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Hospital de Órbigo, Spain

Gaedigk A.,The Childrens Mercy Hospital and Clinics | Jaime L.K.M.,Pharmacology Unit | Bertino Jr. J.S.,Bertino Consulting | Berard A.,University of Montreal | And 3 more authors.
Frontiers in Pharmacology | Year: 2010

Polymorphic expression of CYP2D6 contributes to the wide range of activity observed for this clinically important drug metabolizing enzyme. In this report we describe novel CYP2D7/2D6 hybrid genes encoding non-functional and functional CYP2D6 protein and a CYP2D7 variant that mimics a CYP2D7/2D6 hybrid gene. Five-kilobyte-long PCR products encompassing the novel genes were entirely sequenced. A quantitative assay probing in different gene regions was employed to determine CYP2D6 and 2D7 copy number variations and the relative position of the hybrid genes within the locus was assessed by long-range PCR. In addition to the previously known CYP2D6 *13 and *66 hybrids, we describe three novel non-functional CYP2D7-2D6 hybrids with gene switching in exon 2 (CYP2D6 *79), intron 2 (CYP2D6 *80), and intron 5 (CYP2D6*67). A CYP2D7-specific T-ins in exon 1 causes a detrimental frame shift. One subject revealed a CYP2D7 conversion in the 5′-flanking region of a CYP2D6 *35 allele, was otherwise unaffected (designated CYP2D6*35B). Finally, three DNAs revealed a CYP2D7 gene with a CYP2D6-like region downstream of exon 9 (designated CYP2D7[REP6]). Quantitative copy number determination, sequence analyses, and long-range PCR mapping were in agreement and excluded the presence of additional gene units. Undetected hybrid genes may cause over- estimation of CYP2D6 activity (CYP2D6 *1/ *1 vs *1/hybrid, etc), but may also cause results that may interfere with the genotype determination. Detection of hybrid events, " single" and tandem, will contribute to more accurate phenotype prediction from genotype data. © 2010 Gaedigk, Jaime, Bertino, Jr., Bérard, Pratt, Bradford and Leeder. Source

El-Awady R.A.,Pharmacology Unit | El-Awady R.A.,University of Sharjah | Saleh E.M.,National Cancer Institute | Dahm-Daphi J.,University of Hamburg
Anti-Cancer Drugs | Year: 2010

Inhibition of the repair of 5-fluorouracil (FU)-induced DNA lesions may improve the response of many tumors to this anticancer agent. Despite the identified associations between DNA strand breaks and the lethality of thymidylate synthase inhibitors, the role of DNA double-strand break (DSB) repair pathways in a cellular response to 5-FU treatment has not been studied yet. Isogenic cell lines defective (irs1SF), wild type (AA8), or reconstituted (1SFK8) in the DSB repair protein XRCC3 were used to investigate the effect of defective DSB repair on the overall sensitivity of cells to 5-FU and to see how targeting DSB repair may affect other cellular responses to 5-FU. Treatment with 5-FU resulted in (i) similar induction of DSB in both cell lines as indicated by the formation of γ-H2AX (a marker for DSB). The repair of these breaks was complete in AA8 but not in irs1SF cells. (ii) Concentration-dependent reduction in the survival of both cell lines. The AA8 cells were six times more sensitive to 5-FU than the irs1SF cells. (iii) An earlier and more prolonged G1/S phase arrest in AA8 compared with the irs1SF cells. (iv) Induction of apoptosis as indicated by sub-G1 cells and caspase-3 activity in AA8 but not in irs1SF cells. XRCC3 complementation of irs1SF cells restored the wild-type phenotype. This result shows that targeting DSB repair is not always associated with increased sensitivity to DNA damaging agents such as 5-FU because it may affect other cellular responses such as cell cycle regulation and induction of apoptosis. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Francini E.,University of Rome | Fiaschi A.I.,Pharmacology Unit | Petrioli R.,Medical Oncology Unit | Laera L.,Medical Oncology Unit | And 3 more authors.
Anti-Cancer Drugs | Year: 2015

Both abiraterone acetate (AA) and cabazitaxel (Cbz) have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel (D). Although no standard sequencing has been established as yet, Cbz has recently been proven to be active after AA. However, to date, few data are available on its safety in this setting. Therefore, the primary endpoint of this study was to investigate Cbz tolerability in mCRPC patients treated previously with D and AA. From April 2011 to the present, 43 mCRPC patients received AA after D at our institution. Of these, 22 patients were subsequently treated with Cbz and were evaluable for toxicity in the present retrospective study. Cbz was administered at a dose of 25 mg/m2 plus 10 mg oral prednisone every 3 weeks. Adverse events (AEs) were reported using the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. Despite the advanced stage of disease and frailty of our study population, there were no unexpected side effects. The most common AEs were hematologic. Neutropenia was observed in nine (40.9%) patients and of grade≥3 in six (27.2%). No febrile neutropenia occurred. The most common nonhematologic AEs were diarrhea and asthenia, reported in eight (36.3%) and in five (22.7%) patients, respectively. In this setting, Cbz toxicity seems to be manageable and comparable with second-line Cbz. Therefore, our results seem to support the safety of Cbz as a third-line treatment for mCRPC patients. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Labarga P.,Hospital Carlos III | Medrano J.,Hospital Carlos III | Seclen E.,Hospital Carlos III | Poveda E.,Hospital Carlos III | And 5 more authors.
AIDS | Year: 2010

All 178 HIV-infected individuals who had initiated tenofovir-emtricitabine- nevirapine (TDF/FTC/NVP) at our institution and were adherent to their medication were retrospectively examined. Only 22% were antiretroviral naive. After a median follow-up of 16 months, only five (2.8%) individuals (all with prior exposure to other antiretroviral regimens) experienced virological failure. In all instances, viral rebound occurred after 12 weeks of therapy. These results do not support an increased risk of early virological failure using TDF/FTC/NVP. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Hadas D.,Pharmacology Unit | Youngster I.,Pharmacology Unit | Cohen A.,Clalit Health Services | Leibovitch E.,Soroka Medical Center | And 4 more authors.
Clinical Pediatrics | Year: 2011

In many countries, ibuprofen is available only in oral formulations. The authors aimed to investigate parental satisfaction and possible adverse reactions among children receiving newly marketed ibuprofen suppositories, prior to their arrival at the pharmaceutical points of distribution. Children needing antipyretic medication were recruited from 11 pediatric wards and clinics in Israel. Each patient received ibuprofen suppositories (5-10 mg/kg/dose) after completing a data collection form. After 3 to 7 days of treatment, information regarding parent satisfaction, possible adverse reactions, and concomitant use of drugs was obtained. Overall, 490 children completed the study. Parents' satisfaction was high (4.5 ± 0.47 on a scale of 1-5), and 92.2% reported that they would use the medication in the future. Adverse reactions were reported in 8 patients (1.63%, 95% confidence interval = 1.77-3.25), the most common being diarrhea. Rectal administration of ibuprofen suppositories is well tolerated and overall satisfaction and the repeated expected use were high. © 2011 The Author(s). Source

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