Publications by authors named "Nadine Petitpain"

61 Publications

[Medication errors reporting in drug clinical trials: Role of the clinical research pharmacist?]

Therapie 2021 Feb 5. Epub 2021 Feb 5.

Direction de la recherche et de l'enseignement, CHU de Caen, 14033 Caen, France.

The investigational drugs circuit has specific risks, and medication errors may occur in clinical trials, possibly associated with adverse reactions. These risks must therefore be managed. In fact, there are few reports of medication errors during clinical trials. In a context of regulatory interpretation difficulties on this subject, we conducted a national survey that highlighted the heterogeneity of the methods used by academic sponsors to collect, code and report medication errors and the need to develop a culture of reporting these errors in clinical trials. This is why the REVISE group (safety officers of French institutional sponsors) has issued recommendations to clarify the sponsor and investigator responsibilities and guide them in the management of medication errors. These new guidelines recommend that any serious or potentially serious medication error or other "special situation" (e.g. overdose, misuse, quality defect) should be notified immediately to the sponsor by the investigator. The clinical research pharmacist place is strategic to detect medication errors and other special situations. The integration of the pharmacist into the reporting system, in collaboration with the investigator, could be discussed with clinical research professionals and health authorities.
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http://dx.doi.org/10.1016/j.therap.2021.02.002DOI Listing
February 2021

Drug adulteration of sexual enhancement supplements: a worldwide insidious public health threat.

Fundam Clin Pharmacol 2021 Jan 22. Epub 2021 Jan 22.

CHRU-Nancy, Department of Clinical Pharmacology, Toxicology and Pharmacovigilance, Regional University Hospital of Nancy, Université de Lorraine, Nancy, France.

Worldwide, the consumption of dietary supplements for the enhancement of sexual performance is common. Consumers are generally fond of these products because they often want to avoid drugs, preferring "natural" than "chemical" solutions. This is challenging, as many of these supplements labelled "herbal" or "natural" are actually adulterated with drugs, mainly phosphodiesterase-5 inhibitors. This phenomenon is facilitated by fewer demanding regulations for marketing supplements. Thus, consumers may be widely exposed to serious adverse events, such as acute liver injury, kidney failure, pulmonary embolism, stroke or even death. We aim to warn physicians about this issue. This multidisciplinary review simultaneously deals with clinical consequences of this phenomenon, analytical toxicology and regulation. Indeed, after outlining this worldwide issue and highlighting that a drug-adulterated dietary supplement is actually a falsified drug, we discuss its main contributing factors. Then, we describe some examples of adverse events of which a case of sildenafil-tadalafil-induced ischaemic stroke that benefited medical care in our hospital. Furthermore, we present some means to avoid adulteration and discuss their limitations that may be explained by the heterogeneity of the regulation of dietary supplements between countries. Doing so, we point out the requirement of a global harmonization of this regulation for an efficient eradication of this public health threat. Meanwhile, dietary supplements should be considered adulterated until proven otherwise. Thus, we encourage physicians to investigate these products in the drug histories of their patients, especially when clinical conditions cannot be explained by classical aetiologies.
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http://dx.doi.org/10.1111/fcp.12653DOI Listing
January 2021

Immunoglobulin Preparations Can Mislead Clinical Decision-Making in Follow-Up of Differentiated Thyroid Cancer.

Endocr Pract 2020 Sep;26(9):1031-1038

Université de Lorraine, CHRU-Nancy, Department of Endocrinology, Diabetology and Nutrition, Nancy, France; Université de Lorraine, Inserm UMR_S 1116 - DCAC, Nancy, France.. Electronic address:

Objective: Intravenous and subcutaneous immunoglobulins are commonly used for immune substitution or as immune modulators in a variety of inflammatory and autoimmune disorders. Exogenous thyroid-specific thyroglobulin (Tg) antibodies present in the donor plasma may interfere with the interpretation of measurements of Tg autoantibodies (Tg-Abs) in the recipient's plasma and potentially trigger an immune response in the recipient's immune cells. Levels of antibodies causing bioassay interferences or those leading to clinically relevant changes in patient outcomes are not known. Tg is used as a biomarker in the long-term surveillance of patients with differentiated thyroid cancer (DTC) following total thyroidectomy and radioactive iodine ablation. However, the presence of Tg-Abs in the circulation interferes with Tg measurements. Assessment of levels of Tg-Abs is thus recommended as a part of standard follow-up of DTC together with Tg testing.

Methods: To understand the potential mechanisms and pathophysiologic significance of possible interferences associated with administration immunoglobulin preparations and Tg measurement, we overview the current knowledge on interactions between Tg autoimmunity and immunoglobulin preparations and illustrate diagnostic challenges and perspectives for follow-up of patients with DTC treated with exogenous immunoglobulins.

Results: In patients with DTC treated with immunoglobulin preparations, monitoring of thyroid cancer using Tg and Tg-Abs is challenging due to possible analytical interferences through passive transfer of exogenous antibodies from immunoglobulin preparations.

Conclusion: Analytical interferences must be suspected when a discrepancy exists between clinical examination and diagnostic tests. Collaboration between endocrinologists, biologists, and pharmacologists is fundamental to avoid misdiagnosis and unnecessary medical or radiologic procedures.

Abbreviations: CT = computed tomography; DTC = differentiated thyroid cancer; FNAB = fine-needle aspiration biopsy; HAb = heterophile antibody; IMA = immunometric assay; IVIg = intravenous immunoglobulin; RAI = radioactive iodine; RIA = radioimmunoassay; SCIg = subcutaneous immunoglobulin; Tg = thyroglobulin; Tg-Ab = thyroglobulin autoantibody; Tg-MS = thyroglobulin mass spectrometry; TPO-Ab = thyroid peroxidase autoantibody; TSHR-Ab = thyrotropin receptor autoantibody.
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http://dx.doi.org/10.4158/EP-2020-0053DOI Listing
September 2020

IL-17 Inhibitors and Inflammatory Bowel Diseases: A Postmarketing Study in Vigibase.

Clin Pharmacol Ther 2021 Jan 7. Epub 2021 Jan 7.

Regional Centre of Pharmacovigilance, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.

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.
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http://dx.doi.org/10.1002/cpt.2155DOI Listing
January 2021

TNF-α inhibitors and psychiatric adverse drug reactions in the spectrum of bipolar (manic) or psychotic disorders: Analysis from the French pharmacovigilance database.

Therapie 2020 Sep 25. Epub 2020 Sep 25.

Inserm U1167; CHU Lille, service de médecine interne et de médecine polyvalente-post urgences, 59000 Lille, France; Université de Lille, 59000 Lille, France.

Objective: This study aimed to describe reports of psychiatric adverse drug reaction (ADR) in the spectrum of bipolar (manic features) or psychotic disorders that occurred under tumor necrosis factor alpha (TNF-α) inhibitors therapy.

Methods: We searched the French pharmocovigilance database for reports of psychiatric ADR in the spectrum of bipolar (manic features) or psychotic disorders during treatment with TNF-α inhibitors. Psychiatric symptoms were divided in 2 categories: (i) confirmed diagnosis of manic episode or acute psychosis and (ii) psychiatric symptoms with psychotic or manic features but not meeting sufficient criteria for diagnosis of psychosis or manic disorder.

Results: Overall, 9942 reports of ADR were registered in the French pharmacovigilance database with TNF-α inhibitors, including 243 reports of psychiatric ADR. Among them, we identified 41 reports of psychotic or manic disorders as define above: 9 characterised manic episodes and 32 psychiatric disorders with psychotic or manic features. TNF-α inhibitors were the only medication suspected in 23 reports (56%). The delay between starting TNF-α inhibitors treatment and onset of symptoms varied from hours to years with a median time of 40 days. Psychiatric symptoms improved in 22/23 patients in whom the TNF-α inhibitor was withdrawn.

Conclusion: Depressive disorders are well-known ADR of TNF-α inhibitors, but we report, here, 41 reports of psychiatric ADR diagnosed as manic or psychotic disorders or in the spectrum of bipolar or psychotic disorders with these treatments. Epidemiological studies are needed to confirm this signal.
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http://dx.doi.org/10.1016/j.therap.2020.09.003DOI Listing
September 2020

Hepatitis B reactivation and immune check point inhibitors.

Dig Liver Dis 2021 Apr 10;53(4):452-455. Epub 2020 Sep 10.

Regional Pharmacovigilance Centre, Department of Clinical Pharmacology, Toxicology, University Hospital CHRU Nancy, Vandœuvre-lès-Nancy 54511, France.

Background: Liver toxicity during immune checkpoint inhibitor treatment is mostly due to immune mediated hepatitis. Viral hepatitis, as well as auto-immune or metabolic hepatitis, are considered as exclusion criteria for ICI induced immune hepatitis diagnosis. However, considering the high prevalence of viral hepatitis B infection and the increasing prescription of immune checkpoint inhibitors, their use in patients with HBV chronic viral infection may be common, even more if patients are treated for hepatocellular carcinoma. Few clinical studies directly deal with the risk of HBV reactivation during ICI therapy and real-life data is currently based on five reported cases of HBV reactivation, one with fatal outcome. In this review, we summarize the current available clinical information about HBV reactivation risk during ICI treatment, its hypothetic mechanism, and propose practical recommendations about verifying and monitoring HBV status throughout the treatment.
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http://dx.doi.org/10.1016/j.dld.2020.08.041DOI Listing
April 2021

Paradoxical gastrointestinal effects of interleukin-17 blockers.

Ann Rheum Dis 2020 09 21;79(9):1132-1138. Epub 2020 Jul 21.

Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France

Secukinumab, ixekizumab and brodalumab are monoclonal antibody therapies that inhibit interleukin (IL)-17 activity and are widely used for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. The promising efficacy results in dermatology and rheumatology prompted the evaluation of these drugs in Crohn's disease and ulcerative colitis, but the onset of paradoxical events (disease exacerbation after treatment with a theoretically curative drug) prevented their approval in patients with inflammatory bowel diseases (IBDs). To date, the pathophysiological mechanisms underlying these paradoxical effects are not well defined, and there are no clear guidelines for the management of patients with disease flare or new IBD onset after anti-IL-17 drug therapy. In this review, we summarise the literature on putative mechanisms, the clinical digestive effects after therapy with IL-17 inhibitors and provide guidance for the management of these paradoxical effects in clinical practice.
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http://dx.doi.org/10.1136/annrheumdis-2020-217927DOI Listing
September 2020

Paradoxical adverse drug reactions: descriptive analysis of French reports.

Eur J Clin Pharmacol 2020 Aug 16;76(8):1169-1174. Epub 2020 May 16.

Centre De Pharmacovigilance, De Pharmacoépidémiologie Et D'informations Sur Le Médicament, Inserm UMR 1027, Faculté De Médecine, Centre Hospitalier Universitaire, Toulouse, France.

Introduction: Paradoxical adverse drug reactions (ADRs) are defined as being opposing reactions to the pharmacological effect of drugs in relation to its pharmacodynamic properties. Their diagnosis is difficult as they are relatively rare with atypical clinical presentation (with the possibility of being confused with drug ineffectiveness or the worsening of the underlying disease). This kind of ADR may be particularly subject to under-notification. The aim of the present study is to describe paradoxical ADRs using the French PharmacoVigilance DataBase (FPVDB).

Method: We analysed all reports recorded in the FPVDB with drugs defined as "suspect" and which included the term "paradoxical reaction" (PR) (according to MedDRA classification) from 01/01/1984 to 12/31/2018. The drugs were classified according to the Chemical Therapeutic Anatomical Classification (ATC).

Results: We found 57 reports of PR, with half of them recorded between 2015 and 2018. The median age of patients was 46 years, mainly male (54%). The most frequently involved drugs were immunomodulating agents (n = 28, 49%) and psychotropics (n = 28, 49%). The leading paradoxical ADRs were psychiatric (anxiety, sleep and behavioural disorders) and skin-related. In 19 cases (33%), PR was related to benzodiazepines mainly occurring in patients in extreme ages (five cases in children and patients > 70, respectively, 53%). For psychotropic-induced PR (n = 28), known contributory factors (alcohol consumption, underlying psychiatric diseases) were found in 18 cases (64%). Paradoxical reactions with immunomodulating agents were mainly related to skin ADRs (n = 25). For psychotropics, paradoxical ADRs occurred rapidly after a mean delay of 1 day, predominantly following high doses. We also identified several "unexpected" paradoxical reactions, such as cognitive degradation with donepezil, or a return to impulsive smoking addiction with varenicline.

Conclusion: This study highlights that pharmacovigilance databases like the French database make it possible to investigate the main characteristics of paradoxical reactions to drugs. This ADR was mainly found in the FPVDB with psychotropic drugs and immunomodulating agents. Moreover, pharmacovigilance databases enable the identification of some signs of "unexpected paradoxical reactions". In order to identify this type of ADR more effectively, work on awareness and harmonization is required to register these reports. The addition of the term "paradoxical reaction to the drug" to the list of other symptoms would facilitate their identification and analysis.
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http://dx.doi.org/10.1007/s00228-020-02892-2DOI Listing
August 2020

Compliance of French academic clinical trials with the Clinical Trial Facilitation and Coordination Group recommendations on contraception and pregnancy testing requirements.

Clin Trials 2020 06 6;17(3):314-322. Epub 2020 Feb 6.

Centre régional de pharmacovigilance, Service de Pharmacologie-Toxicologie et Pharmacovigilance, CHU de Limoges, Limoges, France.

Background/aims: The Clinical Trials Coordination and Facilitation Group has issued recommendations on contraception and pregnancy testing to help sponsors meet regulatory expectations and harmonize practices to limit embryofetal risks in clinical trials. Our objective was to assess the compliance of French academic clinical trials with these recommendations and to describe the mitigation measures required by sponsors in their trials.

Methods: A cross-sectional study was performed on the French academic drug trials authorized by the national competent authority between January 2015 and June 2018. We included trials which tested systemic administration of drugs and enrolled men or women of childbearing potential.

Results: Data from 97 trials included were compiled. One-third of the trials (23.8%-43.3%, 95% confidence interval) complied with the Clinical Trial Facilitation and Coordination Group recommendations. No improvement over time or according to embryofetotoxic status or drug duration exposure was found. Contraception was required in 56.7% of trials and was more often required in case of potentially embryofetotoxic drugs (68.5% vs 41.9%, p = 0.013) or exposure over 1 month (71.7% vs 43.8%, p = 0.006). Pregnancy testing at inclusion was required in 59.1% of trials and additional testing in 17.2%. Pregnancy testing at inclusion was more often required in trials with drug exposure above 1 month (67.4% vs 45.8%, p = 0.035).

Conclusion: French academic sponsors barely met the recommendations on contraception and pregnancy testing potentially leading to potential embryofetal risks in case of pregnancy. They need to implement these recommendations quickly.
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http://dx.doi.org/10.1177/1740774520903720DOI Listing
June 2020

PGxCorpus, a manually annotated corpus for pharmacogenomics.

Sci Data 2020 01 2;7(1). Epub 2020 Jan 2.

Université de Lorraine, CNRS, Inria, LORIA, Nancy, France.

Pharmacogenomics (PGx) studies how individual gene variations impact drug response phenotypes, which makes PGx-related knowledge a key component towards precision medicine. A significant part of the state-of-the-art knowledge in PGx is accumulated in scientific publications, where it is hardly reusable by humans or software. Natural language processing techniques have been developed to guide experts who curate this amount of knowledge. But existing works are limited by the absence of a high quality annotated corpus focusing on PGx domain. In particular, this absence restricts the use of supervised machine learning. This article introduces PGxCorpus, a manually annotated corpus, designed to fill this gap and to enable the automatic extraction of PGx relationships from text. It comprises 945 sentences from 911 PubMed abstracts, annotated with PGx entities of interest (mainly gene variations, genes, drugs and phenotypes), and relationships between those. In this article, we present the corpus itself, its construction and a baseline experiment that illustrates how it may be leveraged to synthesize and summarize PGx knowledge.
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http://dx.doi.org/10.1038/s41597-019-0342-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940385PMC
January 2020

Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.

Sci Rep 2019 12 19;9(1):19419. Epub 2019 Dec 19.

Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Nancy Brabois, Biologie Médicale & Biopathologie, Rue du Morvan, 54511, Vandoeuvre Lès Nancy, France.

Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
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http://dx.doi.org/10.1038/s41598-019-56026-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923385PMC
December 2019

Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population.

Therapie 2020 Sep - Oct;75(5):471-480. Epub 2019 Oct 28.

Department of medical pharmacology, CRPV, CHU de Clermont-Ferrand,63003 Clermont-Ferrand, France.

Background: Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal.

Methods: We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (<18 y.o.) receiving liquid formulation or lyophilized powder formulation during the study period were included. Patients with at least one occurrence of encephalopathy were considered as cases. Logistic regression model was used to estimate the odds ratio of encephalopathy between exposure groups.

Results: During the study period, 52 cases and 495 controls were included. A residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation compared to lyophilized powder (adjusted OR 1.91, 95% CI: 1.03-3.53).

Conclusions: Observed difference does not seem to be related to the pathology treated, the doses used, the co-medications, a meningeal localization and/or an irradiation of the central nervous system. This study confirms data from spontaneous reports that led to the precautionary measure for the liquid formulation. Even if the risk of encephalopathy seems reduced, our study suggests the persistence of a residual risk of encephalopathy associated with liquid formulation compared to the lyophilized powder.
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http://dx.doi.org/10.1016/j.therap.2019.08.001DOI Listing
October 2019

Cluster headache-like symptoms during treatment with tenofovir disoproxil fumarate and emtricitabine.

AIDS 2019 07;33(9):1535-1536

Clinical Pharmacology Department, Regional Pharmacovigilance Center, University Hospital CHRU Nancy.

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http://dx.doi.org/10.1097/QAD.0000000000002198DOI Listing
July 2019

Is TNF inhibitor exposure a risk factor for amyotrophic lateral sclerosis?

Fundam Clin Pharmacol 2019 Dec 29;33(6):689-694. Epub 2019 May 29.

Regional Pharmacovigilance Centre of Caen, University Hospital Centre of Caen, UMR, UMR University of Caen Normandie/Inserm U1075, Caen, France.

TNFα modulation has been reported to be either beneficial or detrimental in amyotrophic lateral sclerosis (ALS) and therefore appears as a key issue. We analysed the relationship between TNFα inhibitor (TNFi) exposure and ALS. We performed descriptive analysis of ALS reports in patients treated with TNFi, registered in the French Pharmacovigilance Database (FPvD) and disproportionality analyses by the 'case'/'non-case' method in FPvD and worldwide database (Vigibase ). The 8 retrieved ALS cases from the FPvD were 5 with limb-onset and 3 with bulbar-onset forms, in patients aged 43-75 years old, mainly treated for inflammatory rheumatism. The time to onset of the first symptoms ranged from 12 to 108 months, and the cumulative TNFi exposure before the diagnosis ranged from 12 to 120 months. TNFi was discontinued and thereafter survival ranged between 12 and 20 months. Disproportionality analyses showed significant associations between TNFi exposure and ALS in the FPvD and Vigibase (160 ALS cases), regardless comparators. A putative association between TNFi and ALS must be interpreted cautiously, but TNFi could act as a predisposing or risk factor. TNFi should therefore be avoided in patients with a known risk of ALS and discontinued in the case of neurological signs of ALS.
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http://dx.doi.org/10.1111/fcp.12480DOI Listing
December 2019

Paracetamol Misuse and Dental Pain: Results from the French Observational DAntaLor Study.

J Oral Facial Pain Headache 2019 Winter;33(1):123-129

Aims: To evaluate the risk of hepatotoxicity due to unintentional paracetamol misuse in patients with acute dental pain.

Methods: A prospective multicenter observational survey was performed in patients consulting, without appointment, the odontology departments of three main French hospitals in the Lorraine region over a 3-month period. Patients were asked to fill out a medical questionnaire while seated in the waiting room. Those who completed the questionnaire, had dental pain, and took paracetamol were included in the DAntaLor study. Misuse was defined as a daily dose of more than 4 g of paracetamol per day. The risk of hepatotoxicity was considered high if the supposed ingested dose was above the threshold of 150 mg.kg.24h, 125 mg.kg.24h, or 100 mg.kg.24h over periods of 24, 48, and 72 hours, respectively. Hepatotoxicity was suspected in the presence of clinical symptoms.

Results: Of the 1,810 patients consulting the odontology departments, 741 were included in the study. Painkillers were used in 74.4% of the cases, and paracetamol was taken by 81.7%. Paracetamol was self-medicated in 85.5% of the patients and misused by 6.0%. Clinical symptoms were observed in 1.6% of the patients with no paracetamol misuse. For patients consuming more than 4 g per day and experiencing mild unspecific clinical symptoms of hepatotoxicity, the suspected ingested dose category was below one of the three previously defined thresholds for 11.8% and was above for 40.0%.

Conclusion: Patients with dental pain are at risk of paracetamol overdose and hepatotoxicity.
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http://dx.doi.org/10.11607/ofph.1861DOI Listing
November 2019

Drugs of porcine origin-A risk for patients with α-gal syndrome?

J Allergy Clin Immunol Pract 2019 May - Jun;7(5):1687-1690.e3. Epub 2018 Dec 15.

Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.12.005DOI Listing
August 2020

Thyroiditis and immune check point inhibitors: the post-marketing experience using the French National Pharmacovigilance database.

Fundam Clin Pharmacol 2019 Apr 14;33(2):241-249. Epub 2018 Nov 14.

Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Nancy, 29 avenue du Maréchal de Lattre de Tassigny, Nancy, 54035, France.

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.
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http://dx.doi.org/10.1111/fcp.12423DOI Listing
April 2019

Pulmonary arterial hypertension in patient treated for multiple sclerosis with 4-aminopyridine.

Fundam Clin Pharmacol 2019 Feb 15;33(1):127-129. Epub 2018 Jul 15.

Département de pneumologie, CHRU de Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.

4-Aminopyridine (4-AP) is a recent treatment indicated to improve walking in patient with multiple sclerosis. We report the first case of pulmonary arterial hypertension (PAH) that we attribute to the use of 4-AP. A 64-year-old woman with multiple sclerosis presented with dyspnea. After excluding other secondary causes of pulmonary hypertension, a diagnosis of severe PAH due to 4-AP was made based on right heart catheterization. History revealed that the dyspnea began with the initiation of 4-AP. After discontinuation of 4-AP therapy and initiation of ambrisentan and tadalafil, dyspnea and pulmonary arterial pressure have improved significantly and one specific PAH treatment was stopped. 4-AP is an outward rectifying potassium channel blocker with a vasoconstrictor effect in animal's pulmonary artery. According to the chronological sequence of events, the lack of other etiology, and its pharmacological plausibility, 4-AP is highly suspected to have induced our patient's PAH.
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http://dx.doi.org/10.1111/fcp.12396DOI Listing
February 2019

Nicorandil-induced ulcerations: a 10-year observational study of all cases spontaneously reported to the French pharmacovigilance network.

Int Wound J 2018 Aug 16;15(4):508-518. Epub 2018 May 16.

Regional Center of Pharmacovigilance, University Hospital, Nancy, France.

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.
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http://dx.doi.org/10.1111/iwj.12845DOI Listing
August 2018

Acute kidney injury after high dose etoposide phosphate: A retrospective study in children receiving an allogeneic hematopoetic stem cell transplantation.

Pediatr Blood Cancer 2018 07 12;65(7):e27038. Epub 2018 Mar 12.

CHU Lille, Institut de Pharmacie, F-59000, Lille, France.

Background: Etoposide phosphate (EP; single injection, 60 mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo-SCT) conditioning regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context.

Materials And Methods: A retrospective study was carried out on children hospitalized between 2007 and 2015 for allo-SCT with TBI-based myeloablative conditioning associated with cyclophosphamide (CY, 60 mg/kg/day × 2 days) or EP. The primary endpoint of the study was the occurrence of acute kidney injury (AKI). Additional endpoints were time to recovery for children with AKI, survival, and treatment-related mortality.

Results: Thirty-five patients were analyzed (CY: 22 vs. EP: 13). AKI occurred more frequently in the EP group than in the CY one (69% vs. 27%, adjusted odds ratio 6.0, 95% confidence interval [CI] [1.145; 31.445], P = 0.03). The median time to recovery was estimated at 3 days, 95% CI (2; 17), with CY and 11 days 95% CI (5; 18) with EP (adjusted hazard ratio of recovery for EP vs. CY 0.262, 95% CI [0.071; 0.969], P = 0.04). No significant difference was highlighted between the two treatments for survival or for treatment-related mortality.

Discussion: This study shows that EP at high dosage or one of its excipients is probably responsible for AKI, as compared to CY. Further studies are required to explore the origin of this adverse effect.
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http://dx.doi.org/10.1002/pbc.27038DOI Listing
July 2018

Detection of drug safety signals from clinical trials data: Role of SUSARs.

Pharmacol Res 2018 05 11;131:218-223. Epub 2018 Feb 11.

Direction de la recherche et Clinique et de l'Innovation, Unité de Sécurité et Vigilance de la Recherche Clinique, CHU de Bordeaux, F-33000, Bordeaux, France; Univ. Bordeaux, INSERM U1219, Pharmacoepidemiology Team, F-33000, Bordeaux, France. Electronic address:

One of the main goals of safety management in clinical trials is to detect suspected unexpected serious adverse reactions (SUSARs). The unexpectedness concerns the nature, frequency or severity of an adverse reaction. Drug safety signals could thus be retrieved, and a study was performed to investigate whether SUSARs allow signal detection in pharmacovigilance. Data from six academic safety units were collected from 2005 to 2016. Characteristics of SUSARs were analysed and signals were identified i) by evaluating the presence of other causes, ii) by assessing the summary of product characteristics (SPC), iii) by searching for specific safety information in Pubmed and health agencies, and iv) by investigating the narrative of each case. Pharmacological plausibility was evaluated by compatible mechanism of reaction and time-to-onset. During the study period, 211 SUSARs were collected. They mostly concerned general disorders (26.1%) and protein kinase inhibitors (24.6%). After eliminating SUSARs with other causes or those considered as expected, 50 SUSARs (23.7%), involving a total of 115 drug-reaction pairs, concerned potential safety signals. Among these pairs, 12 (10.4%) were considered as pharmacologically plausible. This study indicates that one quarter of SUSARs collected in academic clinical trials refers to potential safety signals, especially for oncologic drugs. One tenth of drug-reaction pairs was considered to have a pharmacological plausibility and could merit further evaluation. This is the first study suggesting that SUSARs could be a source of safety signals and that their routine analysis should be complementary to spontaneous reporting.
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http://dx.doi.org/10.1016/j.phrs.2018.02.010DOI Listing
May 2018

Drug-induced aseptic meningitis: a mini-review.

Fundam Clin Pharmacol 2018 Jun 9;32(3):252-260. Epub 2018 Mar 9.

Centre Régional de Pharmacovigilance, CHRU de Nancy, Hôpital Central, 29, avenue du Maréchal de Lattre de Tassigny, 60034, 54035, Nancy, France.

Aseptic meningitis associates a typical clinical picture of meningitis with the absence of bacterial or fungal material in the cerebrospinal fluid. Drug-induced aseptic meningitis (DIAM) may be due to two mechanisms: (i) a direct meningeal irritation caused by the intrathecal administration of drugs and (ii) an immunologic hypersensitivity reaction to a systemic administration. If the direct meningeal irritation allows a rather easy recognition, the immunologic hypersensitivity reaction is a source of challenging diagnostics. DIAM linked to a systemic treatment exerts typically an early onset, usually within a week. This period can be shortened to a few hours in case of drug rechallenge. The fast and spontaneous regression of clinical symptoms is usual after stopping the suspected drug. Apart from these chronological aspects, no specific clinical or biological parameters are pathognomonic. CSF analysis usually shows pleiocytosis. The proteinorachia is increased while glycorachia remains normal. Underlying pathologies can stimulate the occurrence of DIAM. Thus, systemic lupus erythematosus appears to promote DIAM during NSAID therapy, especially ibuprofen-based one. Similarly, some patients with chronic migraine are prone to intravenous immunoglobulin-induced aseptic meningitis. DIAM will be mainly evoked on chronological criteria such as rapid occurrence after initiation, rapid regression after discontinuation, and recurrence after rechallenge of the suspected drug. When occurring, positive rechallenge may be very useful in the absence of initial diagnosis. Finally, DIAM remains a diagnosis of elimination. It should be suggested only after all infectious causes have been ruled out.
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http://dx.doi.org/10.1111/fcp.12349DOI Listing
June 2018

Severe headaches and 3rd or 6th nerve palsy associated with nicorandil: A hypothesis.

Am J Emerg Med 2018 08 5;36(8):1500-1501. Epub 2017 Dec 5.

CIC-IT Nancy, Inserm U947, France.

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http://dx.doi.org/10.1016/j.ajem.2017.12.001DOI Listing
August 2018

[Cutaneous pigmentation related to intravenous iron extravasation: Analysis from the French pharmacovigilance database].

Therapie 2018 May - Jun;73(3):193-198. Epub 2017 Nov 16.

Centre régional de pharmacovigilance de Nancy, CHRU de Nancy, 54035 Nancy, France.

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.
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http://dx.doi.org/10.1016/j.therap.2017.10.005DOI Listing
September 2018

Curative or pre-emptive adenovirus-specific T cell transfer from matched unrelated or third party haploidentical donors after HSCT, including UCB transplantations: a successful phase I/II multicenter clinical trial.

J Hematol Oncol 2017 05 8;10(1):102. Epub 2017 May 8.

Unité de Thérapie cellulaire et Tissus and FR 3209, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT), the most widely used potentially curable cellular immunotherapeutic approach in the treatment of hematological malignancies, is limited by life-threatening complications: graft versus host disease (GVHD) and infections especially viral infections refractory to antiviral drugs. Adoptive transfer of virus-specific T cells is becoming an alternative treatment for infections following HSCT. We report here the results of a phase I/II multicenter study which includes a series of adenovirus-specific T cell (ADV-VST) infusion either from the HSCT donor or from a third party haploidentical donor for patients transplanted with umbilical cord blood (UCB).

Methods: Fourteen patients were eligible and 11 patients received infusions of ADV-VST generated by interferon (IFN)-γ-based immunomagnetic isolation from a leukapheresis from their original donor (42.9%) or a third party haploidentical donor (57.1%). One patient resolved ADV infection before infusion, and ADV-VST could not reach release or infusion criteria for two patients. Two patients received cellular immunotherapy alone without antiviral drugs as a pre-emptive treatment.

Results: One patient with adenovirus infection and ten with adenovirus disease were infused with ADV-VST (mean 5.83 ± 8.23 × 10 CD3+IFN-γ+ cells/kg) up to 9 months after transplantation. The 11 patients showed in vivo expansion of specific T cells up to 60 days post-infusion, associated with adenovirus load clearance in ten of the patients (91%). Neither de novo GVHD nor side effects were observed during the first month post-infusion, but GVHD reactivations occurred in three patients, irrespective of the type of leukapheresis donor. For two of these patients, GVHD reactivation was controlled by immunosuppressive treatment. Four patients died during follow-up, one due to refractory ADV disease.

Conclusions: Adoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a pre-emptive treatment. Our study highlights that third party haploidentical donors are of great interest for ADV-VST generation in the context of UCB transplantation. (N° Clinical trial.gov: NCT02851576, retrospectively registered).
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http://dx.doi.org/10.1186/s13045-017-0469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421327PMC
May 2017

[Acetaminophen: Knowledge, use and overdose risk in urban patients consulting their general practitioner. A prospective, descriptive and transversal study].

Therapie 2017 Sep 20;72(4):453-463. Epub 2017 Feb 20.

Laboratoire de pharmacologie clinique et toxicologie, centre régional de pharmacovigilance de Lorraine, hôpital Central, CHRU de Nancy, 29, avenue du Maréchal-de-Lattre-de-Tassigny, CO 60034, 54035 Nancy, France.

Introduction: Acetaminophen is the most involved active substance in both unintentional and intentional drug poisoning. However, its availability outside community pharmacies is being debated in France.

Methods: We made, via a self-administered questionnaire, a prospective assessment of knowledge, use and acetaminophen overdose risk in patients consulting their general practitioner, in the Metz Métropole urban area, between May 2015 and February 2016. We estimated the prevalence of potential unintentional overdosage by capture-recapture method.

Results: Among 819 responding patients, only 17.9 % had a sufficient knowledge and 20.3 % were at risk for potential unintentional overdose. The risk was higher for patients aged over 55 years or belonging to socioprofessional categories of laborers and inactive. A good knowledge score was a protective factor for overdose risk (P<0.0001). The liver toxicity of acetaminophen was particularly unknown. The prevalence of potential unintentional acetaminophen overdose was estimated at 1 to2 % of the population.

Conclusion: Proposing acetaminophen outside of pharmacies cannot be recommended in France in such conditions. Information campaigns are needed to limit the risk of unintentional overdose and its consequences on liver toxicity.
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http://dx.doi.org/10.1016/j.therap.2016.12.012DOI Listing
September 2017

Opioid substitution therapy or hidden opioids are a minefield for nalmefene: an atypical case series of 11 patients in Lorraine.

Fundam Clin Pharmacol 2017 Oct 9;31(5):574-579. Epub 2017 May 9.

Centre Régional de Pharmacovigilance de Lorraine, Laboratoire de Pharmacologie Clinique et de Toxicologie, CHRU de Nancy, Hôpital Central, 29 avenue du Maréchal de Lattre de Tassigny, CO 60034, 54035, Nancy cedex, France.

Opioid antagonists such as naltrexone and nalmefene are used in drug therapy for alcoholism. Nalmefene, approved in Europe in February 2013 for the reduction of alcohol consumption, is used in patients with alcohol dependence. We report 11 cases of opioid withdrawal syndrome after a single dose of nalmefene in patients usually treated with methadone, buprenorphine, but also with fentanyl or loperamide. Nalmefene is both a partial agonist and an antagonist of opioid receptors. Regarding to its opioid antagonist activity, nalmefene is contraindicated in patients with an opioid treatment. Therefore, when prescribing or delivering nalmefene, healthcare professionals need to be vigilant about any type of opioid exposure, even masked or hidden, to avoid these potential life-threatening syndromes.
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http://dx.doi.org/10.1111/fcp.12286DOI Listing
October 2017

Serious adverse drug events related to non-investigational drugs in academic clinical trials: another source of safety data for risk assessment?

Br J Clin Pharmacol 2016 10 13;82(4):1069-75. Epub 2016 Jul 13.

Centre Régional de Pharmacovigilance de Lorraine, Laboratoire de Pharmacologie Clinique et de Toxicologie Hôpital Central, 29 avenue du Maréchal de Lattre de Tassigny CO 60034, 54035, Nancy cedex.

Aims: Sponsors of clinical trials have to analyze serious adverse events (SAEs). Both sponsors and investigators determine the relationship between the investigational medicinal product, the investigational device or procedure and SAEs. SAEs related to another cause, such as a non-investigational medicinal product (NIMP), do not have clear pharmacovigilance reporting requirements. The aim of this study was to evaluate the amount and the nature of NIMP-related SAEs recorded by three French academic sponsors and to propose pharmacovigilance requirements for these cases.

Methods: This was a retrospective descriptive study including all cases of NIMP-related SAEs occurring in clinical trials and reported to three academic sponsors between January 2009 and October 2014.

Results: Among 5870 cases of SAEs, 300 (5%) were related to a NIMP in 50 clinical trials. Involved NIMPs were mainly antithrombotics, cytostatics and immunosuppressants. Some of these drugs were currently followed by a risk management plan (e.g. rivoxaban). The most frequent NIMP-related SAEs were neurological, gastrointestinal and infectious disorders. Seven NIMP-related SAEs were known as 'rare' or 'very rare' and two were 'unlabelled'.

Conclusions: As far as we know, this is the first study to focus about NIMP-related SAEs occurring in clinical trials. This work highlights the potential high quality source of safety data via NIMP-related SAE collection. Globally, we propose that NIMP-related SAEs occurring in clinical trials should systematically be notified to the pharmacovigilance system of the concerned country. Clearer procedures of interactions between safety units of academic sponsors and pharmacovigilance systems are needed to allow an effective recording of NIMP-related SAEs.
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http://dx.doi.org/10.1111/bcp.13035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137832PMC
October 2016

Acute withdrawal syndrome after discontinuation of a short analgesic treatment with tramadol.

Therapie 2016 Jun 17;71(3):347-8. Epub 2016 Mar 17.

Centre régional de pharmacovigilance de Lorraine, CHRU de Nancy, 54000 Nancy, France.

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http://dx.doi.org/10.1016/j.therap.2015.11.007DOI Listing
June 2016