Nathalie K. Zgheib

Liver disease selectively modulates cytochrome P450--mediated metabolism.

The liver plays a significant role in drug metabolism; thus it would be expected that liver disease may have a detrimental effect on the activity of cytochrome P450 (CYP) enzymes. The extent to which the presence and severity of liver disease affect the activity of different individual drug‐metabolizing enzymes is still not well characterized. The purpose of this study was to assess the effect of liver disease on multiple CYP enzymes by use of a validated cocktail approach.

Using team-based learning to teach pharmacology to second year medical students improves student performance

Background: Team-based learning (TBL) is an innovative instructional method that fosters active learning. It has been shown to improve student performance in some health care education courses. Aim: To examine the effect of teaching pharmacology using a TBL approach on second year medical students’ satisfaction and performance. Methods: A modified TBL method was used in two case-based discussion sessions of the second year pharmacology course: a relatively easy drug metabolism/pharmacogenetics session and a more challenging pharmacokinetics/pharmacodynamics (PK/PD) session. Individual and group answers to all questions were recorded, and an evaluation form was collected for each session. Class performance on a summative quiz was compared to previous years. Results: Students provided positive feedback. Group performance was better than individual performance during the TBL exercises. TBL was less successful when the questions were very difficult, with a difficulty range of 30–70% being the most appropriate. Performance of the class on the pharmacology summative quiz showed significant improvement over that in previous years in the PK/PD part, but was unchanged in other topics taught traditionally. Conclusion: The results suggest that TBL provides a better outcome for students, and provide insight into appropriate design of TBL exercises.

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10−77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Validation of incorporating flurbiprofen into the Pittsburgh cocktail

We have previously shown that flurbiprofen metabolism to 4′‐hydroxyflurbiprofen provides an in vivo measure of cytochrome P450 (CYP) 2C9 activity. This study evaluated the possibility of incorporating flurbiprofen into the current 5‐drug Pittsburgh cocktail.

Using Team-based Learning to Teach Clinical Pharmacology in Medical School: Student Satisfaction and Improved Performance

Formal teaching in clinical pharmacology was never part of the curriculum at the American University of Beirut Faculty of Medicine. Based on feedback from students and on recommendations of academic bodies, we have introduced, since June 2008, twice‐monthly “rational prescribing” sessions during the required internal medicine rotation in year 4 of medical school. All sessions were designed according to the innovative Team‐based Learning format and concluded by having the students practice prescription writing and personal formulary development based on the World Health Organization criteria. Our 18‐month experience showed that students were very satisfied with the course and the teaching approach, and that their performance on prescription writing and formulary development had improved. Although further studies are needed to explore the impact of team‐based learning on additional performance measures, we recommend it as an effective alternative for teaching clinical pharmacology in medical schools.

Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia.

Background The aim of this study is to analyze polymorphisms in genes involved in 6-mercaptopurine detoxification (TPMT); methotrexate (MTX) metabolism including ABCB1 (or MDR1), ABCC2, SLC19A1 (or RFC1), and SLCO1B1; and the MTX effect mainly MTHFR and TYMS, and to assess whether these polymorphisms are predictors of treatment toxicity and/or MTX clearance. Materials and methods This study included 127 Lebanese acute lymphoblastic leukemia patients, of whom 117 were treated following the St Jude’s Children Research Hospital protocol. Genotyping was performed using real-time PCR or restriction fragment length polymorphism. MTX levels were measured using a polarization fluorescence assay from Roche. MTX clearance was estimated on the basis of all available MTX levels measured after high-dose MTX treatment during the consolidation phase. Results Five variants in four genes (MTHFR, ABCB1, ABCC2, and TYMS) were shown to be associated with toxicity, but neither was associated with MTX pharmacokinetic parameters. For instance, during the consolidation phase, a statistically significant association was found between MTHFR rs1801133 variant allele carriers and a decrease in hemoglobin levels [odds ratio (OR)=3.057; 95% confidence interval (CI): 1.217; 7.680]. In addition, a statistically significant association was found among neutropenia (absolute neutrophil count<500) and variant allele carriers of ABCB1 rs1045642 (OR=5.174; 95% CI: 1.674; 15.989) and ABCB1 rs1128503 (OR=3.364; 95% CI: 1.257; 9.004), respectively. ABCC2 rs717620 variant allele carriers needed significantly more time to reach a MTX level below 0.1 µmol/l (&bgr;=5.122; 95% CI: 1.412; 8.831). During the continuation phase, a statistically significant association was found between ABCC2 rs717620 and TYMS 28-bp tandem repeats carriers with the need to decrease weekly MTX doses (&bgr;=−4.905; 95% CI: −9; −0.809 and &bgr;=−5.770; 95% CI: −10.138; −1.403), respectively. Conclusion Genotyping for MTHFR, ABCB1, ABCC2, and TYMS polymorphisms may be useful in identifying patients at risk of increased MTX toxicity and the need for dose optimization before treatment initiation.

Influence of CYP2C9 and VKORC1 Polymorphisms on Warfarin and Acenocoumarol in a Sample of Lebanese People

The authors assessed the impact of CYP2C9*2, CYP2C9*3, and/or VKORC1−1639G>A/1173C>T single‐nucleotide polymorphisms on oral anticoagulants in a Lebanese population. This study recruited 231 Lebanese participants on long‐term warfarin or acenocoumarol maintenance therapy with an international normalized ratio (INR) monitored at the American University of Beirut Medical Center. CYP2C9 and VKORC1 variant alleles were screened by real‐time PCR. Plasma R‐ and S‐warfarin and R‐ and S‐acenocoumarol levels were assayed using high‐performance liquid chromatography. The variant allele frequencies of CYP2C9*2, CYP2C9*3, and VKORC1 −1639G>A/1173C>T were 15.4%, 7.8%, and 52.4%, respectively. Fifty‐five participants were excluded from analysis because of nontherapeutic INR values at recruitment, leaving 43 participants taking warfarin and 133 taking acenocoumarol. There was a significant decrease in the weekly maintenance dose of both drugs with CYP2C9 and VKORC1 variants when compared with wild‐type patients. CYP2C9*2 had the least impact on the response to both drugs. The concentrations of R‐ and S‐warfarin in plasma were significantly correlated with CYP2C9 genotypes. For acenocoumarol, time to reach target INR was more prolonged in patients carrying any CYP2C9 variant allele but failed to reach statistical significance because of low numbers of patients. There was no association between allelic variants and bleeding events. This is the first pharmacogenetic study of oral anticoagulants in Arabs. The authors showed that both CYP2C9 and VKORC1 polymorphisms are common in Lebanon and influence warfarin and acenocoumarol dose requirements, with the CYP2C9*2 polymorphism having less effect on acenocoumarol, the most commonly used oral anticoagulant in Lebanon.

Theranostics in primary care: pharmacogenomics tests and beyond

Theranostics represents a broadening in the scope of personalized medicine to include companion diagnostics for health interventions ranging from drugs to vaccines, as well as individual susceptibility to disease. Surprisingly, in the course of this broadening of personalized medicine discourse, relatively little attention has been paid to primary care (as compared with tertiary healthcare settings) despite its vast patient population and being a crucial entry point to health services. Recent advances in pharmacogenomics (PGx), a classical theranostics application whereby genotyping and/or gene expression-based tests are used for targeted or optimal therapy, revealed new opportunities to characterize more precisely human genomic variation and the ways in which it contributes to person-to-person and population variations in drug response. In the immediate foreseeable future, the primary-care physicians are expected to play an ever increasing crucial role in PGx-based prescribing in order to reduce the rates of adverse drug events and improve drug efficacy, yet PGx testing in primary care remains limited. In this article, the authors review the advances in PGx applications, the barriers for their adoption in the clinic from a primary care point of view and the efforts that are being undertaken to move PGx forward in this hitherto neglected application context of theranostic medicine. Finally, the authors propose several salient recommendations, including a 5-year forecast, to accelerate the current convergence between PGx and primary care.

miRNA as Potential Biomarkers of Breast Cancer in the Lebanese Population and in Young Women: A Pilot Study

Relative to western populations, the percentage of women diagnosed with breast cancer at a young age in Lebanon is high. While the younger age of the Lebanese population compared to the West certainly contributes to this difference, potential genetic, reproductive and/or biological factors likely play an important role. The objective of this study is to investigate the contribution of miRNAs in this setting through the analysis of the expression of five reported dysregulated miRNAs, miR-148b, miR-10b, miR-21, miR-221, and miR-155 in 20 normal and 57 cancerous breast tissues from Lebanese breast cancer patients. After finding their relative expression by quantitative reverse transcription real time PCR, the results were analyzed with respect to the patients’ clinical and histopathology presentations. Compared to normal breast tissues, significant upregulation of miR-155, miR-21 and miR-148b, notable downregulation of miR-10b and non-significant expression of miR-221 were observed in tumor tissues. Moreover, miR-10b was significantly underexpressed in estrogen/progesterone receptor (ER/PR) negative tumors relative to ER/PR positive tumor tissues. miR-155 was also significantly overexpressed in postmenopausal patients and in those of age at diagnosis greater than 40 years old as well as in PR negative or in human epidermal growth factor 2 (Her2) positive tissues. This study is the first one to report miRNA expression patterns in Lebanese breast cancer patients. We found that differential miRNA expression in breast cancer could be variable between Lebanese and Western populations. miR-10b was positively correlated with the ER and PR status and miR-155 could be a noteworthy biomarker for the menopausal state, age at diagnosis, PR and Her2 status. Hence, miRNA can be used as biomarkers for early breast cancer detection.

United States medical practice summary: innovative off-label medication use.

Data are limited regarding how academic medical centers (AMCs) deal with medication use that represents a departure from product labeling; has reasonable rationale for use, but insufficient evidence to allay safety, efficacy, and cost-effectiveness concerns; yet is not clinical research (defined as innovative off-label medication use). This report describes national trends in management of innovative off-label medication use. A cross-sectional survey of US AMCs was conducted. Survey questionnaires were directed to drug information centers or pharmacy directors. Of 469 AMCs contacted, 104 responded (22%). Fifty-nine AMCs identified innovative off-label use as a challenge. Only 18 AMCs developed strategies to address this issue: 12 requiring initial reviews and 8 requiring clinical monitoring. Sixty-five AMCs indicated interest in data sharing of clinical outcomes for innovative off-label protocol(s). Innovative off-label medication use is a widely recognized challenge; however, few prospectively active AMC responses exist. The authors suggest development of systematic structured approaches within and across AMCs.