A meta-analysis of the pooled impact of CYP7A1 single nucleotide polymorphisms on serum lipid responses to statins.

Background and Aims: Various publications suggested that there is an association between CYP7A1 single nucleotide polymorphisms (SNP) and a reduced response to statin therapy, but the results were inconsistent. This study aimed to collectively review these publications to appraise the effect of statins on cholesterol control in carriers of CYP7A1 variant alleles. Methods: PUBMED, Cochrane and EMBASE were searched systematically to identify reported studies on the lipid responses to statin treatment between carriers of the variant allele versus the non-variant allele of CYP7A1 SNPs. The change from baseline in lipid responses for all included studies were calculated using weighted mean differences (WMD) (with 95% confidence interval (CI)). A meta-analysis was conducted to pool results using either the random-effects model or the fixed effects model. Results: A total of 6 publications comprising of 1,686 subjects for the assessment of total cholesterol, LDL-C and HDL-C and 1,156 subjects for the assessment of triglycerides were included in the meta-analyses. Subjects who were non-carriers of a CYP7A1 SNP (-204 A/C (rs3808607), -278 A/C (rs3808607) and rs8192875) had a greater reduction in total cholesterol (overall WMD -0.17, 95% CI -0.29, -0.06) and LDL-C levels (overall WMD -0.16, 95% CI -0.26, -0.05) as compared with subjects who borne the variant allele of CYP7A1 SNPs when administered a statin. Conclusion: The presence of variant allele of CYP7A1 SNPs may result in suboptimal control of total cholesterol and LDL-C levels as compared with individuals who do not carry the variant allele, when administered an equivalent dose of statin.

Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND Tacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes between formulations are lacking. We conducted a systematic literature review and network meta-analysis assessing tacrolimus (primarily Advagraf [once-daily] and Prograf [twice-daily])-based maintenance regimens. MATERIAL AND METHODS Embase, MEDLINE, and Cochrane databases and congress proceedings were searched to identify studies of adult de novo KTRs who received tacrolimus-based therapy in phase II/III randomized controlled trials. Outcomes were acute rejection, graft/patient survival, and incidence of new-onset diabetes mellitus after transplantation (NODAT) and cytomegalovirus (CMV) infection. Bayesian network meta-analysis was used to analyze treatment effects on graft/patient survival. RESULTS Sixty-eight publications (61 primary) were included. Of 21 publications reporting graft rejection following Advagraf or Prograf treatment in ≥1 study arm, 12-month biopsy-proven acute rejection (BPAR) ranged from 3.3% with Prograf to 55.0% with mycophenolic acid (MPA)+corticosteroids (CS); >24 month BPAR ranged from 0% to 58.7% (the latter with bleselumab-based therapy). Fourteen publications reported graft loss following Advagraf (0-9.6%) or Prograf (0-7.5%). Patient mortality ≤24 months after transplantation (14 publications) ranged from 0% to 8.1% with Advagraf or Prograf. Advagraf+MPA+CS and reference treatment, Prograf+MPA+CS, were associated with a similar risk of graft loss (odds ratio 1.19; 95% credible-interval 0.51, 3.06) and mortality (odds ratio 1.21; 95% credible-interval 0.1557, 9.03). Incidence of NODAT and CMV varied by treatment arm. CONCLUSIONS Graft loss and patient mortality rates were generally comparable between Advagraf- and Prograf-based regimens. Further prospective studies are needed to evaluate longer-term outcomes.

Association between family history and lung cancer risk among Chinese women in Singapore.

Risk factors of lung cancer unrelated to smoking are not well-studied, especially among women. Family history has been shown to play a role in predisposing individuals to lung cancer, but this relationship has not been investigated in the Southeast Asian population. A total of 1159 women were recruited in a case-control study conducted in public hospitals in Singapore from 2005 to 2008. After excluding participants with incomplete family history information, 374 cases and 785 controls remained in the final analysis. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression, adjusting for potential confounders. Overall, family history of lung cancer was associated with a higher risk for lung cancer (aOR 2.08, 95% CI 1.25-3.47). When stratified by smoking status, a significant association was observed among never-smokers (aOR 2.78, 95% CI 1.57-4.90). Further stratification by fruit consumption identified a significant association between family history of lung cancer and higher risk of lung cancer among never-smokers who had low fruit consumption (aOR 3.09, 95% CI 1.37-7.01). Our findings suggest that family history of lung cancer is a significant risk factor for lung cancer in Singaporean Chinese women, especially among never-smokers.

Association between Metabolites and the Risk of Lung Cancer: A Systematic Literature Review and Meta-Analysis of Observational Studies.

Globally, lung cancer is the most prevalent cancer type. However, screening and early detection is challenging. Previous studies have identified metabolites as promising lung cancer biomarkers. This systematic literature review and meta-analysis aimed to identify metabolites associated with lung cancer risk in observational studies. The literature search was performed in PubMed and EMBASE databases, up to 31 December 2019, for observational studies on the association between metabolites and lung cancer risk. Heterogeneity was assessed using the I2 statistic and Cochran's Q test. Meta-analyses were performed using either a fixed-effects or random-effects model, depending on study heterogeneity. Fifty-three studies with 297 metabolites were included. Most identified metabolites (252 metabolites) were reported in individual studies. Meta-analyses were conducted on 45 metabolites. Five metabolites (cotinine, creatinine riboside, N-acetylneuraminic acid, proline and r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene) and five metabolite groups (total 3-hydroxycotinine, total cotinine, total nicotine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (sum of concentrations of the metabolite and its glucuronides), and total nicotine equivalent (sum of total 3-hydroxycotinine, total cotinine and total nicotine)) were associated with higher lung cancer risk, while three others (folate, methionine and tryptophan) were associated with lower lung cancer risk. Significant heterogeneity was detected across most studies. These significant metabolites should be further evaluated as potential biomarkers for lung cancer.

Association between family history of lung cancer and lung cancer risk: a systematic review and meta-analysis.

BACKGROUND: Familial risk of lung cancer has been widely studied but the effects of sociodemographic factors and geographical regions are largely unknown. METHODS: PubMed and Embase were systematically searched until 1st October 2019. A total of 84 articles were identified and (19 cohort and 66 case control studies) included in this systematic review and meta-analysis. Pooled summary estimates and 95% confidence intervals were estimated, and the analysis was stratified by sociodemographic factors and geographical regions. RESULTS: Geographical regions, sex, age of proband, smoking status, type of first-degree relatives, number of affected relatives, and early onset of lung cancer in affected relatives were significant determinants of familial risk of lung cancer. Higher risk of familial lung cancer was found among Asians as compared to non-Asians, younger individuals (age≤50) as compared with older individuals (age>50), individuals with ≥2 affected relatives as compared with individuals with one affected relative, ever-smokers as compared with never-smokers, Asian females as compared with Western females, and never-smokers in Asia as compared with never-smokers in the West. CONCLUSIONS: Familial risk of lung cancer is influenced by both genetic and environmental factors. Future studies should control for environmental factors such as air pollution and environmental tobacco smoke which are prevalent in Asia.

Temporal Trends and Patient Characteristics Associated With Drug Utilisation After First-Ever Stroke: Insights From Chronic Disease Registry Data in Singapore.

INTRODUCTION: Data on drug utilisation among stroke patients of Asian ethnicities are lacking. The objectives of the study were to examine the temporal trends and patient characteristics associated with prescription of thrombolytic, antithrombotic and statin medications among patients with first-ever stroke. MATERIALS AND METHODS: First-ever ischaemic and haemorrhagic stroke patients admitted to 2 Singapore tertiary hospitals between 2010‒2014 were included. Data were extracted from the National Healthcare Group Chronic Disease Management System. Association between drug utilisation and admission year, as well as characteristics associated with drug use, were explored using multivariable logistic regression. RESULTS: There was an increasing trend in the combined use of all 3 guideline medications in ischaemic stroke patients (P <0.001)-specifically thrombolytic agents (P <0.001), oral antithrombotics (P = 0.002) and statins (P = 0.003) at discharge. Among antithrombotics, the use of clopidogrel (P <0.001) and aspirin-clopidogrel (P <0.001) had increased, whereas prescription of dipyridamole (P <0.001) and aspirin-dipyridamole (P <0.001) had declined. For statins, the increase in atorvastatin prescription (P <0.001) was accompanied by decreasing use of simvastatin (P <0.001). Age, ethnicity and certain comorbidities (hyperlipidaemia, atrial fibrillation and chronic kidney disease) were associated with the combined use of all 3 guideline medications (P <0.05). In haemorrhagic stroke, prescription of statins at discharge were comparatively lower. CONCLUSION: This study reveals changes in prescription behaviour over time in a multiethnic Asian population with first-ever stroke. Patient characteristics including younger age, Malay ethnicity and certain comorbidities (i.e. hyperlipidaemia, atrial fibrillation) were associated with the combined use of all 3 guideline medications among ischaemic stroke patients.

Impact of medication nonadherence on stroke recurrence and mortality in patients after first-ever ischemic stroke: Insights from registry data in Singapore.

PURPOSE: This retrospective cohort study aims to examine adherence to secondary stroke preventive medications and their association with risk of stroke recurrence and mortality in patients after first-ever ischemic stroke. METHODS: Using data from the National Healthcare Group and Singapore Stroke Registry, patients with first-ever ischemic stroke between 2010 and 2014 were included, and categorized based on antithrombotic or statin adherence using the proportion of days covered: high (≥75%), intermediate (50%-74%), low (25%-49%), and very low (<25%). The primary outcome was first recurrent ischemic stroke within a year after hospital discharge, while the secondary composite outcomes were (a) stroke recurrence and all-cause mortality and (b) stroke recurrence and cardiovascular mortality. The Cox proportional hazard model was used to examine the association between medication adherence and outcomes. Adjusted hazard ratios (aHRs) and the corresponding 95% confidence intervals (CIs) were reported. RESULTS: Among ischemic stroke patients prescribed with antithrombotics (n = 1139) or statins (n = 1160) at hospital discharge, about one-third were highly adherent to their medications. Patients with lower medication adherence tended to be younger, were admitted to private ward classes, and were without hypertension. Compared with the patients with high medication adherence, the risk of stroke recurrence was higher in patients with very low antithrombotic (aHR = 4.65; 95% CI: 1.45-14.89) or statin (aHR = 3.44; 95% CI: 0.93-12.74) adherence. Similar findings were observed for the secondary outcomes. CONCLUSIONS: Poor adherence to antithrombotic and statin treatment increases the risk of recurrent stroke and mortality in patients after first-ever ischemic stroke. Further measures are needed to improve medication adherence among stroke survivors.

Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave's disease: a metabolomic approach.

Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave's disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography-tandem mass spectrometry (GC-MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6, which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.

Use of Selective Serotonin Reuptake Inhibitors and Outcomes in Stroke Rehabilitation: A Prospective Observational Pilot Cohort Study.

PURPOSE: The aim of this study was to examine the association between selective serotonin reuptake inhibitor (SSRI) therapy and rehabilitation outcomes, specifically disability and quality of life (QOL), in a real-world setting of multi-ethnic Asian patients with first-ever stroke. METHODS: In this prospective observational pilot cohort study, we included patients with first-ever stroke admitted to two inpatient rehabilitation centres in Singapore between January and July 2018. Outcomes were measured using Functional Independence Measure (FIM)-motor scale, modified Barthel Index (MBI) and the Stroke and Aphasia Quality of Life Scale-39 generic (SAQOL-39g) questionnaire. Linear regression was used to assess the association between SSRI therapy and outcomes. Regression coefficients and 95% confidence intervals (CIs) were reported. RESULTS: Among 57 patients included for analyses, 38.6% received SSRIs. Although SSRI therapy was significantly associated with gains in MBI (coefficient 11.35; 95% CI 0.21-22.50) and SAQOL-39g overall score (coefficient 0.45; 95% CI 0.05-0.85) based on simple linear regression, no significant association between SSRI therapy and any of the investigated outcomes was found after adjustment for confounders. However, an increase in the mean number of physiotherapy and occupational therapy (PT/OT) sessions per day significantly improved FIM-motor (coefficient 16.86; 95% CI 2.64-31.07) and MBI (coefficient 22.79; 95% CI 2.35-43.23) scores. CONCLUSION: SSRI therapy did not improve disability and QOL in multi-ethnic Asian patients with first-ever stroke undergoing rehabilitation.

Temporal Trends and Predictors of Drug Utilization and Outcomes in First-Ever Stroke Patients: A Population-Based Study Using the Singapore Stroke Registry.

INTRODUCTION: Drug utilization and outcomes research in multi-ethnic Asian stroke populations is lacking. OBJECTIVES: Our objective was to examine temporal trends and predictors of drug utilization and outcomes in a multi-ethnic Asian stroke population. METHODS: This registry-based study included ischemic and hemorrhagic first-ever stroke patients hospitalized between 2009 and 2016. Utilization of medications included in-hospital thrombolytic agents, early antithrombotics (antiplatelets, anticoagulants) within 48 h of admission, and antithrombotics and statins at discharge. Outcomes analyzed were in-hospital all-cause mortality; 28-day, 90-day, and 1-year case fatality (CF); and discharge destination. RESULTS: Of the 36,615 included patients, 81.6% had ischemic stroke and 18.4% had hemorrhagic stroke (15.5% intracerebral hemorrhage [ICH] and 2.8% subarachnoid hemorrhage [SAH]). For ischemic stroke, the combined use of all three guideline medications (in-hospital thrombolytic therapy, as well as antithrombotics and statins at discharge) increased (P = 0.006). Being on the stroke pathway was associated with prescription of all three guideline medications in ischemic stroke. Decreasing trends for in-hospital mortality, 28-day, 90-day, and 1-year CF and proportion of patients discharged home without rehabilitation appointment were observed in ischemic stroke (P < 0.05) but not in ICH or SAH (apart from 28-day CF). Ischemic stroke patients who received guideline medications were less likely to die or be discharged to nursing homes and chronic sick hospitals. Hemorrhagic stroke patients prescribed statins at discharge were less likely to have 28-day and 1-year CF. CONCLUSIONS: Prescription of secondary stroke preventive medications (particularly in ischemic stroke) was associated with more favorable outcomes, highlighting the importance of physician adherence to evidence-based pharmacotherapy.

Conversion from Twice-Daily Prograf® to Once-Daily Advagraf® in Multi-ethnic Asian Adult Renal Transplant Recipients With or Without Concomitant Use of Diltiazem: Impact of CYP3A5 and MDR1 Genetic Polymorphisms on Tacrolimus Exposure.

BACKGROUND AND OBJECTIVES: Tacrolimus is the mainstay of immunosuppression in renal transplantation. Given that once-daily administration improves patient compliance, 1:1 dose conversion from twice-daily Prograf® to once-daily Advagraf® is recommended. Although cytochrome P450 (CYP) 3A5 and multi-drug resistance 1 (MDR1) polymorphisms influence tacrolimus concentrations, it is unknown if these impact on conversion. This study investigated the change in the pharmacokinetics of tacrolimus after conversion from Prograf® to Advagraf® and examined the impact of CYP3A5 and MDR1 C3435T polymorphisms on those pharmacokinetics. METHODS: A prospective open-label pharmacokinetic study of 1:1 conversion from Prograf® to Advagraf® with or without diltiazem was conducted on 26 stable renal transplant recipients. Blood samples were collected over 24 h during each phase, tacrolimus concentrations were assayed, and noncompartmental pharmacokinetic analysis was performed. All participants were genotyped for CYP3A5*3 and MDR1 C3435T. RESULTS: After conversion, without diltiazem, the area under the concentration-time curve at steady state from 0 to 24 h after dose administration (AUCss, 0-24) was significantly reduced [median 224 (range 172-366) vs. 184 (104-347) ng·h/mL, p = 0.006, n = 26]. A decrease in tacrolimus exposure (median 21%) was only evident among CYP3A5 expressors [227 (172-366) vs. 180 (104-347) ng·h/mL, p = 0.014, n = 18], not among non-expressors [215 (197-290) vs. 217 (129-281) ng·h/mL, p = 0.263, n = 8]. In contrast, among CYP3A5 expressors receiving diltiazem, AUCss, 0-24 did not change significantly upon conversion [229 (170-296) vs. 221 (123-342) ng·h/mL, p = 0.575, n = 10]. An independent effect was not evident for MDR1 C3435T polymorphism. CONCLUSION: The high prevalence of CYP3A5 polymorphism among Asians may lead to a significant reduction in tacrolimus exposure with 1:1 dose conversion of Prograf® to Advagraf®. These results advocate for CYP3A5 determination prior to conversion, and suggest that 1:1.25 conversion should be used for CYP3A5 expressors and 1:1 conversion for other patients.

Effects of Central Nervous System Drugs on Recovery After Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVE: Pilot trials have suggested that pharmacotherapy may aid stroke recovery. The aim of this study was to systematically review the effects of antidepressants, anti-Alzheimer drugs, anti-Parkinson drugs, central nervous system (CNS) stimulants and piracetam on gross motor function, cognition, disability, dependency and quality of life (QOL) after stroke. METHODS: PubMed, EMBASE and the Cochrane Central Register of Controlled Trials databases were searched, and 44 randomized controlled trials that compared outcomes of interest between drug treatment and placebo or no treatment were included. For each study, standardized mean difference (SMD) or mean difference (MD) with 95% confidence interval (CI) were calculated. Meta-analyses were conducted to pool results using either the fixed-effects or random-effects model. RESULTS: Selective serotonin reuptake inhibitors (SSRIs) improved gross motor function (SMD 0.54, 95% CI 0.22-0.85; three studies), disability (SMD 0.49, 95% CI 0.32-0.66; 14 studies) and QOL (MD 6.46, 95% CI 4.71-8.22; two studies), but there was insufficient evidence for their use in enhancing global cognition (SMD 0.23, 95% CI -0.01 to 0.46; five studies) and dependency (risk ratio 0.81, 95% CI 0.68-0.97; one fluoxetine study). In particular, gross motor function was improved by fluoxetine (SMD 0.64, 95% CI 0.31-0.98; two studies), while disability was improved by paroxetine (SMD 1.05, 95% CI 0.63-1.46; two studies), citalopram (SMD 0.51, 95% CI 0.08-0.93; two studies) and fluoxetine (SMD 0.41, 95% CI 0.22-0.60; nine studies). There is insufficient evidence for the use of anti-Alzheimer drugs, anti-Parkinson drugs, CNS stimulants and piracetam to promote stroke recovery. CONCLUSIONS: Administration of SSRIs may improve gross motor function, reduce disability and enhance QOL for patients recovering from stroke.

Establishing population distribution of drug-metabolizing enzyme activities for the use of salivary caffeine as a dynamic liver function marker in a Singaporean Chinese population.

The salivary paraxanthine/caffeine molar ratio has been proposed as a novel dynamic liver function test to guide dose adjustments of drugs hepatically cleared by CYP1A2. Its usability requires an established population norm as well as the factors influencing the ratio and actual concentrations. To address this knowledge gap, salivary caffeine and paraxanthine concentrations were measured at 4 h post caffeine dose in healthy Chinese individuals who had undergone 24 h of caffeine abstinence. The metabolic ratio was calculated and statistical analysis was performed. From the 52 participants (26 males; 30 regular caffeine consumers) recruited, the salivary paraxanthine/caffeine molar ratio was normally distributed with a mean and SD of 0.5 ± 0.2. No statistically significant factors (BMI, body weight, gender and regularity of caffeine intake) affecting the metabolic ratio were found. The caffeine concentration and total caffeine plus paraxanthine concentrations were lower in males than in females, and lower in regular caffeine consumers than in non-regular caffeine consumers. The 4 h salivary metabolic ratio (mean: 0.5) was generally not significantly different from the literature reported salivary, serum and plasma ratios measured at 4-9 h in healthy individuals (mean range 0.4-0.7) but was significantly higher than the literature reported 6 h plasma ratio and salivary ratios measured at 1-6 h in patients with liver disease or mild abnormal liver function tests (mean range 0.03-0.2). Overall, the population norm of the salivary metabolic ratio in a Singaporean Chinese population established in this study is distinct from individuals with liver disease or mild abnormal liver function tests and provides the benchmark for dosage adjustments of drugs metabolized by CYP1A2. Copyright © 2016 John Wiley & Sons, Ltd.

Use of decongestants during pregnancy and the risk of birth defects.

Previous studies suggested that early pregnancy exposure to specific oral decongestants increases the risks of several birth defects. Using January 1993-January 2010 data from the Slone Epidemiology Center Birth Defects Study, we tested those hypotheses among 12,734 infants with malformations (cases) and 7,606 nonmalformed control infants in the United States and Canada. Adjusted odds ratios and 95% confidence intervals were estimated for specific birth defects, with controlling for potential confounders. Findings did not replicate several hypotheses but did support 3 previously reported associations: phenylephrine and endocardial cushion defect (odds ratio = 8.0; 95% confidence interval: 2.5, 25.3; 4 exposed cases), phenylpropanolamine and ear defects (odds ratio = 7.8; 95% confidence interval: 2.2, 27.2; 4 exposed cases), and phenylpropanolamine and pyloric stenosis (odds ratio = 3.2; 95% confidence interval: 1.1, 8.8; 6 exposed cases). Hypothesis-generating analyses involving multiple comparisons identified a small number of associations with oral and intranasal decongestants. Accumulating evidence supports associations between first-trimester use of specific oral and possibly intranasal decongestants and the risk of some infrequent specific birth defects.

Safety of macrolides during pregnancy.

OBJECTIVE: Prior studies have reported increased risks of congenital heart defects (CHD) and pyloric stenosis (PS) after prenatal exposure to macrolide antibiotics. We sought to assess the association between maternal use of erythromycin and nonerythromycin macrolides and the risks of CHD and PS. STUDY DESIGN: Among participants in the Slone Epidemiology Center Birth Defects Study from 1994 through 2008, we identified 4132 infants with CHD and 735 with PS as cases, and 6952 infants without any malformation as controls. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with use of erythromycin or nonerythromycin macrolides in each trimester using conditional logistic regression and adjusting for risk factors for CHD and PS, fever, specific types of infections, and their associated treatments. RESULTS: During the first trimester, 0.4% and 0.7% of control women had used erythromycin and nonerythromycin macrolides, respectively. Compared to non-use during pregnancy, first-trimester exposure to erythromycin was not associated with an increased risk of CHD (OR, 1.3; 95% CI, 0.6-2.6) or PS (OR, 0.9; 95% CI, 0.3-3.0). The corresponding ORs for nonerythromycin macrolides were 0.7 (95% CI, 0.4-1.3) for CHD and 1.7 (95% CI, 0.6-4.6) for PS. We found no association between third-trimester exposure to erythromycin or nonerythromycin macrolides and the risk of PS. Hypothesis generation analyses did not identify appreciable associations between maternal use of macrolides and other common specific birth defects. CONCLUSION: We found no meaningful associations between the risks of CHD, PS, and other common malformations in relation to use of macrolides in pregnancy.

Assessment of antihistamine use in early pregnancy and birth defects.

BACKGROUND: Several studies have reported an association between use of specific antihistamines in early pregnancy and certain specific birth defects. OBJECTIVE: To test 16 previously hypothesized associations between specific antihistamines and specific birth defects, and to identify possible new associations. METHODS: We used 1998-2010 data from the Slone Epidemiology Center Birth Defects Study, a multicenter case-control surveillance program of birth defects in North America. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors, and details on the use of prescription and nonprescription medications. We compared first trimester exposure to specific antihistamines between 13,213 infants with specific malformations and 6982 nonmalformed controls by using conditional logistic regression to estimate odds ratios and 95% confidence intervals (CIs), with adjustment for potential confounders, including indication for use. RESULTS: Overall, 13.7% of controls were exposed to antihistamines during the first trimester. The most commonly used medications were diphenhydramine (4.2%), loratadine (3.1%), doxylamine (1.9%), and chlorpheniramine (1.7%). When estimates were stable, none supported the previously hypothesized associations. Among more than 100 exploratory comparisons of other specific antihistamine-defect pairs, 14 had odds ratios ≥1.5, of which 6 had 95% CI bounds excluding 1.0 before but not after adjustment for multiple comparisons. CONCLUSION: Our findings do not provide meaningful support for previously posited associations between antihistamines and major congenital anomalies; at the same time, we identified associations that had not been previously suggested. We suspect that previous associations may be chance findings in the context of multiple comparisons, a situation that may also apply to our new findings.

Maternal exposure to amoxicillin and the risk of oral clefts.

BACKGROUND: Prior studies have suggested an increased risk of oral clefts after exposure to amoxicillin in early pregnancy, but findings have been inconsistent. METHODS: Among participants in the Slone Epidemiology Center Birth Defects Study from 1994 to 2008, we identified 877 infants with cleft lip with/without cleft palate and 471 with cleft palate alone. Controls included 6952 nonmalformed infants. Mothers were interviewed about demographic, reproductive and medical factors, and details of medication use. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with use of amoxicillin in the first trimester using conditional logistic regression and adjusting for known risk factors for oral clefts, as well as for infections, fever, and concomitant treatments. RESULTS: In the control group, 2.1% of women had used amoxicillin in the first trimester. Maternal use of amoxicillin was associated with an increased risk of cleft lip with/without cleft palate (adjusted OR = 2.0 [95% confidence interval = 1.0-4.1]), with an OR of 4.3 (1.4-13.0) for third-gestational-month use. Risks were not elevated for use of other penicillins or cephalosporins. For cleft palate, the OR for first-trimester amoxicillin was 1.0 (0.4-2.3) with an OR of 7.1 (1.4-36) for third-gestational month use. CONCLUSIONS: Amoxicillin use in early pregnancy may be associated with an increased risk of oral clefts.

Drug certainty-response in interview-based studies.

PURPOSE: Imperfect recall of exposure timing challenges the ascertainment of medications in interview-based studies. METHODS: We propose an algorithm to classify medication exposure, taking into account recall certainty. The availability of medication use details, including duration of use, start and stop dates, and maternal estimates of how certain they were about these dates, allowed classification of subjects as either likely or possibly exposed in the first trimester of pregnancy. We applied the algorithm to study an association between prenatal tetracycline exposure and risk of congenital heart defects previously reported by the National Birth Defects Prevention Study, using 1993-2008 data from 11,517 subjects in the Slone Epidemiology Center Birth Defects Study. RESULTS: Among women exposed to tetracyclines during pregnancy (n = 58), 50% and 19% were likely and possibly exposed, respectively, in the first trimester, and 31% were exposed outside the first trimester. Compared with non-use during pregnancy, the crude OR for exposure outside the first trimester was 1.0 (95%CI 0.4-2.5), and that for exposed (likely or possibly, combined) in the first trimester was 1.7 (95%CI 0.9-3.2); however, the ORs based on the algorithms were 0.9 (95%CI 0.3-3.0) for possibly exposed and 2.2 (95%CI 1.0-4.6) for likely exposed. CONCLUSIONS: A "certainty-response" (stronger association with higher level of certainty) was found within exposures in the window of etiological interest. Algorithms for exposure classification that incorporate recall certainty may be useful in interview-based studies.

Mechanism-based enterohepatic circulation model of mycophenolic acid and its glucuronide metabolite: assessment of impact of cyclosporine dose in Asian renal transplant patients.

Mycophenolic acid (MPA) is mainly metabolized to MPA-glucuronide (MPAG), which may be reconverted to MPA following enterohepatic circulation (EHC). A physiologically realistic EHC model was proposed to estimate and assess the impact of cyclosporine (CsA) dose on the extent of EHC of MPA and MPAG. After the first oral dose of mycophenolate mofetil (MMF), the MPA and MPAG plasma concentration-time data of 14 adult renal transplant patients (12 receiving concomitant CsA and prednisolone and 2 receiving only concomitant prednisolone without CsA) were analyzed by individual pharmacokinetic modeling using a proposed 5-compartment drug and metabolite EHC model with a time-varying gallbladder emptying process. Simulations were performed to assess the influence of the time of bile release after dosing (T(bile)) and the gallbladder emptying interval (tau(gall)) on the EHC process. The extent of EHC for both MPA and MPAG tended to be lower in the group receiving CsA coadministration and decreased with increasing total body weight-adjusted CsA dose. Simulations revealed that T(bile) and tau(gall) influenced the time of occurrence and maximum concentration of the second peak, as well as the extent of EHC, for MPA and MPAG.

Is a standard fixed dose of mycophenolate mofetil ideal for all patients?

BACKGROUND: A standard fixed dose of 2 g/day of mycophenolate mofetil (MMF), irrespective of total body weight (TBW), is recommended when used in combination with cyclosporine and corticosteroids in renal transplantation. METHODS: To determine the optimal MMF dose in a population with wide variation in TBW, steady-state pharmacokinetics of mycophenolic acid (MPA) was performed in 53 Asian (Chinese, Malay, Indian, Eurasian) renal transplant recipients (RTX) receiving MMF [250-1000 mg twice daily (BD)] for at least 3 months. Blood samples were collected at 0, 0.5, 1, 1.5, 2 and 6 h after the MMF dose and total MPA quantified using HPLC. RESULTS: Drug exposure, as evaluated by AUC(ss, 0-12), demonstrated a significant positive correlation with TBW-adjusted MMF dose (outliers omitted: r(2) = 0.49, P < 0.0005). An AUC(ss, 0-12) of 45 mg h/l could be attained with an MMF dose of 12 mg/kg BD. CONCLUSION: This study proposes that MMF should be dosed based on TBW rather than a fixed dose regimen in RTX.