Hedi Schelleman

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (36)149.5 Total impact

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    ABSTRACT: To examine whether initiation of fibrates or statins in sulfonylurea users is associated with hypoglycemia, and examine in vitro inhibition of cytochrome P450 (CYP) enzymes by statins, fenofibrate and glipizide. We used healthcare data to conduct nested case-control studies of serious hypoglycemia (i.e., resulting in hospital admission or emergency department treatment) in persons taking glipizide or glyburide, and calculated adjusted overall and time-stratified odds ratios (ORs) and 95% confidence intervals [CIs]. We also characterized the in vitro inhibition of CYP enzymes by statins, fenofibrate, and glipizide using fluorometric CYP450 inhibition assays, and estimated area under the concentration-time curve ratios (AUCRs) for drug pairs. We found elevated adjusted overall ORs for glyburide-fenofibrate (OR 1.84, 95% CI 1.37-2.47) and glyburide-gemfibrozil (OR 1.57, 95% CI 1.25-1.96). The apparent risk did decline over time as might be expected from a pharmacokinetic mechanism. Fenofibrate was a potent in vitro inhibitor of CYP2C19 (IC50 = 0.2 μM) and CYP2B6 (IC50 = 0.7 μM), and a moderate inhibitor of CYP2C9 (IC50 = 9.7 μM). The predicted CYP-based AUCRs for fenofibrate-glyburide and gemfibrozil-glyburide interactions were only 1.09 and 1.04, suggesting that CYP inhibition is unlikely to explain such an interaction. Use of fenofibrate or gemfibrozil together with glyburide was associated with elevated overall risks for serious hypoglycemia. CYP inhibition seems unlikely to explain this observation. We speculate that a pharmacodynamic effect of fibrates (e.g., activate peroxisome proliferator-activator receptor alpha) may contribute to these apparent interactions.
    British Journal of Clinical Pharmacology 02/2014; 78(3). DOI:10.1111/bcp.12353 · 3.69 Impact Factor
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    ABSTRACT: To compare the incidence rates of serious cardiovascular events in adult initiators of amphetamines or atomoxetine to rates in non-users. This was a retrospective cohort study of new amphetamines (n = 38,586) or atomoxetine (n = 20,995) users. Each medication user was matched to up to four non-users on age, gender, data source, and state (n = 238,183). The following events were primary outcomes of interest 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, 4) a composite endpoint of stroke or myocardial infarction. Cox proportional hazard regression was used to calculate propensity-adjusted hazard ratios for amphetamines versus matched non-users and atomoxetine versus matched non-users, with intracluster dependence within matched sets accounted for using a robust sandwich estimator. The propensity-score adjusted hazard ratio for amphetamines use versus non-use was 1.18 (95% CI: 0.55-2.54) for sudden death/ventricular arrhythmia, 0.80 (95% CI: 0.44-1.47) for stroke, 0.75 (95% CI: 0.42-1.35) for myocardial infarction, and 0.78 (95% CI: 0.51-1.19) for stroke/myocardial infarction. The propensity-score adjusted hazard ratio for atomoxetine use versus non-use was 0.41 (95% CI: 0.10-1.75) for sudden death/ventricular arrhythmia, 1.30 (95% CI: 0.52-3.29) for stroke, 0.56 (95% CI: 0.16-2.00) for myocardial infarction, and 0.92 (95% CI: 0.44-1.92) for stroke/myocardial infarction. Initiation of amphetamines or atomoxetine was not associated with an elevated risk of serious cardiovascular events. However, some of the confidence intervals do not exclude modest elevated risks, e.g. for sudden death/ventricular arrhythmia.
    PLoS ONE 01/2013; 8(1):e52991. DOI:10.1371/journal.pone.0052991 · 3.53 Impact Factor
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    ABSTRACT: The authors sought to determine whether use of methylphenidate in adults is associated with elevated rates of serious cardiovascular events compared with rates in nonusers. This was a cohort study of new users of methylphenidate based on administrative data from a five-state Medicaid database and a 14-state commercial insurance database. All new methylphenidate users with at least 180 days of prior enrollment were identified. Users were matched on data source, state, sex, and age to as many as four comparison subjects who did not use methylphenidate, amphetamines, or atomoxetine. A total of 43,999 new methylphenidate users were identified and matched to 175,955 nonusers. Events of primary interest were 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, and 4) a composite endpoint of stroke or myocardial infarction. The age-standardized incidence rate per 1,000 person-years of sudden death or ventricular arrhythmia was 2.17 (95% CI=1.63-2.83) in methylphenidate users and 0.98 (95% CI=0.89-1.08) in nonusers, for an adjusted hazard ratio of 1.84 (95% CI=1.33-2.55). Dosage was inversely associated with risk. Adjusted hazard ratios for stroke, myocardial infarction, and the composite endpoint of stroke or myocardial infarction did not differ statistically from 1. Although initiation of methylphenidate was associated with a 1.8-fold increase in risk of sudden death or ventricular arrhythmia, the lack of a dose-response relationship suggests that this association may not be a causal one.
    American Journal of Psychiatry 02/2012; 169(2):178-85. DOI:10.1176/appi.ajp.2011.11010125 · 13.56 Impact Factor
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    ABSTRACT: Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those ≥18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk.
    PLoS ONE 06/2011; 6(6):e21447. DOI:10.1371/journal.pone.0021447 · 3.53 Impact Factor
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    ABSTRACT: The objective of this study was to compare the rate of severe cardiovascular events and death in children who use attention-deficit/hyperactivity disorder (ADHD) medications versus nonusers. We performed a large cohort study using data from 2 administrative databases. All children aged 3 to 17 years with a prescription for an amphetamine, atomoxetine, or methylphenidate were included and matched with up to 4 nonusers on the basis of data source, gender, state, and age. Cardiovascular events were validated using medical records. Proportional hazards regression was used to calculated hazard ratios. We identified 241 417 incident users (primary cohort). No statistically significant difference between incident users and nonusers was observed in the rate of validated sudden death or ventricular arrhythmia (hazard ratio: 1.60 [95% confidence interval (CI): 0.19-13.60]) or all-cause death (hazard ratio: 0.76 [95% CI: 0.52-1.12]). None of the strokes identified during exposed time to ADHD medications were validated. No myocardial infarctions were identified in ADHD medication users. No statistically significant difference between prevalent users and nonusers (secondary cohort) was observed (hazard ratios for validated sudden death or ventricular arrhythmia: 1.43 [95% CI: 0.31-6.61]; stroke: 0.89 [95% CI: 0.11-7.11]; stroke/myocardial infarction: 0.72 [95% CI: 0.09-5.57]; and all-cause death: 0.77 [95% CI: 0.56-1.07). The rate of cardiovascular events in exposed children was very low and in general no higher than that in unexposed control subjects. Because of the low number of events, we have limited ability to rule out relative increases in rate.
    PEDIATRICS 06/2011; 127(6):1102-10. DOI:10.1542/peds.2010-3371 · 5.30 Impact Factor
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    ABSTRACT: To evaluate whether exposure to Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)-inducing antiepileptics increases fracture risk compared to CYP3A4-non-inducing antiepileptics. We performed a retrospective cohort study of initiators of antiepileptic agents using a UK medical record database (The Health Improvement Network) from 1995 to 2007. We considered an antiepileptic user an initiator if he or she had not received a prescription for an antiepileptic agent within the first year after entry in the database. Proportional hazards regression was used to calculate hazard ratios for fracture during long-term (≥ 6 months) exposure to CYP3A4 inducing versus CYP3A4 non-inducing antiepileptics. We identified 4077 initiators of CYP3A4-inducing antiepileptics and 6433 initiators of CYP3A4-non-inducing antiepileptics with at least 6 months of antiepileptic exposure. During 6006 person-years exposed to CYP3A4-inducing antiepileptics, 118 fractures were identified for an incidence rate of 1.96 (95% confidence interval (CI): 1.63-2.35) fractures per 100 person-years. During 7184 person-years exposed to CYP3A4-non-inducing antiepileptics, 127 fractures were identified, for an incidence rate of 1.77 (95% CI: 1.47-2.10) fractures per 100 person-years. The adjusted hazard ratio for CYP3A4-inducing antiepileptic versus CYP3A4-non-inducing antiepileptic was 1.21 (95% CI: 0.93-1.56). No duration-response relationship was evident. Our results do not support the hypothesis that CYP3A4 induction by antiepileptic agents increases the fracture risk. Further research will be needed to evaluate whether mechanisms other than CYP3A4 induction might explain some of the elevated risk of fractures associated with long-term use of antiepileptic agents.
    Pharmacoepidemiology and Drug Safety 06/2011; 20(6):619-25. DOI:10.1002/pds.2141 · 3.17 Impact Factor
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    ABSTRACT: To evaluate whether selective serotonin re-uptake inhibitor (SSRI) exposure influences the risk of myocardial infarction (MI) in patients with depression. This study included 693 patients with MI (cases) and 2772 controls. Conditional logistic regression was used to calculate the odds ratio (OR). SSRI exposure may be associated with a reduced MI risk (OR = 0.77, 95% CI 0.57, 1.03). However, reduced risk was only observed with longer term use (OR = 0.73, 95% CI 0.53, 1.00) and not with shorter term use (OR = 1.15, 95% CI: 0.65, 2.05). Only longer term use of SSRIs was associated with reduced MI risk, suggesting that other mechanisms, besides an acute anti-platelet effect, may reduce MI risk.
    British Journal of Clinical Pharmacology 05/2011; 72(3):514-7. DOI:10.1111/j.1365-2125.2011.04008.x · 3.69 Impact Factor
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    ABSTRACT: Variants in the CYP2C9 (i.e. *2 and *3) and VKORC1 (i.e. 1173C/T or -1639G/A) genes have been shown to influence warfarin dose requirements. However, these factors seem to explain less of the dose variability in African Americans who have a lower prevalence of the CYP2C9*2 and *3 and VKORC1 1173T alleles. In African Americans, the VKORC1 rs17886199 variant was statistically significantly associated with log-transformed warfarin maintenance dose, independent of the influence of VKORC1 1173C>T and CYP2C9*2 and *3. However, replication of our finding is needed to confirm the association of rs1786199 SNP in African Americans, since Limdi et al.[3] did not examine the effect of this SNP because the prevalence of the rs1786199 A-allele was too low. To raise hypotheses with regards to whether genetic variants in the VKORC1, CYP2C9, EPHX1, GGCX and ALB genes might influence warfarin dose in African Americans and Caucasians, independent of the effects of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. From a prospective cohort study, we obtained additional DNA on 36 Caucasian and 22 African American warfarin users who reached maintenance dose and genotyped them for tagSNPs (r2<0.8) in VKORC1, EPHX1, GGCX and ALB genes, and one exonic CYP2C9 SNP. Linear regression models were fitted to estimate the relationship (P value) between log-transformed maintenance dose and each SNP and the amount of the warfarin dose variability accounted for by each SNP (partial R2). In African Americans, the VKORC1 rs17886199 A-allele was associated with a lower dose (GG=46.3 mg and GA=25.6 mg; P=0.002), independent of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. Even after applying Bonferroni correction, the P value would still be considered statistically significant. The VKORC1 rs17886199 variant was not found in Caucasians. In Caucasians, the EPHX1 rs1051741 T-allele was associated with a lower dose (CC=41.3 mg and CT=30.0 mg; P=0.04). The latter was no longer statistically significant after applying Bonferroni correction. Our pilot study suggests that the VKORC1 rs17886199 variant could influence warfarin maintenance dose among African Americans, even after accounting for the influence of the VKORC1 1173C>T variant. Future studies with a larger sample size will be needed to confirm our findings.
    British Journal of Clinical Pharmacology 09/2010; 70(3):393-9. DOI:10.1111/j.1365-2125.2010.03709.x · 3.69 Impact Factor
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    ABSTRACT: To describe the design and rationale of an investigator-initiated observational study to examine the cardiovascular safety of the following commonly-used medications to treat attention deficit hyperactivity disorder (ADHD): amphetamines, methylphenidate, and atomoxetine. We are conducting an observational cohort study using data from five large Medicaid programs and the HealthCore Integrated Research Database (HIRD(SM)), which is derived from administrative data from commercial health plans. Our primary outcomes of interest are (1) sudden death/ventricular arrhythmia, (2) stroke, (3) myocardial infarction, and (4) stroke or myocardial infarction as a composite outcome. These claims diagnoses have been previously validated in adults, and the positive predictive value in children will be examined as part of this study. Secondary outcomes are (1) all-cause death, (2) non-suicide death, and (3) non-accident death. All design decisions have been made to minimize bias toward the null. Based on our pilot data, we expect to have at least 90% power to detect a minimum detectable hazard ratio (HR) of 3.0 in children and adolescents who initiate an ADHD medication for each outcome of interest (except for MI, for which the expected minimum detectable HR is 7.9). The expected minimum detectable HR is 1.7 for each outcome for adult incident ADHD medication users. Forthcoming. Potential limitations to this study include a low expected event rate in children and adolescents, potentially incomplete ascertainment of outcomes, and potential confounding by unmeasured variables. Nevertheless, this study will provide important information about the cardiovascular safety of ADHD medications.
    Pharmacoepidemiology and Drug Safety 09/2010; 19(9):934-41. DOI:10.1002/pds.1992 · 3.17 Impact Factor
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    ABSTRACT: The objective of this study was to evaluate whether orally administered anti-infectives increase the risk of severe hypoglycemia in users of glipizide or glyburide. We performed two case-control studies and two case-crossover studies using US Medicaid data. All the anti-infectives examined were associated with an elevated risk of severe hypoglycemia. Using cephalexin as the reference category, in glipizide users, statistically significant associations were found with co-trimoxazole (odds ratio (OR) = 3.14; 95% confidence interval (CI): 1.83-5.37); clarithromycin (OR = 2.90; 95% CI: 1.69-4.98); fluconazole (OR = 2.53; 95% CI: 1.23-5.23); and levofloxacin (OR = 2.09; 95% CI: 1.35-3.25). In glyburide users, with cephalexin as the reference, statistically significant associations were found with clarithromycin (OR = 5.02; 95% CI: 3.35-7.54); levofloxacin (OR = 2.83; 95% CI: 1.73-4.62); co-trimoxazole (OR = 2.68; 95% CI: 1.59-4.52); fluconazole (OR = 2.20; 95% CI: 1.04-4.68); and ciprofloxacin (OR = 2.08; 95% CI: 1.23-3.52). In conclusion, exposure to all studied anti-infective agents were associated with subsequent severe hypoglycemia. Using cephalexin as the reference, drug-drug interactions were evident with ciprofloxacin (in glyburide users only), clarithromycin, co-trimoxazole, fluconazole, and levofloxacin.
    Clinical Pharmacology &#38 Therapeutics 08/2010; 88(2):214-22. DOI:10.1038/clpt.2010.74 · 7.39 Impact Factor
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    ABSTRACT: To evaluate whether initiation of a fibrate or statin increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. We used Medicaid claims data (1999-2003) to perform an observational case-control study nested within person-time exposed to warfarin in those > or =18 years (n=353,489). Gastrointestinal bleeding cases were matched to 50 controls based on index date and state. Chronic warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of gemfibrozil (1.88; 95% confidence interval [CI], 1.00-3.54] for the first prescription; 1.75; 95% CI, 0.77-3.95 for the second prescription); simvastatin (1.46; 95% CI, 1.03-2.07 for the first prescription; 1.60; 95% CI, 1.07-2.39 for the second prescription); or atorvastatin (1.39; 95% CI, 1.07-1.81 for the first prescription; 1.05; 95% CI, 0.73-1.52 for the second prescription). In contrast, no increased risk was found with pravastatin initiation (0.75; 95% CI, 0.39-1.46 for the first prescription; 0.90; 95% CI, 0.43-1.91 for the second prescription). Initiation of a fibrate or statin that inhibits CYP3A4 enzymes, including atorvastatin, was associated with an increased risk of hospitalization for gastrointestinal bleeding. Initiation of pravastatin, which is mainly excreted unchanged, was not associated with an increased risk.
    The American journal of medicine 02/2010; 123(2):151-7. DOI:10.1016/j.amjmed.2009.07.020 · 5.30 Impact Factor
  • Article: Reply.
    Andrea J Apter, Hedi Schelleman, Timothy Rebbeck
    The Journal of allergy and clinical immunology 02/2009; DOI:10.1016/j.jaci.2008.10.059 · 11.25 Impact Factor
  • Hedi Schelleman, Nita A Limdi, Stephen E Kimmel
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    ABSTRACT: Warfarin is a highly efficacious drug, but management of warfarin is difficult, in part because of the large interindividual maintenance dose differences. Warfarin dose requirements differ by race and it has been suggested that some of these differences are owing to genetic diversity. For example, persons of African descent have lower allele frequencies of the CYP2C9*2 and *3 and VKORC1 1173T allele, which have been associated with lower warfarin dose requirements in Caucasians. Since there is currently debate whether genetic information should be used in clinical practice to determine the starting dose for a warfarin initiator, it is of great importance to determine whether everyone will benefit from this knowledge.
    Pharmacogenomics 10/2008; 9(9):1331-46. DOI:10.2217/14622416.9.9.1331 · 3.43 Impact Factor
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    ABSTRACT: The objective of this study was to determine whether warfarin dosing algorithms developed for Caucasians and African Americans on the basis of clinical, environmental, and genetic factors will perform better than an empirical starting dose of 5 mg/day. From April 2002 through December 2005, 259 subjects (Caucasians and African Americans) who started using warfarin were prospectively followed until they reached maintenance dose. The Caucasian algorithm included 11 variables (R(2) = 0.43). This model (which predicted 51% of the doses to within 1 mg of the observed dose) performed better than 5 mg/day (which predicted 29% of the doses to within 5 +/- 1 mg). The African-American algorithm included 10 variables (R(2) = 0.28). This model predicted 37% of the doses to within 1 mg of the observed dose, representing a small improvement compared with 5 mg/day (which predicted 34% of the doses to within 1 mg of 5 mg/day). These results were similar to the results we obtained from testing other published algorithms. The dosing algorithms explained <45% of the observed variability in Caucasians, and the algorithms performed only marginally better for African Americans when compared with giving 5 mg empirically.
    Clinical Pharmacology &#38 Therapeutics 08/2008; 84(3):332-9. DOI:10.1038/clpt.2008.101 · 7.39 Impact Factor
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    ABSTRACT: Patients with self-reported penicillin allergy are frequently denied beta-lactam antibiotics. To identify and correlate clinical and genetic risk factors of self-reported penicillin allergy. We conducted a case-control study of adults recruited from allergists' offices. Cases had a history of urticaria, angioedema, wheeze, hypotension, vomiting, or anaphylaxis after a dose of penicillin. DNA from buccal swabs was genotyped for variants associated with candidate genes linked to immediate hypersensitivity (IL4, IL4R, and IL10) and penicillin metabolism (LACTB). Logistic regression was used to calculate the association between penicillin allergy and clinical and genetic factors. Seventeen allergists identified 76 adults. Complete data were available for 23 cases and 39 controls. Penicillin allergy was associated with a history of penicillin allergy in first-degree relatives (P = .002), a history of other adverse drug reactions (P = .008), and atopy (P = .039). However, in the multivariable analysis, only family history of penicillin allergy remained significant. IL4 single nucleotide polymorphisms (SNPs) rs11740584 (P = .012), rs10062446 (P = .021), and rs2070874 (P = .035) were associated and LACTB SNP rs2729835 (P = .058) was marginally associated with penicillin allergy. Adding rs11740584 or rs10062446 individually improved the clinical multivariable model (R(2) increased from 0.23 to 0.33). Haplotype analysis did not provide additional information to the SNP analysis. Self-reported penicillin allergy may be influenced by clinical and genetic factors such as IL4.
    The Journal of allergy and clinical immunology 08/2008; 122(1):152-8. DOI:10.1016/j.jaci.2008.03.037 · 11.25 Impact Factor
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    ABSTRACT: The aim of this study was to determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. We conducted a nested case-control and case-crossover study using US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, co-trimoxazole, or fluconazole vs. no exposure and also vs. use of cephalexin, which would not be expected to interact with warfarin. All of the anti-infectives examined were associated with elevated odds ratios (ORs) when compared to no exposure to these drugs. With cephalexin data as the reference, the ORs for co-trimoxazole (OR: 1.68 (95% confidence interval (CI): 1.21-2.33) in the prior 6-10 days) and fluconazole (OR: 2.09 (95% CI: 1.34-3.26) in the prior 11-15 days) were significantly elevated. Warfarin users who had received an anti-infective agent showed a substantially increased risk of GI bleeding. However, a drug-drug interaction with warfarin was evident only for co-trimoxazole and fluconazole.
    Clinical Pharmacology &#38 Therapeutics 08/2008; 84(5):581-8. DOI:10.1038/clpt.2008.150 · 7.39 Impact Factor
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    ABSTRACT: This study investigates whether the interaction between angiotensin-converting enzyme (ACE) inhibitors or beta-blockers and the ACE insertion/deletion (I/D) polymorphism or angiotensin receptor II type 1 (AGTR1) 573C/T polymorphism modifies the risk of myocardial infarction (MI) or stroke. In total, 4097 subjects with hypertension were included in this study. The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model. The risk of MI was reduced in current users of ACE inhibitors with the AGTR1 573CT or CC genotype compared to ACE inhibitors with the AGTR1 573TT genotype (synergy index (SI):0.32; 95% confidence interval (CI): 0.14-0.70). No significant drug-gene interaction was found on the risk of stroke (SI:0.82; 95% CI: 0.44-1.52) or in beta-blocker users. Also, no significant drug-gene interaction was found with the ACE I/D polymorphism. In conclusion, subjects with at least one copy of the AGTR1 573C allele might have more benefit from ACE inhibitor therapy.
    The Pharmacogenomics Journal 04/2008; 8(6):400-7. DOI:10.1038/sj.tpj.6500493 · 5.51 Impact Factor
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    ABSTRACT: This study investigates whether the interaction between diuretics and alpha-adducin (ADD1) G460W or G-protein beta3-subunit (GNB3) rs2301339 polymorphism modifies the risk of myocardial infarction (MI) or stroke. Data were used from the Rotterdam Study. The drug-gene interaction was determined with a Cox proportional hazard model with adjustment for each drug class as time-dependent covariates. The risk of MI in current users of low-ceiling diuretics with one or two copies of the ADD1 W-allele (hazard ration (HR)=0.92) was similar compared to the expected joint effect of the W-allele and low-ceiling diuretics on a multiplicative scale (1.04 x 0.90=0.94) (synergy index (SI):0.99; 95% confidence interval (CI): 0.43-2.27). No drug-gene interaction was found on the risk of stroke (SI:0.66; 95% CI:0.43-1.27). In addition, a trend towards an interaction was found between current use and the GNB3 rs230119 G/A polymorphism on the risk of MI (SI: 0.51; 95% CI: 0.23-1.15), whereas no interaction on the risk of stroke was found (SI: 0.84; 95% CI: 0.46-1.56).
    The Pharmacogenomics Journal 11/2007; 7(5):346-52. DOI:10.1038/sj.tpj.6500428 · 5.51 Impact Factor
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    ABSTRACT: To investigate whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen M235T or angiotensin II receptor type 1 573C/T polymorphism modify the risk of atherosclerosis associated with beta-blocker or ACE-inhibitor therapy. Data were used from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects of >or= 55 years. In this study, 2216 subjects with hypertension were included. Three subclinical measurements were used for atherosclerosis, i.e. peripheral arterial disease, carotid atherosclerosis and aortic atherosclerosis. The interaction between antihypertensive drugs and genetic polymorphisms on the risk of atherosclerosis was determined with binary logistic regression analysis. The risk of aortic atherosclerosis associated with long-term (>or=4 years) beta-blocker treatment compared with no use of beta-blockers was higher in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene [synergy index (SI) = 3.36; 95% confidence interval (CI) 1.14, 9.97]. The risk of carotid atherosclerosis associated with long-term ACE-inhibitor treatment compared with no use of ACE-inhibitors was lower in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene (SI = 0.20; 95% CI 0.04, 0.95). Overall, the risk of atherosclerosis in hypertensives taking a beta-blocker or ACE-inhibitor-based regimen was not strongly modified by any of the three candidate gene polymorphisms.
    British Journal of Clinical Pharmacology 08/2007; 64(1):57-66. DOI:10.1111/j.1365-2125.2007.02848.x · 3.69 Impact Factor
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    ABSTRACT: The objective of this study was to determine whether two vitamin K epoxide reductase complex 1 (VKORC1) polymorphisms contribute to the variability in warfarin response, particularly in African Americans. The effect of the VKORC1 1173C/T and -1639G/A polymorphisms was examined in a prospective cohort study of 338 warfarin users. Subjects carrying an 1173T allele had a lower warfarin maintenance dose compared with subjects with the CC genotype in African Americans (-12.10 mg/week+/-4.93; P=0.02) and Caucasians (-14.41 mg/week+/-3.28; P<0.001). Before reaching maintenance dose, only Caucasians with the T allele had significantly increased risk of international normalized ratio >3 (odds ratio=3.10; 95% confidence interval: 1.73-5.55) compared with Caucasians with the CC genotype. Polymorphisms in the VKORC1 gene are associated with warfarin maintenance dose requirements among both African Americans and Caucasians. However, these polymorphisms may not be as useful in predicting over-anticoagulation among African Americans.
    Clinical Pharmacology &#38 Therapeutics 05/2007; 81(5):742-7. DOI:10.1038/sj.clpt.6100144 · 7.39 Impact Factor

Publication Stats

661 Citations
149.50 Total Impact Points

Institutions

  • 2011–2014
    • University of Pennsylvania
      • Center for Clinical Epidemiology and Biostatistics
      Philadelphia, Pennsylvania, United States
  • 2012
    • The Children's Hospital of Philadelphia
      Filadelfia, Pennsylvania, United States
  • 2008–2010
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2004–2008
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 2005–2007
    • Universiteit Utrecht
      • Division of Pharmacoepidemiology and Pharmacotherapy
      Utrecht, Utrecht, Netherlands