translation: From source to clinical trial.

While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.

Are newborn outcomes different for term babies who were exposed to antenatal corticosteroids?

BACKGROUND: Antenatal corticosteroids improve newborn outcomes for preterm infants. However, predicting which women presenting for threatened preterm labor will have preterm infants is inaccurate, and many women receive antenatal corticosteroids but then go on to deliver at term. OBJECTIVE: This study aimed to compare the short-term outcomes of infants born at term to women who received betamethasone for threatened preterm labor with infants who were not exposed to betamethasone in utero. STUDY DESIGN: We performed a retrospective cohort study of infants born at or after 37 weeks' gestational age to mothers diagnosed as having threatened preterm labor during pregnancy. The primary neonatal outcomes of interest included transient tachypnea of the newborn, neonatal intensive care unit admission, and small for gestational age and were evaluated for their association with betamethasone exposure while adjusting for covariates using multiple logistic regression. RESULTS: Of 5330 women, 1459 women (27.5%) received betamethasone at a mean gestational age of 32.2±3.3 weeks. The mean age of women was 27±5.9 years and the mean gestational age at delivery was 38.9±1.1 weeks. Women receiving betamethasone had higher rates of maternal comorbidities (P<.001 for diabetes mellitus, asthma, and hypertensive disorder) and were more likely to self-identify as White (P=.022). Betamethasone-exposed neonates had increased rates of transient tachypnea of the newborn, neonatal intensive care unit admission, small for gestational age, hyperbilirubinemia, and hypoglycemia (all, P<.05). Controlling for maternal characteristics and gestational age at delivery, betamethasone exposure was not associated with a diagnosis of transient tachypnea of the newborn (adjusted odds ratio, 1.10; 95% confidence interval, 0.80-1.51), although it was associated with more neonatal intensive care unit admissions (adjusted odds ratio, 1.49; 95% confidence interval, 1.19-1.86) and higher odds of the baby being small for gestational age (adjusted odds ratio, 1.78; 95% confidence interval, 1.48-2.14). CONCLUSION: Compared with women evaluated for preterm labor who did not receive betamethasone, women receiving betamethasone had infants with higher rates of neonatal intensive care unit admission and small for gestational age. Although the benefits of betamethasone to infants born preterm are clear, there may be negative impacts for infants delivered at term.

A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects.

BACKGROUND: Intraoperative methadone, a long-acting opioid, is increasingly used for postoperative analgesia, although the optimal methadone dosing strategy in children is still unknown. The use of a single large dose of intraoperative methadone is controversial due to inconsistent reductions in total opioid use in children and adverse effects. We recently demonstrated that small, repeated doses of methadone intraoperatively and postoperatively provided sustained analgesia and reduced opioid use without respiratory depression. The aim of this study was to characterize pharmacokinetics, efficacy, and safety of a multiple small-dose methadone strategy. METHODS: Adolescents undergoing posterior spinal fusion (PSF) for idiopathic scoliosis or pectus excavatum (PE) repair received methadone intraoperatively (0.1 mg/kg, maximum 5 mg) and postoperatively every 12 hours for 3-5 doses in a multimodal analgesic protocol. Blood samples were collected up to 72 hours postoperatively and analyzed for R-methadone and S-methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) metabolites, and alpha-1 acid glycoprotein (AAG), the primary methadone-binding protein. Peak and trough concentrations of enantiomers, total methadone, and AAG levels were correlated with clinical outcomes including pain scores, postoperative nausea and vomiting (PONV), respiratory depression, and QT interval prolongation. RESULTS: The study population included 38 children (10.8-17.9 years): 25 PSF and 13 PE patients. Median total methadone peak plasma concentration was 24.7 (interquartile range [IQR], 19.2-40.8) ng/mL and the median trough was 4.09 (IQR, 2.74-6.4) ng/mL. AAG concentration almost doubled at 48 hours after surgery (median = 193.9, IQR = 86.3-279.5 µg/mL) from intraoperative levels (median = 87.4, IQR = 70.6-115.8 µg/mL; P < .001), and change of AAG from intraoperative period to 48 hours postoperatively correlated with R-EDDP (P < .001) levels, S-EDDP (P < .001) levels, and pain scores (P = .008). Median opioid usage was minimal, 0.66 (IQR, 0.59-0.75) mg/kg morphine equivalents/d. No respiratory depression (95% Wilson binomial confidence, 0-0.09) or clinically significant QT prolongation (median = 9, IQR = -10 to 28 milliseconds) occurred. PONV occurred in 12 patients and was correlated with morphine equivalent dose (P = .005). CONCLUSIONS: Novel multiple small perioperative methadone doses resulted in safe and lower blood methadone levels, <100 ng/mL, a threshold previously associated with respiratory depression. This methadone dosing in a multimodal regimen resulted in lower blood methadone analgesia concentrations than the historically described minimum analgesic concentrations of methadone from an era before multimodal postoperative analgesia without postoperative respiratory depression and prolonged corrected QT (QTc). Larger studies are needed to further study the safety and efficacy of this methadone dosing strategy.

Do maternal demographics and prenatal history impact the efficacy of betamethasone therapy for threatened preterm labor?

BACKGROUND: Betamethasone (BMZ) is used to accelerate fetal lung maturation in women with threatened preterm birth, but its efficacy is variable and limited by the lack of patient individualization in its dosing and administration. To determine sources of variability and potential opportunities for individualization of therapy, the objective of this study was to evaluate maternal factors associated with development of neonatal respiratory distress syndrome (RDS) in a cohort of women who received betamethasone. METHODS: This study prospectively enrolled women, gestational ages 23-34 weeks, who received betamethasone for threatened preterm birth. Maternal demographics, prenatal history, and neonatal outcomes were abstracted from hospital records. RDS was the primary outcome. Associations between RDS diagnosis and maternal demographics, prenatal history, and betamethasone dosing were evaluated in a case-control analysis and multivariable regression adjusted for gestational age at delivery. Secondary analyses limited the cohort to women who delivered within 1 or 2 weeks of betamethasone dosing. RESULTS: Of 209 deliveries, 90 (43 %) resulted in neonatal RDS. Within the overall cohort and controlling for gestational age at birth, RDS was only associated with cesarean births compared to vaginal births (adjusted OR 1.17 [1.06-1.29]). Route of delivery was also the only significant factor related to RDS in the 83 neonates delivered within 7 days of BMZ dosing. However, among 101 deliveries within 14 days of betamethasone dosing and controlling for gestational age at birth, women who experienced preterm premature rupture of membranes (PPROM) had lower RDS rates than those without PPROM (57.9 % vs. 80.2 %, adjusted OR 0.81 [0.67-0.99]). Maternal age, BMI, race, and ethnicity were not associated with RDS in the regression models. CONCLUSIONS: Of maternal characteristics analyzed, only delivery by cesarean was associated with neonatal RDS after antenatal betamethasone use.

Stereoselective Analysis of Methadone and EDDP in Laboring Women and Neonates in Plasma and Dried Blood Spots and Association with Neonatal Abstinence Syndrome.

OBJECTIVE: This pilot study evaluated the relationship between maternal and neonatal R- and S-methadone and R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) exposure and the severity of neonatal abstinence syndrome (NAS). The use of dried blood spots (DBS) as an alternative for plasma in assessing methadone and EDDP was also assessed. STUDY DESIGN: Women receiving methadone for medication assisted treatment of opioid use disorder during pregnancy were eligible for recruitment. Plasma and DBS samples were collected from mothers during labor, from cord blood, and from newborns during genetic screen. R-/S-methadone and EDDP were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS). Associations between methadone exposure, neonatal morphine requirements, and severity of NAS were examined. RESULTS: Twenty women and infants completed the study. Maternal methadone dose at delivery was 112 mg/day (range = 60-180 mg/day). Sixteen neonates experienced NAS requiring morphine; three also required phenobarbital. Higher cord blood concentrations of R-methadone, R- and S-EDDP were associated with higher maximum doses of morphine (p < 0.05). CONCLUSION: Maternal methadone and cord blood concentration at delivery are variable and may be potential markers of neonatal abstinence syndrome.

Effects of Pregnancy on the Pharmacokinetics of Metformin.

This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (n = 24) or a combination with glyburide (n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V ß ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V ß /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V ß /F by 28%, weight-adjusted V ß /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.

The Impact of Hepatitis C Virus Infection on Buprenorphine Dose in Pregnancy.

OBJECTIVE: Buprenorphine (BUP) is commonly used for opioid maintenance therapy in pregnancy. Our goal was to determine whether liver dysfunction related to hepatitis C virus (HCV) infection impacts BUP dosing requirements in pregnancy. STUDY DESIGN: This was a retrospective cohort study of pregnant women with antenatal exposure to BUP to compare dosing between individuals positive versus negative for HCV infection. Spearman correlation tests were used to assess the relationship between BUP dose and HCV status. RESULTS: HCV infection was present in 103 (39%) of the patients. Patients with HCV infection required lower dose increases of BUP throughout pregnancy (p = 0.02). HCV viral load was positively correlated with the liver enzymes aspartate transaminase (r = 0.30, p = 0.003) and alanine transaminase (r = 0.25, p = 0.01). There was a negative correlation between HCV viral load and BUP dose during the second trimester (r = -0.27, p = 0.01) and third trimester (r = -0.20, p = 0.04). CONCLUSION: Women with HCV infection required less of an increase in BUP dose throughout pregnancy compared with women without HCV infection. Severity of HCV infection, as measured by viral load and liver enzymes, was also associated with BUP dosing.

Inquiry into the short- and long-term effects of Roux-en-Y gastric bypass on the glomerular filtration rate.

Bariatric surgery is known to attenuate glomerular hyperfiltration over the long term and thereby protect the kidney from mechanical damage. Whether this effect is directly related to weight loss or is independent of weight as are some of its other beneficial metabolic effects is not known. We explored this question in a preliminary study that directly measured glomerular filtration rate (GFR) before, immediately after, and again many months after Roux-en-Y gastric bypass after large weight loss had occurred. We simultaneously measured stimulated circulating glucagon-like peptide-1, which is upregulated after Roux-en-Y gastric bypass and is a putative mediator of GFR after bariatric surgery. We found no weight-independent effect of Roux-en-Y gastric bypass on GFR nor an association between circulating GLP-1 levels and GFR. These findings, if confirmed in larger studies, will help steer future enquiries in this area.

A comparison of vaginal versus buccal misoprostol for cervical ripening in women for labor induction at term (the IMPROVE trial): a triple-masked randomized controlled trial.

BACKGROUND: Cervical ripening is commonly needed for labor induction. Finding an optimal route of misoprostol dosing for efficacy, safety, and patient satisfaction is important and not well studied for the buccal route. OBJECTIVE: To compare the efficacy and safety of vaginal and buccal misoprostol for women undergoing labor induction at term. STUDY DESIGN: The IMPROVE trial was an institutional review board-approved, triple-masked, placebo-controlled randomized noninferiority trial for women undergoing labor induction at term with a Bishop score ≤6. Enrolled women received 25 mcg (first dose), then 50 mcg (subsequent doses) of misoprostol by assigned route (vaginal or buccal) and a matching placebo tablet by the opposite route. The primary outcomes were time to delivery and the rate of cesarean delivery performed urgently for fetal nonreassurance. A sample size of 300 was planned to test the noninferiority hypothesis. RESULTS: The trial enrolled 319 women, with 300 available for analysis, 152 in the vaginal misoprostol group and 148 in the buccal. Groups had similar baseline characteristics. We were unable to demonstrate noninferiority. The time to vaginal delivery was lower for the vaginal misoprostol group (median [95% confidence interval] in hours: vaginal: 20.1 [18.2, 22.8] vs buccal: 28.1 [24.1, 31.4], log-rank test P = .006, Pnoninferiority = .663). The rate of cesarean deliveries for nonreassuring fetal status was 3.3% for the vaginal misoprostol group and 9.5% for the buccal misoprostol group (P = .033). The rate of vaginal delivery in <24 hours was higher in the vaginal group (58.6% vs 39.2%, P = .001). CONCLUSION: We were unable to demonstrate noninferiority. In leading to a higher rate of vaginal deliveries, more rapid vaginal delivery, and fewer cesareans for fetal issues, vaginal misoprostol may be superior to buccal misoprostol for cervical ripening at term.

Buccal versus Vaginal Misoprostol for Term Induction of Labor: A Retrospective Cohort Study.

OBJECTIVE: To compare the efficacy of similar buccal and vaginal misoprostol doses for induction of labor. STUDY DESIGN: Retrospective chart review of 207 consecutive women undergoing term induction of labor with misoprostol. Misoprostol route and dosing were collected. Time to delivery and other labor outcomes (e.g., vaginal delivery less than 24 hours) were compared between women receiving buccal and vaginal misoprostol. RESULTS: There was no significant difference in time to delivery for women receiving buccal (median 18.2 hour, 95% confidence interval [CI] = [14.9, 21.5]) versus vaginal (median 18.3 hour, 95% CI = [15.0, 20.4]) misoprostol (p = 0.428); even after adjusting for covariates (p = 0.381). Women who presented with premature rupture of membranes were more likely to receive buccal misoprostol (92.7% received buccal vs. 7.3% received vaginal, p < 0.001). A similar number of women delivered vaginally in the buccal group (88.2%) and vaginal misoprostol group (86.8%, p = 0.835). The proportion of women who experienced uterine tachysystole or chorioamnionitis did not significantly differ by route of administration. CONCLUSION: We found no significant differences in time to delivery or other labor outcomes between buccal or vaginal dosing of misoprostol in women undergoing labor induction at term.

Mixture drug-count response model for the high-dimensional drug combinatory effect on myopathy.

Drug-drug interactions (DDIs) are a common cause of adverse drug events (ADEs). The electronic medical record (EMR) database and the FDA's adverse event reporting system (FAERS) database are the major data sources for mining and testing the ADE associated DDI signals. Most DDI data mining methods focus on pair-wise drug interactions, and methods to detect high-dimensional DDIs in medical databases are lacking. In this paper, we propose 2 novel mixture drug-count response models for detecting high-dimensional drug combinations that induce myopathy. The "count" indicates the number of drugs in a combination. One model is called fixed probability mixture drug-count response model with a maximum risk threshold (FMDRM-MRT). The other model is called count-dependent probability mixture drug-count response model with a maximum risk threshold (CMDRM-MRT), in which the mixture probability is count dependent. Compared with the previous mixture drug-count response model (MDRM) developed by our group, these 2 new models show a better likelihood in detecting high-dimensional drug combinatory effects on myopathy. CMDRM-MRT identified and validated (54; 374; 637; 442; 131) 2-way to 6-way drug interactions, respectively, which induce myopathy in both EMR and FAERS databases. We further demonstrate FAERS data capture much higher maximum myopathy risk than EMR data do. The consistency of 2 mixture models' parameters and local false discovery rate estimates are evaluated through statistical simulation studies.

Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism.

INTRODUCTION: Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone meta-bolism, specifically the contribution of CYP3A isoforms. MATERIALS AND METHODS: In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6ß-hydroxyprogesterone (6ß-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis-Menten equation to determine Km and Vmax. The effect of CYP3A5 expression on progesterone clearance was determined by in vitro in vivo extrapolation. RESULTS: Ketoconazole inhibited formation of both 6ß-OHP and 16α-OHP more than 95%. 6ß-OHP and 16α-OHP were both produced by CYP3A4 (2.3 and 1.3 µL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 µL/min/pmol) and CYP3A7 (0.004 and 0.003 µL/min/pmol). CONCLUSIONS: Maternal clearance of progesterone by hepatic CYP450's is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7.

Fetal hyperglycemia and a high-fat diet contribute to aberrant glucose tolerance and hematopoiesis in adult rats.

BACKGROUND: Children exposed to gestational diabetes mellitus (GDM) during pregnancy are at increased risk of obesity, diabetes, and hypertension. Our goal was to identify metabolic and hematopoietic alterations after intrauterine exposure to maternal hyperglycemia that may contribute to the pathogenesis of chronic morbidities. METHODS: Streptozotocin treatment induced maternal hyperglycemia during the last third of gestation in rat dams. Offspring of control mothers (OCM) and diabetic mothers (ODM) were evaluated for weight, glucose tolerance, insulin tolerance, and hematopoiesis defects. The effects of aging were examined in normal and high-fat diet (HFD)-fed young (8-wk-old) and aged (11-mo-old) OCM and ODM rats. RESULTS: Young adult ODM males on a normal diet, but not females, displayed improved glucose tolerance due to increased insulin levels. Aged ODM males and females gained more weight than OCM on a HFD and had worse glucose tolerance. Aged ODM males fed a HFD were also neutrophilic. Increases in bone marrow cellularity and myeloid progenitors preceded neutrophilia in ODM males fed a HFD. CONCLUSION: When combined with other risk factors like HFD and aging, changes in glucose metabolism and hematopoiesis may contribute to the increased risk of obesity, type 2 diabetes, and hypertension observed in children of GDM mothers.