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A medicinal chemistry approach combining in silico and in vitro methodologies was performed aiming at identifying and characterizing putative allosteric drug-binding sites (aDBSs) at the interface of the transmembrane- and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified, one in TMD1/NBD1 and another one in TMD2/NBD2, by means of in silico fragment-based molecular dynamics and characterized in terms of size, polarity, and lining residues. From a small library of thioxanthone and flavanone derivatives, experimentally described to bind at the TMD-NBD interfaces, several compounds were identified to be able to decrease the verapamil-stimulated ATPase activity. An IC50 of 81 ± 6.6 μM is reported for a flavanone derivative in the ATPase assays, providing evidence for an allosteric efflux modulation in P-glycoprotein. Molecular docking and molecular dynamics gave additional insights on the binding mode on how flavanone derivatives may act as allosteric inhibitors.

The modulation of drug efflux by P-glycoprotein (P-gp, ABCB1) represents one of the most promising approaches to overcome multidrug resistance (MDR) in cancer cells, however the mechanisms of drug specificity and signal-transmission are still poorly understood, hampering the development of more selective and efficient P-gp modulators. In this study, the impact of four P-gp mutations (G185V, G830V, F978A and ΔF335) on drug-binding and efflux-related signal-transmission mechanism was comprehensively evaluated in the presence of ligands within the drug-binding pocket (DBP), which are experimentally related with changes in their drug efflux profiles. The severe repacking of the transmembrane helices (TMH), induced by mutations and exacerbated by the presence of ligands, indicates that P-gp is sensitive to perturbations in the transmembrane region. Alterations on drug-binding were also observed as a consequence of the TMH repacking, but were not always correlated with alterations on ligands binding mode and/or binding affinity. Finally, and although all P-gp variants holo systems showed considerable changes in the intracellular coupling helices/nucleotide-binding domain (ICH-NBD) interactions, they seem to be primarily induced by the mutation itself rather than by the presence of ligands within the DBP. The data further suggest that the changes in drug efflux experimentally reported are mostly related with changes on drug specificity rather than effects on signal-transmission mechanism. We also hypothesize that an increase in the drug-binding affinity may also be related with the decreased drug efflux, while minor changes in binding affinities are possibly related with the increased drug efflux observed in transfected cells.

Radiation recall reactions are inflammatory reactions confined to previously irradiated tissues, often of drug-induced etiology, particularly with anticancer therapies. Other drugs, in particular COVID-19 vaccines, may also be involved.To describe radiation recall reactions under non-anticancer drugs more precisely. Material and method We extracted the cases of radiation recall reactions associated with non-anticancer drugs from WHO pharmacovigilance database VigiBase®. We performed two analyses from this extraction: a global analysis and an analysis focusing on vaccination-related issues.We extracted 120 cases corresponding to 269 drugs, of which 130 were non-anticancer (22 vaccines). Among the non-anticancer drugs, tozinameran was the most reported treatment (4.46% of cases), followed by levofloxacin (2.97%) and folinic acid (2.60%), dexamethasone (2.23), ChAdOx1 nCoV-19 vaccine and prednisone (1.86% each). Among vaccines, tozinameran (54.55% of cases) was the most reported, followed by ChAdOx1 nCoV-19 (22.73%), HPVinactivated influenza vaccine (9.09% each), and elasomeran (4.55%).Our study first describes the occurrence of radiation recall reactions during non-anticancer treatment. It also highlights a potential safety signal with COVID-19 vaccines.

ABCB5 encodes a full transporter (ABCB5FL) and a half transporter (ABCB5β), which is unique in the ATP binding cassette (ABC) transporter superfamily. We discuss the roles of both isoforms in undifferentiated slow-cycling cells, multidrug resistance, and tumorigenesis, and their regulation pathways.

Objective: Limited data are available on adverse drug reactions (ADRs) of gender-affirming hormone therapy (HT), mainly due to the lack of population-based studies with adequate controls, thus making spontaneous reporting systems a valuable tool to detect potential side reactions. In this nationwide retrospective study, we aimed to analyze ADRs related to gender-affirming HT reported in the French pharmacovigilance database (FPVD). Design: We requested all the individual case safety reports related to gender-affirming HT recorded in the FPVD before the 27th of May 2020. We excluded previously published cases and those for which gender-affirming hormone therapy was not the suspected drug. Results: A total of 28 reports of ADRs were identified. Six concerned transgender men (age range 21-40 years) and 22 transgender women (age range 22-68 years). In transgender men taking testosterone enanthate, all reported adverse effects were cardiovascular events with pulmonary embolism in 50% of cases. In transgender women, antiandrogens, mainly cyproterone acetate, were involved in 68% of cases. Estrogens were involved in 77% of cases, mostly in association with progestin or cyproterone acetate. Meningioma was the principal ADR, followed by cardiovascular events. Conclusions: Our data show a previously unreported and non-negligible proportion of cases indicating cardiovascular ADRs in transgender men younger than 40 years, taking testosterone enanthate. In transgender women, cardiovascular events were the second most frequently reported ADR. Further research is necessary to identify risk factors that might help to the individualization of treatment strategies. There is a necessity to increase awareness and implement preventive and education measures.

Supplementary Materials from Evaluation of current methods used to analyze the expression profiles of ATP-binding cassette transporters yields an improved drug-discovery database

Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters that function as drug efflux pumps. The majority of these proteins have not yet been examined in malignant diseases.Experimental Design: A newly developed microarray for the simultaneous quantification of 38 ABC transporter genes and Taqman real-time PCR was used to analyze the expression of ABC transporters in pediatric AML and healthy bone marrow. Small interfering RNA was used to verify the role of ABCA3 in drug resistance.Results: Using the microarray, we identified four new ABC transporters, which were overexpressed in many AML samples compared with healthy bone marrow: ABCA2, ABCA3, ABCB2, and ABCC10. The overexpression of these four genes was verified by real-time PCR in 42 samples from children with AML and 18 samples of healthy bone marrow. The median expression of ABCA3 was three times higher in 21 patients who had failed to achieve remission after the first course of chemotherapy than in a well-matched group of 21 patients who had achieved remission at this stage (P = 0.023). Incubation of cell lines with a number of different cytostatic drugs induced an up-regulation of ABCA3. Down-regulation of ABCA3 by small interfering RNA sensitized cells to doxorubicin.Conclusion: Our results show that ABCA2, ABCA3, ABCB2, and ABCC10 are overexpressed in childhood AML compared with healthy bone marrow. ABCA3 is the most likely transporter to cause drug resistance.

PDF file, 1202KB, Supplementary Figure 1. Kaplan-Meier Survival Curves. Supplementary Figure 2. Kaplan-Meier Survival Curves. Supplementary Table 1. Univariate analysis of clinical covariates.

Purpose: This study assesses the ability of multidrug resistance (MDR)–associated gene expression patterns to predict survival in patients with newly diagnosed carcinoma of the ovary. The scope of this research differs substantially from that of previous reports, as a very large set of genes was evaluated whose expression has been shown to affect response to chemotherapy.Experimental Design: We applied a customized TaqMan low density array, a highly sensitive and specific assay, to study the expression profiles of 380 MDR-linked genes in 80 tumor specimens collected at initial surgery to debulk primary serous carcinoma. The RNA expression profiles of these drug resistance genes were correlated with clinical outcomes.Results: Leave-one-out cross-validation was used to estimate the ability of MDR gene expression to predict survival. Although gene expression alone does not predict overall survival (OS; P = 0.06), four covariates (age, stage, CA125 level, and surgical debulking) do (P = 0.03). When gene expression was added to the covariates, we found an 11-gene signature that provides a major improvement in OS prediction (log-rank statistic P < 0.003). The predictive power of this 11-gene signature was confirmed by dividing high- and low-risk patient groups, as defined by their clinical covariates, into four specific risk groups on the basis of expression levels.Conclusion: This study reveals an 11-gene signature that allows a more precise prognosis for patients with serous cancer of the ovary treated with carboplatin- and paclitaxel-based therapy. These 11 new targets offer opportunities for new therapies to improve clinical outcome in ovarian cancer. Clin Cancer Res; 18(11); 3197–206. ©2012 AACR.

The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by multiple mechanisms. These mechanisms can act individually or synergistically, leading to MDR, in which the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been successful. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing highly homologous genes from small amounts of tissue is fundamental to achieving any significant enhancement in our understanding of MDR mechanisms and could lead to treatments designed to circumvent it. In this study, we use a previously established database that allows the identification of lead compounds in the early stages of drug discovery that are not ATP-binding cassette (ABC) transporter substrates. We believe this can serve as a model for appraising the accuracy and sensitivity of current methods used to analyze the expression profiles of ABC transporters. We found two platforms to be superior methods for the analysis of expression profiles of highly homologous gene superfamilies. This study also led to an improved database by revealing previously unidentified substrates for ABCB1, ABCC1, and ABCG2, transporters that contribute to MDR. [Mol Cancer Ther 2009;8(7):2057–66]

Supplementary Figures 1-2 from ABCA3 as a Possible Cause of Drug Resistance in Childhood Acute Myeloid Leukemia

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The lack of markers to predict chemotherapy responses in patients poses a major handicap in cancer treatment. We searched for gene expression patterns that correlate with docetaxel or cisplatin response in a mouse model for breast cancer associated with BRCA1 deficiency. Array-based expression profiling did not identify a single marker gene predicting docetaxel response, despite an increase in Abcb1 (P-glycoprotein) expression that was sufficient to explain resistance in several poor responders. Intertumoral heterogeneity explained the inability to identify a predictive gene expression signature for docetaxel. To address this problem, we used a novel algorithm designed to detect differential gene expression in a subgroup of the poor responders that could identify tumors with increased Abcb1 transcript levels. In contrast, standard analytical tools, such as significance analysis of microarrays, detected a marker only if it correlated with response in a substantial fraction of tumors. For example, low expression of the Xist gene correlated with cisplatin hypersensitivity in most tumors, and it also predicted long recurrence-free survival of HER2-negative, stage III breast cancer patients treated with intensive platinum-based chemotherapy. Our findings may prove useful for selecting patients with high-risk breast cancer who could benefit from platinum-based therapy. Cancer Res; 72(9); 2350–61. ©2012 AACR.

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BackgroundNeuromuscular blocking agents (NMBAs) are the leading cause of perioperative anaphylaxis (POA), most reactions being IgE mediated. Allergic sensitization induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related POA.MethodsALPHO is a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related POA (cases) and control patients with uneventful anaesthesia. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated.ResultsOverall, 167 cases were matched with 334 controls. NMBA-related POA was significantly associated with pholcodine consumption (OR =4.2; CI95% 2.3-7.0) and occupational exposure to quaternary ammoniums (OR = 6.1; CI95% 2.7-13.6). Anti-pholcodine and anti-quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (< 3%) for identifying NMBA-related POA.ConclusionPatients exposed to pholcodine 12 months prior to NMBA exposure have a significantly higher risk of a NMBA-related POA. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related POA. The strong association of NMBA-related POA with occupational exposure suggests that other environmental factors may also lead to sensitization to NMBAs.

Introduction Interleukin 17 is a proinflammatory cytokine considered to play a significant role in the immunopathogenesis of many chronic immune-mediated disorders. Interleukin 17 inhibitors provide an excellent treatment option for patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. However, Interleukin 17 inhibitors have been suspected of worsening or triggering new-onset inflammatory bowel disease. Areas covered A literature search was conducted until March 2021 to investigate reporting prevalence, and characteristics of all gastroenterological adverse events in patients treated with Interleukin 17 inhibitors. One hundred and six clinical randomized trials were included, involving 40,053 patients. Inflammatory bowel disease cases were reported in 0.4% of patients exposed to Interleukin 17 inhibitors. The most frequent other gastrointestinal adverse events were diarrhea (2.5%), nausea or vomiting (0.7%), and gastroenteritis (0.2%). Sixty-one uncontrolled or retrospective studies were included, involving 16,791 patients. Sixty (0.36%) inflammatory bowel disease cases were reported, 0.6% of patients reported other gastrointestinal adverse events. Expert opinion Interleukin 17 inhibitors are safe and effective in the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Low incidence rate of developing new-onset inflammatory bowel disease or exacerbating preexisting inflammatory bowel disease with anti-IL-17 agents has been reported. Clinicians should be aware of the possibility of these concerns when considering this therapy.

ABCB5 is a member of the ABC transporter superfamily composed of 48 transporters, which have been extensively studied for their role in cancer multidrug resistance and, more recently, in tumorigenesis. ABCB5 has been identified as a marker of skin progenitor cells, melanoma, and limbal stem cells. It has also been associated with multidrug resistance in several cancers. The unique feature of ABCB5 is that it exists as both a full transporter (ABCB5FL) and a half transporter (ABCB5β). Several studies have shown that the ABCB5β homodimer does not confer multidrug resistance, in contrast to ABCB5FL. In this study, using three complementary techniques; (1) nanoluciferase-based bioluminescence resonance energy transfer, (2) co-immunoprecipitation, and (3) proximity ligation assay, we identified two novel heterodimers in melanoma: ABCB5β/B6 and ABCB5β/B9. Both heterodimers could be expressed in high-five insect cells and ATPase assays revealed that they have a basal ATPase activity. These results are an important step toward untangling the functional role of ABCB5β in melanocytes and melanoma.

A medicinal chemistry approach combining in silico and in vitro methodologies was performed aiming at identifying and characterizing putative allosteric drug-binding sites (aDBS) at the interface of the transmembrane- and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified, one in each NBD, by means of in silico fragment-based molecular dynamics, and characterized in terms of size, polarity, and lining residues. From a small library of thioxanthone and flavanone derivatives, experimentally described to bind at the TMD-NBD interfaces, several compounds were identified to be able to decrease the verapamil-stimulated ATPase activity. An IC50 of 81 ± 6.6 μM is reported for a flavanone derivative in the ATPase assays, providing evidence for an allosteric efflux modulation in P-glycoprotein. Molecular docking and Molecular Dynamics gave additional insights on the binding mode on how flavanone derivatives may act as allosteric inhibitors.

For many drugs, the liver is the major site of metabolism. Uptake transporters from the solute carrier superfamily, cytochrome P450 enzymes, and efflux transporters from the adenosine triphosphate (ATP) binding cassette (ABC) transporters play major roles in systemic pharmacokinetics and drug-drug interactions. Solute carriers may facilitate drug passage from blood to the liver for further processing by metabolizing enzymes and efflux transporters. This chapter reviews the dual role of ABC transporters in drug metabolism and cancer multidrug resistance. It highlights the critical role of polymorphisms in treatment success. ABC transporter encoding genes are widely dispersed in the genome and show a high degree of sequence identity among eukaryotes. They translocate a wide range of substrates across cell or organelle membranes using the energy from ATP hydrolysis. The survival benefit of systemic chemotherapy in the treatment of liver cancer is only marginal at best.

Intra-articular (IA) injection of a chondroprotective candidate may delay the osteoarthritis (OA) course, but its rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics (PK) of IA rapamycin injected as sustained release in nanoparticles (NPs) versus a free rapamycin suspension in the rat knee compared to an intravenous (IV) free rapamycin shot taken as a reference. Rats received either a single IV injection of free rapamycin (10 µM) or an IA of free or NPs-loaded rapamycin. After sequential exsanguination (15, 30, 60, 180, 360 min, D1, and D7), knee synovial tissue (ST) and cartilage histology were performed. Blood and ST concentrations (LC-MS/MS), PK parameters (area under the curve: AUC; mean residence time: MRT; elimination half-life: T

Aims: Baclofen is widely used for spastic disorders, and most recently for addictive disorders. The first signals of baclofen abuse occurred in the last decade. This study aims to assess the motives, diversion sources and routes of administration associated with the non-medical use of baclofen and examine health problems related to the non-medical use of baclofen. Methods: Spontaneous reports of baclofen abuse reported to the addictovigilance center of East France were analyzed. A literature search was simultaneously conducted using PubMed®, Web of Sciences®, and Google Scholar® databases. Both searches were performed in February 2021 without a time limit. Results: Forty-six cases were analysed (33-from the literature review and 13-from addictovigilance base). Baclofen’s non-medical use mainly affected male subjects with addictive history, but cases of primary abuse in subjects without any substance abuse history were also observed. Euphoria search was the most common reason for misuse. Route of administration included oral, snorting and sublingual use. Physicians were a common source for misused baclofen, but cases involving illegal sources were also observed. Most of the patients misusing baclofen presented serious complications, mainly represented by neurological and respiratory disturbances. Physical and psychological dependence to baclofen was observed in three persons. Conclusion: Although baclofen abuse remains relatively infrequent or (most likely) underestimated, this study helped to confirm the intrinsic abuse potential of baclofen and make visible the baclofen-abuse-related health harms. Careful consideration and benefit-risk analysis should be employed when prescribing baclofen, and emergency departments should be aware of baclofen dangers in abuse situations.

International audience; Background: 3D printing has become a promising tool for cartilage engineering, combining 3D deposition of cells seeded in supporting biomaterials. Objective: Our goal was to evaluate the chondrogenic properties of three different bioinks, seeded with human bone marrow mesenchymal stem cells (bMSCs). Methods: The three different tested bioinks are seeded with 2 × 106 cells/mL bMSCs. The bioink#1 is composed of gelatin, fibrinogen, and very low viscosity alginate. The bioink#2 has the same composition, excepted for the alginate that is a low viscosity one. The bioink#3 is manufactured by CELLINK®. The cartilaginous substitutes were cultivated for 28 days in the presence of ITS vs TGF-ß1. The extracellular matrix synthesis is evaluated at D28 by histology (Hematoxylin-Eosin-Saffron & Alcian Blue) and immunostaining (type II collagen). Results: The bioink#1 better promoted type II collagen synthesis, although the three bioink were equipotent in terms of proteoglycan content. Despite its universal characteristics, the bioink#3 failed to encourage the hyaline-like matrix synthesis. Conclusion: The bioink#1 containing gelatin, fibrinogen, and very low viscosity seems to be the fittest of the three bio-inks to obtain a cartilaginous substitute presenting a remarkable matrix synthesis. This study confirms the importance of the choice of bioink for cartilage engineering.

Hip arthroplasty (HA) is a frequently used procedure with high success rates, but 7% to 27% of the patients complain of persistent postsurgical pain 1 to 4 years post-operation. HA complications depend on the post-operative delay, the type of material used, the patient’s characteristics, and the surgical approach. Radiographs are still the first imaging modality used for routine follow-up, in asymptomatic and painful cases. CT and MRI used to suffer from metallic artifacts but are nowadays central in HA complications diagnosis, both having their advantages and drawbacks. Additionally, there is no consensus on the optimal imaging workup for HA complication diagnosis, which may have an impact on patient management. After a brief reminder about the different types of prostheses, this article reviews their normal and pathologic appearance, according to each imaging modality, keeping in mind that few abnormalities might be present, not anyone requiring treatment, depending on the clinical scenario. A diagnostic imaging workup is also discussed, to aid the therapist in his imaging studies prescription and the radiologist in their practical aspects.

Introduction Teledermoscopy using smartphone-based applications is becoming more and more important in a setting of increasing frequency of skin cancer and difficult access to specialized care. The TELESPOT project aimed to provide rapid diagnosis and speed up patient flow between primary healthcare centers and a tertiary care center in Belgium. The aim of the present study is to describe the development of an in-house smartphone-based dermoscopy application, evaluate its real-life value in a series of primary healthcare centers, and present preliminary diagnostic data. Methods Modified Likert scales were used to assess patient and general practitioner (GP) satisfaction rates for the system. Furthermore, a total of 105 photographic and dermoscopic images were acquired in a series of 80 patients at participating centers. Results Overall, patient and GP satisfaction levels were 89% and 94%, respectively. High-priority management was recommended in 7.6% of cases (8/105: 3 basal cell carcinoma, 1 primary cutaneous B-cell lymphoma, 1 Spitz melanocytic nevus, 1 congenital nevus, 1 in situ melanoma, and 1 invasive melanoma, proven by histology). Conclusions The primary healthcare centers were highly satisfied with the TELESPOT project in terms of user-friendliness, efficacy, and reliability as well as in providing a reinforced image of first-line medicine efforts in combating skin cancer.

Several gastrointestinal symptoms and chronic inflammatory bowel diseases (IBDs) have been reported after therapy with IL-17 inhibitors. To date, however, no study has shown a clear association between these drugs and IBD onset. We searched on Vigibase, the worldwide pharmacovigilance database, to investigate reporting prevalence, characteristics, and prognosis of all gastroenterological adverse events in patients treated with IL-17 inhibitors. In total, 1,129 gastrointestinal Individual Case Safety Reports (ICSRs) were identified, including 850 IBD (42.5% Crohn's disease, 31.9% ulcerative colitis, and 25.6% undifferentiated IBD) and 279 colitis (mainly undifferentiated colitis (79.2%), and microscopic colitis (10.4%)). ICSRs were associated with secukinumab (SEC, 83.6%) or ixekizumab (IXE, 16.3%), whereas only one colitis occurred with brodalumab (0.1%). Most IBD and colitis cases were detected within 6 months from therapy start in both the SEC (68.8% and 73.5%) and IXE groups (100% and 66.7%). Patients' outcomes were reported in 428 ICSRs (37.9%). Complete or ongoing recovery from symptoms was detected in about two-thirds of patients experiencing IBD (59.5%) or colitis (64.2%), whereas in the other cases, there was no recovery (33.9% and 29.5%) or there were sequelae (5.4% and 4.2%). Fatal events occurred in four patients (1.2%) in the IBD group (3 after SEC and on1e with IXE) and two SEC-treated subjects in the colitis group (2.1%). Treatment with IL-17 inhibitors is associated with a relevant number of exacerbations and new onset of IBD and colitis. Careful evaluation of gastrointestinal symptoms and the monitoring of intestinal inflammatory biomarkers should be recommended before prescribing these drugs.

Immunotherapy with immune checkpoint inhibitors (ICIs) for cancer has become increasingly prescribed in recent years. Indeed, it is used to treat both solid and hematological malignancies due to their considerable potential in treating melanoma, non-small cell lung and other cancers. Immune-mediated related adverse endocrine toxicity, and especially thyroiditis, is seen as a growing problem needing specific screening and management. This study aims at describing thyroid dysfunctions induced by the ICIs marketed in France, which are registered in the French Pharmacovigilance database. This database was queried for nivolumab, pembrolizumab, and ipilimumab-induced adverse drug reactions reported before April 30, 2017. Both a pharmacologist and an endocrinologist have reviewed each case to select only those of peripheral thyroiditis (thyrotoxicosis and hypothyroidism). During this period, 110 thyroiditis following ICI therapy were reported. Sex/ratio was around one. Most of the cases (47.2%) were asymptomatic. Although some thyrotoxicosis cases were severe, no orbitopathy was reported. Hypothyroidism and thyrotoxicosis were equally described. Antithyroid antibodies were positive in only 16% patients. The ultrasonography was informative in 19% patients. Levothyroxine supplementation was necessary in 57% patients, leading to 19% recovery. With a dedicated optimized management, most of the cases did not require immunotherapy discontinuation. Finally, immune-mediated related thyroiditis is increasing due to a wider prescription of ICI therapy in various cancer conditions and systematic screening. Often asymptomatic, they lead to a local activation accompanied by hormonal deficiency in the long run. It is necessary to carry out an early and sustained multidisciplinary screening to allow immunotherapy continuation.

Nicorandil-induced ulcers remain often poorly recognised, with a late diagnosis and an inadequate management. We aimed to provide a clinical overview of the 148 spontaneously reported cases of nicorandil-induced ulcers to the French pharmacovigilance network between 2005 and 2014 and to complete this picture with worldwide published cases over the same period. Spontaneously reported nicorandil-induced ulcers were mainly mucosal (oral and anal) with a previous trauma in 23·0% of patients, revealed by a severe complication in 12·8% of cases. The mean cumulative dose of nicorandil was higher in serious cases. The median delay between the start of nicorandil use and the onset of the ulcer was 23·4 months, and after the ulcer was diagnosed, the median time to incriminate nicorandil was still 3·3 months, being shorter for mucosal ulcerations than for cutaneous ulcerations (5·2 versus 14·0 months, P = 0·001). The anatomic distribution in the 199 published cases differed slightly, but delays were similar. The hypothesis of mechanism becomes more precise, leaving no doubt about the necessity to discontinue the treatment. Practitioners need to be aware that nicorandil-induced ulcers can occur in many locations, possibly multiple and complicated, and should be simply managed by discontinuing treatment with no further reintroduction of nicorandil.

Summary Introduction Intravenous iron infusion may be complicated by extravasation and lead to cutaneous pigmentation. Methods We queried the French pharmacovigilance database to assess the spontaneously reported cases over the 2000–2016 period. Results Fifty-one cases of cutaneous pigmentation related to intravenous iron extravasation were retrieved, none was associated to necrosis. Most of patients were women aged 20 to 49 years old. The pigmentation was mostly a brown coloration, persisting over one month in 19 cases (37.2%) and over 6 months in 9 cases (17.6%). The management of extravasation and pigmentation was heterogeneous and was rarely followed by a decrease of the coloration. Conclusion Cutaneous pigmentation after intravenous iron extravasation can persist over time and create an aesthetic prejudice, particularly in young women. Standardized extravasation and iron-induced pigmentation management procedures appear necessary.

Osteoarthritis (OA) is the most common degenerative joint disease. Rapamycin is a potential candidate for OA treatment by increasing the autophagy process implicated in its physiopathology. To optimize Rapamycin profit and avoid systemic side effects, intra-articular (i.a.) administration appeared helpful. However, Rapamycin's highly hydrophobic nature and low bioavailability made it challenging to develop purpose-made drug delivery systems to overcome these limitations. We developed Rapamycin-loaded nanoparticles (NPs) using poly (lactic-co-glycolic acid) by emulsion/evaporation method. We evaluated these NPs' cytocompatibility towards cartilage (chondrocytes) and synovial membrane cells (synoviocytes) for a potential i.a. administration. The in vitro characterization of Rapamycin-loaded NPs had shown a suitable profile for an i.a. administration. In vitro biocompatibility of NPs was highlighted to 10 µM of Rapamycin for both synoviocytes and chondrocytes, but significant toxicity was observed with higher concentrations. Besides, synoviocytes are more sensitive to Rapamycin-loaded NPs than chondrocytes. Finally, we observed in vitro that an adapted formulated Rapamycin-loaded NPs could be safe at suitable i.a. injection concentrations. The toxic effect of Rapamycin encapsulated in these NPs on both articular cells was dose-dependent. After Rapamycin-loaded NPs i.a. administration, local retention, in situ safety, and systemic release should be evaluated with experimental in vivo models.

Contexte Les effets indesirables a long terme de l’hormonotherapie (HT) d’affirmation de genre sont mal elucides, en raison du manque des etudes de cohorte prospectives. Les declarations aupres des centres de pharmacovigilance representent donc un outil precieux pour detecter les effets indesirables potentiels. Objectif Decrire le profil d’effets indesirables imputables a l’HT chez les personnes transgenres Methode Etude descriptive, retrospective des cas enregistres dans la base de donnees nationale de pharmacovigilance depuis sa creation jusqu’au 27 mai 2020 pour identifier les effets indesirables lies a l’HT d’affirmation de genre. Les cas deja publies ont ete exlus. Resultats Vingt huit cas d’effets indesirables ont ete identifies. Six concernaient les hommes transgenres (21–40 ans) et 22 femmes transgenres (22–68 ans). Chez les hommes transgenres sous traitement par l’enanthate de testosterone, tous les effets indesirables etaient les evenements cardiovasculaires avec une embolie pulmonaire dans 50 % des cas. Chez les femmes transgenres, les anti-androgenes, principalement l’acetate de cyproterone, etaient impliques dans 68 % des cas. Les œstrogenes etaient impliques dans 77 % des cas, principalement en association avec la progestine ou l’acetate de cyproterone. Le meningiome etait le principal effet indesirable, suivi des evenements cardiovasculaires. Conclusion Nos resultats montrent une proportion non negligeable des cas d’evenements cardiovasculaires chez les jeunes hommes transgenres sous l’enanthate de testosterone. Chez les femmes transgenres, les evenements cardiovasculaires representent le deuxieme effet indesirable signale. Les etudes ulterieures sont necessaires pour identifier des facteurs de risque pouvant contribuer a l’individualisation de la strategie therapeutique en particulier chez les sujets jeunes.

Introduction L’hyperhidrose (HH) peut etre d’origine medicamenteuse et devenir invalidante. Apres l’observation au CHRU de Nancy de 2 cas d’HH invalidante chez des patients traites par adalimumab (ADA) sans autre etiologie identifiee, nous avons analyse retrospectivement les cas d’HH enregistres dans la base nationale de pharmacovigilance (BNPV) impliquant les biotherapies (BT) utilisees en dermatologie. Materiel et methodes Une requete a ete effectuee dans la BNPV le 31 mars 2020 en croisant les termes MedDRA « hyperhidrose », « sueurs nocturnes », « sueurs froides », « hypersudation compensatoire », « trouble des glandes sudoripares » et les BT suivantes : anti-TNFα, anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, risankizumab), anti-IL1 (anakinra, canakinumab), ustekinumab, dupilumab, rituximab, omalizumab, belimumab, inhibiteurs de check-point (ipilimumab, pembrolizumab, nivolumab, avelumab), cetuximab et interferon-alpha. Nous avons exclu les cas ayant une autre etiologie identifiee et ceux sans bilan etiologique ni evolution renseignes. Les HH au cours de reactions liees a la perfusion (RAP) ont ete analysees a part. Resultats Parmi les 240 notifications d’HH, 82 ont ete exclues et 131 etaient des RAP. L’âge moyen des 27 cas analyses etait de 50 ans, le sexe-ratio F/H a 1,7. Les BT les plus frequemment imputables etaient les anti-TNFα (ADA : n = 13, etanercept : n = 4, infliximab : n = 1) et l’ustekinumab (n = 5) en traitement de rhumatismes inflammatoires chroniques (60 %), psoriasis (22 %) et maladies inflammatoires chroniques de l’intestin (17 %). Le delai de survenue, renseigne dans 16/27 cas (60 %), etait inferieur a 1 mois (n = 2, 7 %), de 1 mois a 1 an (n = 7, 26 %) et de plus d’1 an (n = 7, 26 %). La BT etait arretee dans 15 cas (55 %), avec evolution favorable dans 11 cas. Elle etait poursuivie dans 9 cas (33 %), avec persistance de l’HH dans 7 cas, dont un cas d’HH axillaire traitee par toxine botulique. Un bilan etiologique permettait d’exclure les principales causes d’HH dans 13 cas (48 %). Discussion Hors contexte de RAP, l’HH est rarement induite par une BT utilisee en dermatologie et une autre cause doit etre recherchee en priorite (infectieuse, neoplasique, metabolique ou immunologique). De rares cas sont declares en pharmacovigilance, impliquant notamment les anti-TNFα, BT les plus prescrites. Une sous-notification de cet effet indesirable est tres probable. Dans la litterature, un seul cas d’HH est rapporte avec l’ADA et une possible composante familiale. Le mecanisme physiopathologique n’est pas clairement etabli. En cas d’HH invalidante lors d’une BT anti-TNFα, sans cause identifiee au prealable, un changement de classe therapeutique biologique pourrait etre envisage. Conclusion Devant une HH, il faut evoquer une cause medicamenteuse, dont les BT. Apres evaluation de la balance benefice-risque, l’arret du traitement permet souvent une evolution favorable.

P-glycoprotein (P-gp, ABCB1) overexpression is, currently, one of the most important multidrug resistance (MDR) mechanisms in tumor cells. Thus, modulating drug efflux by P-gp has become one of the most promising approaches to overcome MDR in cancer. Yet, more insights on the molecular basis of drug specificity and efflux-related signal transmission mechanism between the transmembrane domains (TMDs) and the nucleotide binding domains (NBDs) are needed to develop molecules with higher selectivity and efficacy. Starting from a murine P-gp crystallographic structure at the inward-facing conformation (PDB ID: 4Q9H), we evaluated the structural quality of the herein generated human P-gp homology model. This initial human P-gp model, in the presence of the “linker” and inserted in a suitable lipid bilayer, was refined through molecular dynamics simulations and thoroughly validated. The best human P-gp model was further used to study the effect of four single-point mutations located at the TMDs, experimentally related with changes in substrate specificity and drug-stimulated ATPase activity. Remarkably, each P-gp mutation is able to induce transmembrane α-helices (TMHs) repacking, affecting the drug-binding pocket volume and the drug-binding sites properties (e.g. volume, shape and polarity) finally compromising drug binding at the substrate binding sites. Furthermore, intracellular coupling helices (ICH) also play an important role since changes in the TMHs rearrangement are shown to have an impact in residue interactions at the ICH-NBD interfaces, suggesting that identified TMHs repacking affect TMD-NBD contacts and interfere with signal transmission from the TMDs to the NBDs.

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Introduction Au cours du premier semestre 2019, plusieurs signalements, concernant majoritairement des adolescents et des jeunes adultes domicilies dans la Marne ayant presente des symptomes apres vapotage ont ete declares au CEIP-A de Nancy. Cette etude visait a etudier ce signal. Methode Deux sources d’information ont ete utilisees : – les notifications spontanees recensees entre le 01/01/2018 et le 22/08/2019 ; – une etude observationnelle retrospective menee au CHU de Reims de janvier 2018 a aout 2019 (mots-cles : cannabis, CBD, cannabidiol, cigarette electronique). Resultats Un total de 101 observations ont ete analysees. Un seul profil de consommation : des adolescents et jeunes adultes d’âge moyen de 18 ± 7 ans (valeurs extremes : 12 a 56 ans), plutot de sexe masculin. La majorite des patients (90 %) ont ete pris en charge apres avoir utilise une e-cigarette supposee contenir du CBD qui leur avait ete offerte gratuitement (60 %), par le biais de dons ou de consommations partagees. Un total de 414 signes cliniques a ete identifie apres vapotage, en particulier : effets neurologiques et psychiatriques (72 %) mais aussi digestifs (13 %) et cardiovasculaires (10 %). Les prelevements biologiques de 48 patients ont ete analyses : 27 patients ont presente un depistage negatif, 12 ont ete testes positifs pour le cannabis, 9 pour le paracetamol et 4 pour l’alcool. Un patient a ete teste positif pour XRL11 et l’acadesine. Quatre cannabinoides synthetiques differents ont ete identifies dans cinq e-liquides : 5F-MDMB-PINACA (n = 1), 5F-CUMYL-PINACA (n = 1), XLR-11 (n = 2), 5F-MDMB-PICA (n = 1). Un autre echantillon d’e-liquide contenait du CBD (1 %) + THC. Conclusion Cette etude a mis en evidence une flambee d’effets nocifs supposes lies au vapotage dans une region specifique du nord-est de la France. Cependant, on ne sait toujours pas exactement ce qui causait ces symptomes. En effet, bien que des produits a base de cannabinoides aient ete identifies dans les six e-liquides testes, les depistages toxicologiques restent rares. En raison de ce signal inexplique, depuis septembre 2019, une enquete prospective (enquete Vapotox) est en cours dans le Nord-Est de la France, afin d’identifier, avec confirmation du laboratoire, la cause exacte de ce probleme de sante.

Introduction Depuis 2003 sont commercialisees des specialites de fentanyl d’action rapide (FAR) par voie transmuqueuse buccale (Abstral®, Actiq®, Breakyl®, Effentora® et Recivit®) ou nasale (Instanyl® et Pecfent®). Elles sont indiquees uniquement dans le traitement des acces douloureux paroxystiques chez les patients adultes recevant deja un traitement de fond opioide pour des douleurs chroniques d’origine cancereuse. Leur pharmacocinetique -forte absorption, action rapide- majore les risques d’abus/dependance et de surdoses [1] . Face au possible mesusage des FAR, l’ANSM a mis en place un suivi national realise par les 2 reseaux nationaux de pharmacovigilance et d’addictovigilance, dont nous presentons ici les donnees actualisees. Methodes Analyse des cas cliniques rapportes aux reseaux de pharmacosurveillance et des donnees des enquetes pharmaco-epidemiologiques d’addictovigilance. La periode d’etude s’etend du 01.01.2016 au 30.06.2019 pour Abstral®, Actiq®, Effentora®, Instanyl® et Pecfent® (suivies depuis 2009) et d’avril 2013 et juin 2014 au 30.06.2019 pour les specialites plus recemment commercialisees (Breakyl® et Recivit®). Resultats Au total, 328 cas signales aupres des reseaux de pharmacovigilance et d’addictovigilance ont ete retenus et analyses. L’analyse montre un non-respect des recommandations, persistant depuis le debut du suivi : indications hors AMM (56 %), absence ou insuffisance de traitement de fond (31 %), frequence de prises superieure a 4 par jour (au-dela de laquelle le risque de surdosage opioide est majeur) [41 %]. Le nombre de surdoses a plus que double entre 2015 et 2019 (13 % entre 2016 et 2019 vs 5 % entre 2013 et 2015) ( Fig. 1 ). Parmi les 328 cas signales entre 2016 et 2019, 47 % des patients presentent un abus et/ou une dependance de FAR (vs 32 % entre 2013 et 2015). 70 % de ces cas concernent des patients avec des douleurs hors cancer, principalement rhumatologiques ou neuropathiques. Pour pres de 30 % des cas d’abus/dependance, le traitement de fond est inexistant ou insuffisant. Les femmes comme les hommes sont concernes et meme si le comprime avec applicateur buccal et les sprays nasaux sont plus frequemment rapportes, toutes les specialites de FAR font l’objet de mesusages et d’abus. Discussion Un mesusage tres important en termes de non-respect de l’AMM persiste [2] . L’addictovigilance pointe, de plus, sur une problematique d’abus/dependance en augmentation chez des patients souffrant majoritairement de douleurs chroniques non cancereuses pour lesquelles, de surcroit, le FTM est inefficace. A la lumiere de ces informations, il apparait necessaire que les prescripteurs soient informes des consequences d’une prescription de FTM non adaptee, et sensibilises a l’importance d’une prescription aux seuls patients relevant de l’AMM, en association avec un traitement de fond opioide stabilise.

During the past two decades, with a huge and rapidly increasing clinical need for bone regeneration and repair, bone substitutes are more and more seen as a potential solution. Major innovation efforts are being made to develop such substitutes, some having advanced even to clinical practice. It is now time to turn to natural biomaterials. Nacre, or mother-of-pearl, is an organic matrix-calcium carbonate coupled shell structure produced by molluscs. In vivo and in vitro studies have revealed that nacre is osteoinductive, osteoconductive, biocompatible, and biodegradable. With many other outstanding qualities, nacre represents a natural and multi-use biomaterial as a bone graft substitute. This review aims at summarising the current needs in orthopaedic clinics and the challenges for the development of bone substitutes; most of all, we systematically review the physiological characteristics and biological evidence of nacre's effects centred on osteogenesis, and finally we put forward the potential use of nacre as a bone graft substitute. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 662-671, 2017.

Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; P

This study investigated the relationship of oxytocin (OT) to chondrogenesis and osteoarthritis (OA). Human bone marrow and multipotent adipose-derived stem cells were cultured in vitro in the absence or presence of OT and assayed for mRNA transcript expression along with histological and immunohistochemical analyses. To study the effects of OT in OA in vivo, a rat model and a human cohort of 63 men and 19 women with hand OA and healthy controls, respectively, were used. The baseline circulating OT, interleukin-6, leptin, and oestradiol levels were measured, and hand X-ray examinations were performed for each subject. OT induced increased aggrecan, collagen (Col) X, and cartilage oligomeric matrix protein mRNA transcript levels in vitro, and the immunolabelling experiments revealed a normalization of Sox9 and Col II protein expression levels. No histological differences in lesion severity were observed between rat OA groups. In the clinical study, a multivariate analysis adjusted for age, body mass index, and leptin levels revealed a significant association between OA and lower levels of OT (odds ratio = 0.77, p = 0.012). Serum OT levels are reduced in patients with hand OA, and OT showed a stimulatory effect on chondrogenesis. Thus, OT may contribute to the pathophysiology of OA.