IU Indianapolis ScholarWorks :: Browsing by Author "Quinney, Sara K."

Browsing by Author "Quinney, Sara K."

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Buccal versus Vaginal Misoprostol for Term Induction of Labor: A Retrospective Cohort Study
(Thieme, 2019-06) Dorr, Meredith L.; Pierson, Rebecca C.; Daggy, Joanne; Quinney, Sara K.; Haas, David M.; Obstetrics and Gynecology, School of Medicine
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.
Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism
(Taylor & Francis, 2017-10) Quinney, Sara K.; Benjamin, Tara D.; Zheng, Xiaomei; Patil, Avinash; Obstetrics and Gynecology, School of Medicine
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. 6β-hydroxyprogesterone (6β-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 6β-OHP and 16α-OHP more than 95%. 6β-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.
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
(Elsevier, 2019) Haas, David M.; Daggy, Joanne; Flannery, Kahtleen M.; Dorr, Meredith L.; Bonsack, Carrie; Bhamidipalli, Surya S.; Pierson, Rebecca C.; Lathrop, Anthony; Towns, Rachel; Ngo, Nicole; Head, Annette; Morgan, Sarah; Quinney, Sara K.; Obstetrics and Gynecology, School of Medicine
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.
CYP2B6 pharmacogenetics-based in vitro-in vivo extrapolation of efavirenz clearance by physiologically based pharmacokinetic modeling
(ASPET, 2013-12) Xu, Cong; Quinney, Sara K.; Guo, Yingyying; Hall, Stephen D.; Li, Lang; Desta, Zeruesenay; Medicine, School of Medicine
Efavirenz is mainly cleared by CYP2B6. The CYP2B6*6 allele is associated with lower efavirenz clearance. Efavirenz clearance was predictable using in vitro data for carriers of the CYP2B6*1/*1 genotype, but the prediction in carriers of the CYP2B6*6 allele was poor. To test the hypothesis that incorporation of mechanism of reduced efavirenz metabolism by the CYP2B6*6 allele can predict the genetic effect on efavirenz pharmacokinetics, in vitro-in vivo extrapolation of efavirenz clearance was performed by physiologically based pharmacokinetic modeling (Simcyp Simulator; Simcyp Ltd., Sheffield, UK) using data obtained from expressed CYP2B6.1 and CYP2B6.6 as well as human liver microsomes (HLMs) with CYP2B6*1/*1, *1/*6, and *6/*6 genotypes. Simulated pharmacokinetics of a single 600-mg oral dose of efavirenz for individuals with each genotype was compared with data observed in healthy subjects genotyped for the CYP2B6*6 allele (n = 20). Efavirenz clearance for carriers of the CYP2B6*1/*1 genotype was predicted reasonably well using HLM data, but the clearance in carriers of the CYP2B6*6 allele was underpredicted using both expressed and HLM systems. Improved prediction of efavirenz clearance was obtained from expressed CYP2B6 after recalculating intersystem extrapolation factors for CYP2B6.1 and CYP2B6.6 based on in vitro intrinsic clearance of bupropion 4-hydroxylation. These findings suggest that genetic effect on both CYP2B6 protein expression and catalytic efficiency needs to be taken into account for the prediction of pharmacokinetics in individuals carrying the CYP2B6*6/*6 genotype. Expressed CYP2B6 proteins may be a reliable in vitro system to predict effect of the CYP2B6*6 allele on the metabolism of CYP2B6 substrates.
Do maternal demographics and prenatal history impact the efficacy of betamethasone therapy for threatened preterm labor?
(BMC, 2021-06-24) Kinney, Mary T.; Quinney, Sara K.; Trussell, Hayley K.; Silva, Larissa L.; Ibrahim, Sherrine A.; Haas, David M.; Obstetrics and Gynecology, School of Medicine
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.
Effect of Gastric Fluid Volume on the in Vitro Dissolution and in Vivo Absorption of BCS Class II Drugs: A Case Study with Nifedipine
(Springer, 2016-07) Nader, Ahmed M.; Quinney, Sara K.; Fadda, Hala M.; Foster, David R.; Department of Obstetrics and Gynecology, IU School of Medicine
Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (Cmax, tmax, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250 mL) on Cmax, tmax, or AUC0-6 of orally administered nifedipine IR capsules (10 mg). However, administration of large water volumes resulted in lower variability in nifedipine Cmax (47 vs. 70% for 250 and 50 mL, respectively). Administration of large water volumes with nifedipine 10 mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended.
Fetal hyperglycemia and a high fat diet contribute to aberrant glucose tolerance and hematopoiesis in adulthood
(Nature Publishing Group, 2015-02) Blue, Emily K.; Ballman, Kimberly; Boyle, Frances; Oh, Eunjin; Kono, Tatsuyoshi; Quinney, Sara K.; Thurmond, Debbie C.; Evans-Molina, Carmella; Haneline, Laura S.; Department of Pediatrics, IU School of Medicine
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-week-old) and aged (11-month-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.
How to Choose In Vitro Systems to Predict In Vivo Drug Clearance: A System Pharmacology Perspective
(Hindawi Publishing Corporation, 2015) Wang, Lei; Chiang, ChienWei; Liang, Hong; Wu, Hengyi; Feng, Weixing; Quinney, Sara K.; Li, Jin; Li, Lang; Department of Obstetrics and Gynecology, IU School of Medicine
The use of in vitro metabolism data to predict human clearance has become more significant in the current prediction of large scale drug clearance for all the drugs. The relevant information (in vitro metabolism data and in vivo human clearance values) of thirty-five drugs that satisfied the entry criteria of probe drugs was collated from the literature. Then the performance of different in vitro systems including Escherichia coli system, yeast system, lymphoblastoid system and baculovirus system is compared after in vitro-in vivo extrapolation. Baculovirus system, which can provide most of the data, has almost equal accuracy as the other systems in predicting clearance. And in most cases, baculovirus system has the smaller CV in scaling factors. Therefore, the baculovirus system can be recognized as the suitable system for the large scale drug clearance prediction.
Identification and mechanistic investigation of clinically important myopathic drug-drug interactions
(2014) Han, Xu; Flockhart, David A.; Bies, Robert R.; Desta, Zeruesenay; Li, Lang; Queener, Sherry F.; Quinney, Sara K.; Zhang, Jian-Ting
Drug-drug interactions (DDIs) refer to situations where one drug affects the pharmacokinetics or pharmacodynamics of another. DDIs represent a major cause of morbidity and mortality. A common adverse drug reaction (ADR) that can result from, or be exacerbated by DDIs is drug-induced myopathy. Identifying DDIs and understanding their underlying mechanisms is key to the prevention of undesirable effects of DDIs and to efforts to optimize therapeutic outcomes. This dissertation is dedicated to identification of clinically important myopathic DDIs and to elucidation of their underlying mechanisms. Using data mined from the published cytochrome P450 (CYP) drug interaction literature, 13,197 drug pairs were predicted to potentially interact by pairing a substrate and an inhibitor of a major CYP isoform in humans. Prescribing data for these drug pairs and their associations with myopathy were then examined in a large electronic medical record database. The analyses identified fifteen drug pairs as DDIs significantly associated with an increased risk of myopathy. These significant myopathic DDIs involved clinically important drugs including alprazolam, chloroquine, duloxetine, hydroxychloroquine, loratadine, omeprazole, promethazine, quetiapine, risperidone, ropinirole, trazodone and simvastatin. Data from in vitro experiments indicated that the interaction between quetiapine and chloroquine (risk ratio, RR, 2.17, p-value 5.29E-05) may result from the inhibitory effects of quetiapine on chloroquine metabolism by cytochrome P450s (CYPs). The in vitro data also suggested that the interaction between simvastatin and loratadine (RR 1.6, p-value 4.75E-07) may result from synergistic toxicity of simvastatin and desloratadine, the major metabolite of loratadine, to muscle cells, and from the inhibitory effect of simvastatin acid, the active metabolite of simvastatin, on the hepatic uptake of desloratadine via OATP1B1/1B3. Our data not only identified unknown myopathic DDIs of clinical consequence, but also shed light on their underlying pharmacokinetic and pharmacodynamic mechanisms. More importantly, our approach exemplified a new strategy for identification and investigation of DDIs, one that combined literature mining using bioinformatic algorithms, ADR detection using a pharmacoepidemiologic design, and mechanistic studies employing in vitro experimental models.
Influence of dietary protein on glomerular filtration before and after bariatric surgery: a cohort study
(Elsevier, 2014-04) Friedman, Allon N.; Quinney, Sara K.; Inman, Margaret; Mattar, Samer G.; Shihabi, Zak; Moe, Sharon; Department of Medicine, IU School of Medicine
BACKGROUND: Obesity-associated elevations in glomerular filtration rate (GFR) are common and may play a role in the development of kidney disease, so identifying the underlying mechanism is important. We therefore studied whether reductions in dietary protein intake, which is known to modulate GFR, explain why GFR decreases after bariatric surgery-induced weight loss. STUDY DESIGN: Cohort study with participants as their own controls. SETTING & PARTICIPANTS: 8 severely obese patients with normal kidney function were recruited from bariatric surgery centers in Indianapolis, IN. All participants were placed on a fixed-protein (50-g/d) diet for 1 week before and after a minimum of a 20-kg weight loss by bariatric surgery and were followed up closely by dieticians for adherence. PREDICTOR: Ad lib versus low-protein diet before versus after bariatric surgery. OUTCOME: Measured GFR, using repeated-measures analysis, was used to estimate the independent effects of diet and surgery. MEASUREMENT: GFR was measured using plasma iohexol clearance. RESULTS: A median of 32.9 (range, 19.5-54.4)kg was lost between the first presurgery visit and first postsurgery visit. Dietetic evaluations and urinary urea excretion confirmed that patients generally adhered to the study diet. GFRs on an ad lib diet were significantly higher before compared to after surgery (GFR medians were 144 (range, 114-178) and 107 (range, 85-147) mL/min, respectively; P=0.01). Although bariatric surgery (-26mL/min; P=0.005) and dietary sodium intake (+7.5mL/min per 100mg of dietary sodium; P=0.001) both influenced GFR, consuming a low-protein diet did not (P=0.7). LIMITATIONS: Small sample size; mostly white women; possible lack of generalizability. CONCLUSIONS: The decrease in GFR observed after bariatric surgery is explained at least in part by the effects of surgery and/or dietary sodium intake, but not by low dietary protein consumption.

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