Polymorphisms in CYP2C9 are associated with response to indomethacin among neonates with patent ductus arteriosus.
ABSTRACT: BackgroundPatent ductus arteriosus (PDA) is a common complication seen in preterm infants. Indomethacin is routinely used to treat PDA. Evidence suggests that the response of indomethacin is highly heritable. This study investigated the association between single-nucleotide polymorphisms (SNPs) in CYP2C9 and the closure of PDA in response to indomethacin.MethodsSix SNPs in CYP2C9 were analyzed for association with indomethacin response. A case-control analysis was performed among neonates who responded to indomethacin (responders) and among those who required surgical ligation (non-responders). Independent transmission disequilibrium tests were performed among parent-child trios of responders and non-responders.ResultsThe G allele of rs2153628 was associated with increased odds of response to indomethacin in the case-control analysis (odds ratios (OR): 1.918, 95% confidence interval (CI): 1.056, 3.483). Among indomethacin responders, the G allele of rs2153628 and the T allele of rs1799853 were overtransmitted from the parents to their child (OR: 2.667, 95% CI: 1.374, 5.177 and OR: 2.375, 95% CI: 1.040, 5.425, respectively), consistent with the case-control analysis.ConclusionWe identified an association between two SNPs in CYP2C9, rs2153628 and rs1799853, and indomethacin response for the treatment of PDA. These findings suggest that response to indomethacin in the closure of PDA may be influenced by polymorphisms associated with altered indomethacin metabolism.
Project description:BACKGROUND: Patent ductus arteriosus (PDA) in extremely preterm infants remains a challenging condition with conflicting treatment strategies. Ibuprofen is currently used to treat PDA with ductal closure failure rate up to 40%. We test the hypothesis that cytochrome P450 CYP2C8/2C9 polymorphisms may predict ibuprofen response. METHODOLOGY/PRINCIPAL FINDINGS: We studied extremely preterm neonates with haemodynamically significant PDA and treated with ibuprofen. One or two variant CYP2C8 and/or 2C9 alleles were found in 17% of the population, most of them were from Caucasian ethnicity (67-74%). Response to ibuprofen and clinical course of infants carrying variants CYP2C8 and CYP2C9 were similar. Comparing infants with wild type or variant CYP2C8 and CYP2C9 genotypes, response rate to ibuprofen was significantly higher in wild type than in mutated carriers in univariate analysis (73% versus 52%, p = 0.04). Comparing responders (ductus closure; n = 75) and non-responders (surgical ligation; n = 36), the only two factors significantly associated with the response to ibuprofen using multivariate analysis were higher gestational age and non Caucasian ethnicity but not CYP2C polymorphism. CONCLUSIONS: CYP2C polymorphism was not associated with PDA response to ibuprofen and this factor appears not appropriate to optimize the ductal closure rate by modulating ibuprofen dosing strategy. This study points out the role for ethnicity in the interindividual variability of response to ibuprofen in extremely preterm infants.
Project description:Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22-32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60-0.96), surfactant use (AOR 9.77, 95% CI 1.15-83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34-10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.
Project description:<h4>Background</h4>The treatment of patent ductus arteriosus (PDA) in very low birth weight (VLBW) infants remains a challenge. The ability to predict which infants will respond to indomethacin could spare some from the risks of unnecessary medications. Our objective was to determine if indicators of acid-base homeostasis could predict response to indomethacin treatment for ductal closure, and thus help guide treatment decisions.<h4>Methods</h4>We performed a retrospective analysis of medical records of VLBW (<?1500?g) neonates with hemodynamically significant PDA born at our institution between January 2009 and December 2012; all infants included in the study were treated with indomethacin for ductal closure within the first 2?weeks of life. We extracted data for a number of clinical variables including gestational age, birth weight, blood chemistries, surfactant use, hematocrit, and blood gas parameters. Our primary outcome measure was successful closure of PDA following the first round of indomethacin. Using variables that were significant on initial testing, we created multivariable regression models to determine the independent association of selected variables with indomethacin response.<h4>Results</h4>Of the 91 infants included in the study, 62 (68%) responded to the first course of indomethacin with successful ductal closure. Multivariable regression modeling revealed that both base excess and hematocrit were independently associated with indomethacin response; odds of PDA closure increased with increasing base excess (OR [odds ratio]: 1.81; 95% confidence interval [CI]: 1.36-2.60) and increasing hematocrit (OR: 1.21; 95% CI: 1.01-1.45). The optimal cutoff value for base excess was -?4.56, with a sensitivity of 96.8% (95% CI: 89-100) and specificity of 79.3% (95% CI: 60-92); optimal cutoff value for hematocrit was 40, with 69.4% sensitivity (95% CI: 56-80) and 65.5% specificity (95% CI: 46-82).<h4>Conclusions</h4>Base excess and hematocrit may be independent predictors of indomethacin response in VLBW infants with PDA. Low-cost and readily accessible, acid-base indicators such as base excess could help guide treatment decisions.
Project description:BACKGROUND:Optimal management of the patent ductus arteriosus (PDA) in preterm infants remains controversial. Therefore, studies identifying infants who are most likely to benefit from PDA treatment are needed. AIM:We sought to examine if significant intrauterine growth restriction, defined by birth weight z-score, reduces the efficacy of PDA closure with indomethacin or ibuprofen and thereby increases the need for surgical closure of PDA after pharmacologic treatment. STUDY DESIGN, SUBJECTS, AND OUTCOME MEASURES:We studied infants 23-28weeks' gestation born 2006-2013 at NICHD Neonatal Research Network centers. We examined the responses to PDA treatment with indomethacin and/or ibuprofen and whether the PDA was subsequently closed surgically. Logistic regression generated adjusted odds ratios (ORs) for the associations between the z-score groups (<-2, -2 to -0.5, and >-0.5) and PDA surgery following pharmacologic treatment. RESULTS:5606 infants were diagnosed with PDA; 3587 (64.0%) received indomethacin or ibuprofen or both, and 909 (25.3%) underwent PDA surgery. Mothers of infants with PDA non-closure were less likely to have hypertension (19% vs. 28%). Infants with non-closure were more likely to be female (53% vs. 49%), have lower gestational age and birth weight and to develop sepsis (42% vs. 31%). Compared to infants with z-score>-0.5, PDA surgery was increased among infants with z-score -2 to -0.5 (OR=1.23; 95% CI 1.02-1.47) but not among infants with z-score<-2. CONCLUSION:Infants with birth weight z-score -2 to -0.5 are more likely than normally grown infants to require PDA surgery following pharmacologic treatment.
Project description:BACKGROUND:Indomethacin treatment for patent ductus arteriosus (PDA) is associated with acute kidney injury (AKI). Fenoldopam, a dopamine (DA) DA1-like receptor agonist dilates the renal vasculature and may preserve renal function during indomethacin treatment. However, limited information exists on DA receptor-mediated signaling in the ductus and fenoldopam may prevent ductus closure given its vasodilatory nature. METHODS:DA receptor expression in CD-1 mouse vessels was analyzed by qPCR and immunohistochemistry. Concentration-response curves were established using pressure myography. Pretreatment with SCH23390 (DA1-like receptor antagonist), phentolamine (? -adrenergic receptor antagonist) or indomethacin addressed mechanisms for DA-induced changes. Fenoldopam's effects on postnatal ductus closure were evaluated in vivo. RESULTS:DA1 receptors were expressed equally in ductus and aorta. High-dose DA induced modest vasoconstriction under newborn O2 conditions. Phentolamine inhibited DA-induced constriction, while SCH23390 augmented constriction, consistent with a vasodilatory role for DA1 receptors. Despite this, fenoldopam had little effect on ductus tone nor indomethacin- or O2-induced constriction and did not impair postnatal closure in vivo. CONCLUSION(S):DA receptors are present in the ductus but have limited physiologic effects. DA-induced ductus vasoconstriction is mediated via ?-adrenergic pathways. The absence of DA1-mediated impairment of ductus closure supports the study of potential role for fenoldopam during PDA treatment.
Project description:We surveyed neonatal leadership at 46 US children's hospitals via web-based survey to identify local preferences and concerns regarding indomethacin prophylaxis, nonsteroidal anti-inflammatory drug (NSAID) treatment, and patent ductus arteriosus (PDA) ligation. We received a 100 % survey response (N?=?46). Practice guidelines for prophylactic indomethacin were reported at 28 % of NICUs, for NSAID treatment of PDA at 39 % and for surgical ligation at 27 %. Respondents noted intra-institutional practice variation for indomethacin prophylaxis (33 %), NSAID treatment (70 %), and PDA ligation (73 %). The majority of institutions did not prescribe indomethacin prophylaxis (72 %). For PDA treatment, indomethacin was preferred over ibuprofen (80 %). We validated our survey results via comparison with billing data as documented in the Pediatric Health Information System (PHIS) database, finding that survey responses directly correlated with local billing data (p?<?0.0001). At institutions that did not typically administer NSAIDs for PDA closure or surgical PDA ligation, a lack of evidence for their effectiveness in improving long-term outcomes and the risk of treatment-associated adverse effects were the most often cited reasons.No consensus exists among providers at US children's hospitals regarding prophylactic indomethacin, NSAID treatment, or PDA ligation. Lack of evidence and safety concerns play a prominent role.• NSAIDs and surgical PDA ligation are efficacious in preventing intraventricular hemorrhage (IVH) and closing PDA in preterm infants, but have not been shown to improve long-term respiratory, neurodevelopmental, or mortality outcomes. What is New: • Practice preferences for indomethacin prophylaxis, NSAID, and surgical PDA treatment vary both among and within institutions. Lack of treatment effectiveness and the risk of adverse effects are major concerns.
Project description:<label>Importance</label>Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA.<label>Objectives</label>To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates.<label>Data Sources and Study Selection</label>The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA.<label>Data Extraction and Synthesis</label>Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses.<label>Main Outcomes and Measures</label>Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage.<label>Results</label>In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities.<label>Conclusions and Relevance</label>A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage.<label>Trial Registration</label>PROSPERO Identifier: CRD42015015797.
Project description:<h4>Objective</h4>To compare effectiveness and safety of combination therapy (acetaminophen and ibuprofen) to monotherapy (ibuprofen, indomethacin, or acetaminophen alone) in treatment of the patent ductus arteriosus (PDA) in premature neonates.<h4>Methods</h4>This was a retrospective cohort study of neonates admitted to a tertiary-level neonatal intensive care unit. Included neonates were born at <32 weeks gestation and received pharmacotherapy for PDA closure. Based on the primary therapy received, our cohort was divided into the following four groups: indomethacin alone, ibuprofen alone, acetaminophen alone, and ibuprofen and acetaminophen (in combination). Baseline characteristics, effectiveness, safety, neonatal mortality, and morbidities rates between these groups were compared.<h4>Results</h4>One hundred and forty neonates were analyzed; 17 received combination therapy, and 123 neonates received monotherapy: 22 (17.9%) ibuprofen, 29 (23.6%) acetaminophen, and 72 (58.5%) indomethacin. The PDA closure rates were 41.7% for indomethacin, 41.2% for combination therapy, 37.9% for acetaminophen, and 31.8% for ibuprofen (P=0.100). Rates of adverse effects were comparable between the groups.<h4>Conclusion</h4>The rate of ductal closure was not different between combination therapy and monotherapy. The study did not demonstrate any increased adverse effects in the combination group. Future well-designed prospective clinical trials are needed to guide clinical practice.
Project description:BACKGROUND AND PURPOSE:Variant alleles of CYP2C9 and VKORC1 account for differences in anticoagulation response. We sought to establish a warfarin dosing formula for individualized target International Normalization Ratio of Prothrombin Times (INRs) using data from single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 in Korean patients. METHODS:Ischemic stroke patients displaying stable target INR for at least 3 months before enrollment were analyzed. Warfarin and vitamin K levels were measured to adjust for confounders. Phenotypes were defined using the 'warfarin response index' (WRI) defined as INR divided by the daily maintenance warfarin dose. We tested SNPs in CYP2C9 (3 sites: 430C>T (rs1799853), 1075A>C (rs1057910), 1076T>C) and VKORC1 (14 sites: 381C>T, 861C>A (rs17880887), 2653G>C, 3673A>G, 5496G>T, 5808T>G (r17882154), 6009C>T, 6484T>C (rs9934438), 6853C>T (rs17886369), 7566T>C, 8767G>C, 8814T>C, 9041G>A (rs17880624), and 9071G>T) using a standard sequencing method. Multivariate linear regression analysis was applied to establish the formula for warfarin dosage. RESULTS:All 204 patients had excellent drug compliance. The mean INR was 2.22 (+0.56) and mean daily maintenance dose of warfarin was 3.92 mg (+1.54). Patients with low WRI were younger (P<0.001) with high body mass index (P=0.003), high prevalence of wild-type CYP2C9 polymorphism (1075A>C, P<0.001), and six heterozygote SNPs in VRORC1 (P<0.001), which were tightly interlinked (381T>C, 3673G>A, 6484T>C, 6853C>G. 7566C>T, 9041G>A) (r(2)=1). Based on these data, a warfarin dosing formula was established. CONCLUSIONS:WRI is influenced by age, body mass index and SNPs in VKORC1 and CYP2C9 in Korean stroke patients. The obtained warfarin dosing formula may be clinically applicable.
Project description:The cytochrome P450 2C9 enzyme (CYP2C9) is involved in metabolism of endogenous compounds, drugs, and procarcinogens. Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L).We investigated whether CYP2C9 genotype was associated with risk of colorectal adenoma and/or modified associations with aspirin treatment or cigarette smoking in a cohort of 928 participants in a randomized trial of aspirin chemoprevention. Generalized linear regression was used to compute relative risks (RRs) and 95 % confidence intervals (95 % CIs). Multiplicative interactions terms were used to assess effect modification.CYP2C9 genotype was associated with increased risks for adenoma recurrence of 29 % (RR = 1.29, 95 % CI 1.09-1.51) for ?1 variant allele (CYP2C9*2 or *3) and 47 % (RR = 1.47, 95 % CI 1.19-1.83) for ?1 CYP2C9*3 allele. The risk for advanced lesions or multiple (?3) adenomas was increased by 64 % (RR = 1.64, 95 % CI 1.18-2.28) for ?1 variant allele (CYP2C9*2 or *3) and 79 % (RR = 1.79, 95 % CI 1.16-2.75) for ?1 CYP2C9*3 allele. Genotype modified associations with smoking, but not aspirin treatment. The adenoma risk was increased by 26 % (RR = 1.26, 95 % CI 0.99-1.58) for former smokers and 60 % (RR = 1.60, 95 % CI 1.19-2.15) for current smokers among wild-type individuals, but there was no increased risk among individuals with ?1 variant allele (CYP2C9*2 or *3) (p (interaction) = 0.04).Carriers of CYP2C9 variants with lower enzyme activity have increased overall risk of colorectal adenoma but reduced adenoma risk associated with cigarette smoking. These results may be due to effects on the synthesis of endogenous eicosanoids and/or reduced activation of procarcinogens in smoke by CYP2C9 variants.