Determination of drug interactions occurring with the metabolic pathways of irinotecan, Drug Metab. Dispos

, and involves cytochrome P450 (3A4 isoform); the second one leads to SN-38 glucuronide (SN-38G) and involves UDP-glucuronosyltransferase (UGT). Using human hepatic microsomes, we studied the interactions of 15 drugs of common use in colorectal cancer patients on these metabolic pathways. Only nifedipine had a significant effect on SN-38 formation, decreasing carboxylesterase activity by 50% at 100 M and 35% at 10 M. Three drugs had a significant effect on SN-38G formation: clonazepam increased UGT activity by 50% at 100 M and 30% at 10 M, and nifedipine and vinorelbine inhibited the activity by 65 and 55% at 100 M, respectively, with no effect at 10 M. Five drugs exerted a significant inhibition on SN-38 formation at 100 M: clonazepam (70%), methylprednisolone (50%), nifedipine (80%), omeprazole (85%), and vinorelbine (100%). Only omeprazole and vinorelbine still exerted a significant inhibition at 10 M (30 and 90%, respectively), whereas only vinorelbine had a significant effect at 2 and 0.5 M (70 and 40%, respectively). In conclusion, potential clinical interactions with the metabolism of irinotecan are likely to be important for vinorelbine, which strongly inhibits irinotecan catabolism by CYP3A4 at clinically relevant concentrations, but not for the other drugs, which exert an effect at concentrations not achievable in patients. Irinotecan [CPT-11 1 ; 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecine] is a water-soluble derivative of camptothecine The availability of SN-38 to its targets is, therefore, determined by a variety of enzyme activities, both for its formation and its detoxification. Since these enzymes are subjected to a wide individual variability, due to both genetic and environmental factors, there should be a similar variability in SN-38 availability, which could explain in turn at least part of the variability in response to irinotecan (about 20% responders in untreated as well as in 5-fluorouracilpretreated patients as stated by Materials and Methods Chemicals and Reagents. Pure irinotecan, SN-38, and NPC were supplied by Aventis (Vitry-sur-Seine, France). 20(S)-Camptothecine was obtained from Sigma-Aldrich Chimie (Saint-Quentin-Fallavier, France). The drugs used for interaction studies were obtained from various sources: carbamazepine, clonazepam, dexamethasone, ftorafur, methylprednisolone, nifedipine, omeprazole, phenobarbital, phenytoine, ranitidine, valproic acid, and warfarin were obtained as pure chemicals from Sigma-Aldrich Chimie, as was bilirubin; capecitabine, gemcitabine, and vinorelbine were obtained as clinical formula

Near infrared spectroscopy would be assessed for lower extremity peripheral artery disease diagnosis in patients with normal ankle-brachial index at rest

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Discordant knowledge about atherosclerosis disease among French general practitioners and residents

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Atherosclerosis knowledge - diagnosis and management in primary care

International audienceBackground - Atherosclerosis is the leading cause of death worldwide. Ischaemic stroke, coronary heart disease (CHD), and peripheral artery disease (PAD) are different forms of atherosclerotic disease. Knowledge among general practitioners (GPs) about the three main locations of atherosclerosis has never been conjointly explored in a single study. The aim of this survey was to compare GP awareness on the subject of these three different clinical presentations. Materials and methods - Between February 2017 and May 2017, a self-administered survey was emailed to 18,500 French GPs. The questionnaire comprised three clinical cases involving cases of transient ischaemic attack (TIA), stable angina (SA), and intermittent claudication (IC). Each case was explored with seven similar questions. The primary endpoint was the number of physicians who correctly answered five questions for each clinical case. Results - The survey was completed by 1,724 GPs. TIA knowledge (48.2 %) was significantly higher than the SA knowledge (3.0 %) and IC knowledge (0.4 %). We also found a significant difference between SA knowledge and IC knowledge. The percentages of GPs who correctly diagnosed TIA, SA or IC were 96.7, 89.7, and 96.5 %, respectively (p < 0.0001). Poor knowledge ratings for all three locations were observed for inadequate prescription of supplementary investigations and treatments. Conclusions - Our study demonstrates that GPs' knowledge about atherosclerosis disease varies significantly depending on disease location. GPs diagnose correctly but need to be backed up for their management of patients with atherosclerosis

KDM5A and KDM5B histone-demethylases contribute to HU-induced replication stress response and tolerance

International audienceABSTRACT KDM5A and KDM5B histone-demethylases are overexpressed in many cancers and have been involved in drug tolerance. Here, we describe that KDM5A, together with KDM5B, contribute to replication stress (RS) response and tolerance. First, they positively regulate RRM2, the regulatory subunit of ribonucleotide reductase. Second, they are required for optimal levels of activated Chk1, a major player of the intra-S phase checkpoint that protects cells from RS. We also found that KDM5A is enriched at ongoing replication forks and associates with both PCNA and Chk1. Because RRM2 is a major determinant of replication stress tolerance, we developed cells resistant to HU, and show that KDM5A/B proteins are required for both RRM2 overexpression and tolerance to HU. Altogether, our results indicate that KDM5A/B are major players of RS management. They also show that drugs targeting the enzymatic activity of KDM5 proteins may not affect all cancer-related consequences of KDM5A/B overexpression

Impact of an educational intervention on ankle-brachial index performance among medical students and fidelity assessment at month-6

International audienceBackground - The resting ankle-brachial index (ABI) is a clinical test to diagnose peripheral artery disease. The Wyatt's score has been proposed to assess the students' performance on ABI measurement on a healthy volunteer (HV). No study has shown that this score is sensitive to different teaching methods. In this randomized controlled trial, we wanted to determine whether didactic learning alone or didactic learning combined with experiential learning improves proficiency in the ABI procedure assessed by the Wyatt's score. Methods - Medical students (n = 30) received a didactic learning, including (1) a presentation of the ABI guidelines and (2) a video demonstration. Each student was then randomized into 2 groups ("the no experiential learning group" and "the experiential learning group"). An initial evaluation was performed after the didactic learning and then the final evaluation at the end of the intervention. A student was considered to be proficient when he performed a correct ABI procedure on an HV. The correct procedure corresponds to the following: (1) correctly answered Wyatt's score and (2) a difference in the ABI measurement between a professor in vascular medicine and a student was ≤0.15. Results - No student was proficient at the initial evaluation. At the final evaluation, there was a significant difference between the number of proficient students for the Wyatt's score depending on their learning group [didactic alone (1/10) or didactic + experiential training (15/20)] and also for the ABI procedure [didactic alone (0/10) or didactic + experiential training (16/20)]. At 6 months, among the 12 students who passed the final evaluation, 4 students passed both the Wyatt's score and the ABI measurement. Conclusions - Our study demonstrates that the Wyatt's score was sensitive to an educational intervention and no improvement was found in the case of "no experiential learning." The Wyatt's score could be used to evaluate the student on ABI measurement after an educational intervention. Trial registration - A randomized controlled trial was conducted in the Vascular Medicine Department of Rennes University Hospital (France). This was approved by the ethics review board of our institution (no. 16.150)

How to become proficient in performance of the resting ankle-brachial index Results of the first randomized controlled trial

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Cancer Therapy Improvement with Mesoporous Silica Nanoparticles Combining Targeting, Drug Delivery and PDT

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Medical students' proficiency in performance of the resting ankle-brachial index is not sustained at 6 months

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