Pharmacology Unit

Paris, France

Pharmacology Unit

Paris, France
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Zappella N.,Center Hospitalier Of Versailles Site Andre Mignot | Perier F.,Center Hospitalier Of Versailles Site Andre Mignot | Palette C.,Pharmacology Unit | Muret A.,Center Hospitalier Of Versailles Site Andre Mignot | And 5 more authors.
Medicine (United States) | Year: 2016

Background: Posterior reversible encephalopathy syndrome (PRES) has well-established links with several drugs. Whether a link also exists with serotonin-norepinephrine reuptake inhibitor such as duloxetine is unclear. Methods: We report on a patient who developed PRES with a coma and myoclonus related to hypertensive encephalopathy a few days after starting duloxetine treatment. Magnetic resonance imaging was performed and catecholamine metabolites assayed. Results: The patient achieved a full recovery after aggressive antihypertensive therapy and intravenous anticonvulsant therapy. Conclusions: The clinical history, blood and urinary catecholamine and serotonin levels, and response to treatment strongly suggest that PRES was induced by duloxetine. Duloxetine should be added to the list of causes of PRES. Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.

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.

Petrioli R.,University of Siena | Roviello G.,University of Siena | Fiaschi A.I.,Pharmacology Unit | Laera L.,University of Siena | And 3 more authors.
Anti-Cancer Drugs | Year: 2015

The primary objective of this study was to determine the activity and safety of 3-weekly oxaliplatin combined with gemcitabine and oral capecitabine in the first-line treatment of advanced biliary tract cancer. Treatment consisted of intravenous oxaliplatin 100 mg/m 2 every 3 weeks combined with intravenous gemcitabine 1000 mg/m 2 on days 1 and 8 and oral capecitabine 1500 mg/m 2 14 days on 21 in two divided doses. Treatment was administered until progressive disease, unacceptable toxicity, or patient refusal. Thirty-seven patients were enrolled: eight patients had Eastern Cooperative Oncology Group 2 performance status at presentation. The overall response rate was 35.1% [95% confidence interval (CI): 20.2-52.5%] and the disease control rate was 72.9%. The median progression-free survival was 9.4 months (95% CI: 4.1-12.2 months) and the median overall survival was 13.8 months (95% CI: 7.7-17.1 months). There were no grade 4 toxicities. Grade 3 neutropenia occurred in 13.5% of patients and grade 3 thrombocytopenia in 10.8%. The present study suggests that 3-weekly oxaliplatin combined with gemcitabine and oral capecitabine is an active and well-tolerated chemotherapy regimen in the first-line treatment of metastatic biliary tract cancer. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

M'Kada H.,Groupe Hospitalier Pitie Salpetriere GHPS | M'Kada H.,University Pierre and Marie Curie | Perazzo H.,University Pierre and Marie Curie | Munteanu M.,Biopredictive | And 24 more authors.
PLoS ONE | Year: 2012

Objective: Identification of drug-induced liver disease (DILI) is difficult, even among hospitalized patients. The aim of this pilot study was to assess the impact of a specific strategy for DILI screening. Design: We prospectively compared the number of acute DILI cases identified in one week of a proactive strategy based on centralized elevated ALT values to those identified with a standard of care strategy for 24-week period based on referral cases to the hepatology unit. In the centralized strategy, a designated study biochemist identified patients with ALT greater than 3 times the upper limit of normal values (ULN) and notified the designated hepatologists, who then went to the patients' wards, analyzed the charts, and if necessary, interviewed the identified patients. During these two periods, patients with possible DILI were included after signing an informed consent in an ongoing European diagnostic study (SAFE-T consortium). Results: During the 24-week period of the standard strategy, 12 (0.04%) patients out of a total of 28,145 were identified as having possible DILI, and 11 of these accepted to be included in the protocol. During the one-week proactive period, 7 patients out of a total of 1407 inpatients (0.498%) [odds ratio vs. standard = 12.1 (95% CI, 3.9-32.3); P<0.0001] were identified with possible DILI, and 5 were included in the protocol. Conclusion: A simple strategy based on the daily analysis of cases with ALT >3 ULN by designated biochemists and hepatologists identified 12 times more acute cases of drug-induced liver disease than the standard strategy. This pilot cohort is registered on the number AP-HP P110201/1/08-03-2011 and AFSSAPS B110346-70. © 2012 M'Kada et al.

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).

Barroso E.,Pharmacology Unit | Barroso E.,University of Barcelona | Barroso E.,Institute Salud Carlos III | Rodriguez-Calvo R.,Pharmacology Unit | And 17 more authors.
Endocrinology | Year: 2011

Metabolic syndrome-associated dyslipidemia is mainly initiated by hepatic overproduction of the plasma lipoproteins carrying triglycerides. Here we examined the effects of the peroxisome pro-liferator-activated receptors (PPAR)-β/δ activator GW501516 on high-fat diet (HFD)-induced hypertriglyceridemia and hepatic fatty acid oxidation. Exposure to the HFD caused hypertriglyceridemia that was accompanied by reduced hepatic mRNA levels of PPAR-γ coactivator 1 (PGC-1)-α and lipin 1, and these effects were prevented by GW501516 treatment. GW501516 treatment also increased nuclear lipin 1 protein levels, leading to amplification in the PGC-1α-PPARα signaling system, as demonstrated by the increase in PPARα levels and PPARα-DNA binding activity and the increased expression of PPARα-target genes involved in fatty acid oxidation. These effects of GW501516 were accompanied by an increase in plasma β-hydroxybutyrate levels, demonstrating enhanced hepatic fatty acid oxidation. Moreover, GW501516 increased the levels of the hepatic endogenous ligand for PPARα, 16:0/18:1-phosphatidilcholine and markedly enhanced the expression of the hepatic Vldl receptor. Interestingly, GW501516 prevented the reduction in AMP-acti-vated protein kinase (AMPK) phosphorylation and the increase in phosphorylated levels of ERK1/2 caused by HFD. In addition, our data indicate that the activation of AMPK after GW501516 treatment in mice fed HFD might be the result of an increase in the AMP to ATP ratio in hepatocytes. These findings indicate that the hypotriglyceridemic effect of GW501516 in HFD-fed mice is accompanied by an increase in phospho-AMPK levels and the amplification of the PGC-1α-lipin 1-PPARα pathway. Copyright© 2011 by The Endocrine Society.

Gaedigk A.,The Childrens Mercy Hospital and Clinics | Jaime L.K.M.,Pharmacology Unit | Bertino Jr. J.S.,Bertino Consulting | Berard A.,University of Montréal | 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.

Ansah C.,Kwame Nkrumah University Of Science And Technology | Adinortey M.B.,University Of Cape Coast | Asiedu-Larbi J.,Pharmacology Unit | Aboagye B.,University Of Cape Coast | And 2 more authors.
Asian Pacific Journal of Tropical Biomedicine | Year: 2016

Objective To assess the toxic potential of Dissotis rotundifolia (D. rotundifolia) whole plant extract in Spraque–Dawley rats within a 2-week period of administration. Methods Methanolic extract of D. rotundifolia was administered orally once daily at dose levels of 0, 100, 300 and 1 000 mg/kg body weight for 14 days. Toxicity was assessed using mortality, clinical signs, body and organ weights, hematological indices, serum chemistry parameters and histopathological analyses. Results There were no treatment-related mortalities or differences in clinical signs, hematology and serum biochemistry. This was confirmed by micrographs obtained from histopathological analysis. Conclusions The results obtained from the sub-acute toxicological assessment of D. rotundifolia extract suggest that the extract is non-toxic at doses up to 1 000 mg/kg/day administered for a period of 14 days. © 2016 Hainan Medical University

Yefet E.,Emek Medical Center | Salim R.,Labor and Delivery Unit | Chazan B.,Technion - Israel Institute of Technology | Chazan B.,Infectious Disease Unit | And 5 more authors.
Obstetrical and Gynecological Survey | Year: 2014

Quinolones and fluoroquinolones are highly efficient antibiotics. However, concerns regarding possible harmful effects have limited their use during pregnancy. Nevertheless, accumulating clinical data suggest that they may be safe during pregnancy. This review aimed to explore the mechanisms of action of the quinolones and fluoroquinolones, which set the stage for concerns regarding possible teratogenic and mutagenic effects; to clarify the clinical dilemmas that brought forth the necessity in reevaluating the use of those medications during pregnancy; and to review the accumulated data regarding their safety during pregnancy in animal models and humans. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to assess the mechanisms of action that had led to concerns regarding the use of fluoroquinolones during pregnancy, appraise the basic knowledge gained from animal studies about the effects of fluoroquinolones during pregnancy, and analyze the human data on the actual effect of variable fluoroquinolones in pregnancy. Copyright © 2014 Lippincott Williams & Wilkins.

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.

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