Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes.

AIMS/HYPOTHESIS Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP. METHODS 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA. RESULTS In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (β = -0.26, p = 0.045) after integrating effects of height (β = -0.38, p = 0.01), insulin treatment (β = 0.42, p = 0.002), retinopathy treated by laser (β = 0.26, p = 0.02), and total cholesterol levels (β = 0.3, p = 0.03) by multivariable analysis. CONCLUSIONS The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy

Contribution des metabolites genetiquement formes et des enantiomeres a l'action des medicaments antiarythmiques chez l'homme: application au procainamide, a l'encaienide, a la propafenone et D-sotalol

SIGLEINIST T 76863 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Indispensable but deceptive evidence-based medicine

International audienc

Les phases précoces du développement clinique d'un médicament

International audienceThe first administrations of a molecule to humans, so-called phase I studies of drug development, follow experimental animal studies which allow to have a first assessment of the pharmacological effects and toxicity of the molecule under development. Typically, these studies are performed in "healthy" subjects or in relapsing patients with cancer. Participants' safety is a priority. Trained professionals administer single doses, followed by repeated doses, in authorized medical centres. They allow to study the pharmacokinetic and pharmacodynamic profile of tested molecules in humans and to explore some sources of variability of these parameters. These studies are highly regulated and their methodology is fairly standardized

Modifications de la biodisponibilité d'un médicament administré par voie orale (étude de l'interaction entre le jus de pamplemousse et l'halofantrine)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

QT long acquis peri-opératoire

Les anomalies du rythme cardiaque sont fréquentes au cours de la période péri-opératoire. Cependant, un type particulier d arythmie, la Torsade de Pointes, reste semble-t-il exceptionnel. L évolution de la durée de la repolarisation ventriculaire, marqueur du risque de développer ce type d arythmie, était peu étudié en péri-opératoire. Le but de ce travail était de préciser le rôle de différents facteurs, en particulier médicamenteux, dans la survenue d arythmies péri-opératoires en étudiant leurs effets sur l allongement de l intervalle QT. Nous avons observé une prévalence très élevée d intervalle QT allongé en périopératoire. Ces anomalies électriques étaient transitoires et dépendantes en partie de facteurs liés à l anesthésie. Dans ce contexte, l oxytocine mais surtout les médicaments anti-émétiques (dropéridol, ondansétron) ont des effets importants sur la durée de la repolarisation ventriculaire. Ceci n a été retrouvé dans un modèle expérimental que pour les anti-émétiques. Nous proposons également dans ce travail deux méthodes permettant d identifier les patients présentant en post-opératoire un QT allongé. La reconnaissance de ces anomalies électriques avant l administration de médicaments allongeant l intervalle QT, par exemple les antiémétiques, pourrait permettre de mieux identifier les patients à risque de développer un trouble du rythme cardiaque en péri-opératoire. Même si à ce stade il est difficile d en préciser les conséquences, il semble bien exister un QT long acquis péri-opératoire .PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

The BIAL/Biotrial case of death of a human volunteer in the first-in-human study of BIA 10-2474: Are we missing the fundamentals?

International audienceThe presentation and discussion of the BIAL/Biotrial case below is based on publicly available information [1], [2] and [3]. On Sunday 10 January 2016 in the afternoon, Mr. X., a 49-year-old healthy subject participating to a first-in-human (FIH) study of the nonselective fatty-acid amide hydrolase (FAAH) inhibitor BIA 10-2474 experienced blurred vision and headache. He was one of the six volunteers receiving BIA 10-2474 in the 5th cohort of the multiple ascending dose part of the protocol and had received in the morning the 5th of 10 doses of 50 mg once a day planned for this part of the study. Forty eight subjects had previously been exposed to single doses of BIA 10-2474 ranging from 0.25 to 100 mg, another 12 had received a single 40 mg dose in a food-interaction part of the study and 24 had received the drug at doses of 2.5, 5, 10 and 20 mg daily for 10 days during earlier stages of the multiple ascending dose part of the study. A few adverse events had occurred in these 84 subjects, as is almost always the case in FIH studies, but not worrisome as to stop the study. The study was conducted at Biotrial, a well-established private phase I clinical research unit located 1.5 miles from the University Hospital of Rennes in Brittany, France. BIA 10-2474 was being developed by BIAL, a Portugal-based international pharmaceutical company

Evaluation de l'effet des médicaments sur l'intervalle QT, au cours des études de phase I

PARIS-BIUP (751062107) / SudocPARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Chloroquine or hydroxychloroquine for COVID-19: why might they be hazardous?

International audienc

Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients

International audienceBackground: Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. Methods: We analysed PCD/T in patients treated with D + T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. Results: We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0 ng/mL; interquartile range (IQR) [4–945]) and of PCT (median: 8.6 ng/mL; IQR [5–39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P = 0.06). However, no difference was observed between mean PCD/T of progressing patients (n = 21; 125 ± 183 ng/mL and 9.3 ± 3.6 ng/mL, respectively) and responders (complete, partial or stable response) (n = 13; 159 ± 225 ng/mL, P = 0.58 and 10.6 ± 24.4 ng/mL, P = 0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n = 16) was significantly higher for female subjects (n = 18; 11.5 ± 4.8 ng/mL) than for male subjects (8.8 ng/mL ± 2.9, P = 0.01), but no difference was observed between sex and CPD (P = 0.32). Conclusion: Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment