Browsing by Author "Mital, Seema"

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    KMT2D-NOTCH Mediates Coronary Abnormalities in Hypoplastic Left Heart Syndrome
    (American Heart Association, 2022) Yu, Zhiyun; Zhou, Xin; Liu, Ziyi; Pastrana-Gomez, Victor; Liu, Yu; Guo, Minzhe; Tian, Lei; Nelson, Timothy J.; Wang, Nian; Mital, Seema; Chitayat, David; Wu, Joseph C.; Rabinovitch, Marlene; Wu, Sean M.; Snyder, Michael P.; Miao, Yifei; Gu, Mingxia; Radiology and Imaging Sciences, School of Medicine
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    Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation
    (Elsevier, 2017-06) Goldberg, David J.; Zak, Victor; Goldstein, Bryan H.; Chen, Shan; Hamstra, Michelle S.; Radojewski, Elizabeth A.; Maunsell, Eileen; Mital, Seema; Menon, Shaji C.; Schumacher, Kurt R.; Payne, R. Mark; Stylianou, Mario; Kaltman, Jonathan R.; deVries, Tina M.; Yeager, James L.; Paridon, Stephen M.; Pediatric Heart Network Investigators; Pediatrics, School of Medicine
    BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.
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    Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome
    (Elsevier, 2020-07) Van Driest, Sara L.; Sleeper, Lynn A.; Gelb, Bruce D.; Morris, Shaine A.; Dietz, Harry C.; Forbus, Geoffrey A.; Goldmuntz, Elizabeth; Hoskoppal, Arvind; James, Jeanne; Lee, Teresa M.; Levine, Jami C.; Li, Jennifer S.; Loeys, Bart L.; Markham, Larry W.; Meester, Josephina A.N.; Mital, Seema; Mosley, Jonathan D.; Olson, Aaron K.; Renard, Marjolijn; Shaffer, Christian M.; Sharkey, Angela; Young, Luciana; Lacro, Ronald V.; Roden, Dan M.; Pediatrics, School of Medicine
    Objective: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. Study design: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. Results: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. Conclusions: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.