Adverse drug reaction related to drug shortage: A retrospective study on the French National Pharmacovigilance Database.

AIM: Drug shortages are a growing global health issue. The aim of the study was to evaluate the consequences of drug shortages on patient safety based on data recorded in the French National Pharmacovigilance Database. METHODS: All cases involving drug shortages reported from 1985 to the end of 2019 were extracted from the database. RESULTS: Following the selection process, 462 cases were included. The number of cases increased significantly from 2004 to 2019. Cases mainly involved drugs from the nervous system (22.1%, 95% confidence interval [CI] 17.5-27.0%), the cardiovascular system (16.4%, 95% CI 11.9-21.4%) and anti-infectives for systemic use (14.3%, 95% CI 9.7-19.2%) ATC classes. Most of the cases reported an adverse drug reaction (ADR) belonging to the SOC nervous system (21%, 95% CI 18-24%), skin and subcutaneous (14%, 95% CI 11-17%), general (13%, 95% CI 10-17%) and gastrointestinal (8%, 95% CI 5-11%) disorders. Disease worsening was observed in 15.9% of the cases, mostly related to a lack of efficacy of the replacement drug. Half of the cases were considered as serious. Evolution was favourable in 79.4% of the cases. Death and/or life-threatening situations were reported in 5.8% of the cases. Medication errors (MEs) were identified in 51 cases (11%), mostly occurring at the administration step and involving a human factor. CONCLUSION: This study emphasizes the clinical impact of drug shortage in terms of ADRs, ME and inefficiency. These observations underline the importance of a global health policy programme to limit the occurrence of drug shortages and to reinforce the information provided to patients and health care professionals in this context to limit risk.

On the Road Toward More Efficient Biocompatible Two-Photon Excitable Fluorophores.

Red-to-NIR absorption and emission wavelengths are key requirements for intravital bioimaging. One of the way to reach such excitation wavelengths is to use two-photon excitation. Unfortunately, there is still a lack of two-photon excitable fluorophores that are both efficient and biocompatible. Thus, we design a series of biocompatible quadrupolar dyes in order to study their ability to be used for live-cell imaging, and in particular for two-photon microscopy. Hence, we report the synthesis of 5 probes based on different donor cores (phenoxazine, acridane, phenazasiline and phenothiazine) and the study of their linear and non-linear photophysical properties. TD-DFT calculations were performed and were able to highlight the structure-property relationship of this series. All these studies highlight the great potential of three of these biocompatible dyes for two-photon microscopy, as they both exhibit high two-photon cross-sections (up to 3650 GM) and emit orange to red light. This potential was confirmed through live-cell two-photon microscopy experiments, leading to images with very high brightness and contrast.

Cellular Detection of a Mitochondria Targeted Brominated Vinyl Triphenylamine Optical Probe (TP-Br) by X-Ray Fluorescence Microscopy.

Triphenylamine (TP) derivatives such as two-branch cationic vinylbenzimidazolium triphenylamine TP-2Bzim are promising turn-on fluorescent probes suitable for two-photon imaging, labelling mitochondria in live cells. Here, we designed two TP-2Bzim derivatives as bimodal probes suitable for X-ray fluorescence imaging. The conjugation of the TP core with a rhenium tricarbonyl moiety in the TP-RePyta probe altered the localisation in live cells from mitochondria to lysosomes. The introduction of bromine on the TP core generated the TP-Br probe retaining good photophysical properties and mitochondria labelling in live cells. The influence of calcium channels in the uptake of TP-Br was studied. Synchrotron Radiation X-ray Fluorescence (SXRF) imaging of bromine enabled the detection of TP-Br and suggested a negligible presence of the probe in an unbound state in the incubated cells, a crucial point in the development of these probes. This study paves the way towards the development of TP probes as specific organelle stainers suitable for SXRF imaging.

Immune checkpoint inhibitors-induced nephropathy: a French national survey.

Immune checkpoint inhibitors (ICIs), aiming to foster cancer-targeted immune response, proved to be effective in several advanced malignancies at the price of immune-related adverse events affecting various organs, notably the kidneys. Herein, a retrospective descriptive analysis was performed on all biopsy-confirmed cases of ICI-induced nephropathy notified to the French Pharmacovigilance database to date. Data were gathered about patients' characteristics, acute kidney injuries and histopathological features. A total of 63 biopsy-proven cases were included for analysis. Immune-related nephropathy occurred after a mean of 105.5 ± 98.6 (standard deviation) days after the introduction of the ICI. Kidney Disease: Improving Global Outcomes acute kidney injury stage 3 occurred in 36.5% of patients, and the mean peak serum creatinine was 288 µmol/L. Histopathology suggested acute tubule-interstitial nephritis in 52 patients (83%), while signs of acute tubular necrosis were found in 18 (29%) and glomerular involvement in 5 of them (8%). Another immune-related adverse event was documented in 25 patients (39.7%). Patients were treated with corticosteroids in 88.9% of cases. All in all, 27.0% fully recovered, 54.0% partially recovered, 12.7% did not recover. Rechallenge was attempted in 19 patients and one patient relapsed. Three-quarters of patients received a medication known to cause acute tubule-interstitial nephritis. The major limits of this study are those inherent to pharmacovigilance studies, such as its retrospective nature and incomplete data. Although it cannot pretend drawing any pathophysiological conclusion, this study depicts the clinical and histopathological pictures of ICI-induced nephropathies in a large cohort of biopsied patients with all grades of severity.

Modulation of Cellular Fate of Vinyl Triarylamines through Structural Fine Tuning: To Stay or Not To Stay in the Mitochondria?

Mitochondria are involved in many cellular pathways and dysfunctional mitochondria are linked to various diseases. Hence efforts have been made to design mitochondria-targeted fluorophores for monitoring the mitochondrial status. However, the factors that govern the mitochondria-targeted potential of dyes are not well-understood. In this context, we synthesized analogues of the TP-2Bzim probe belonging to the vinyltriphenylamine (TPA) class and already described for its capacity to bind nuclear DNA in fixed cells and mitochondria in live cells. These analogues (TP-1Bzim, TPn -2Bzim, TP1+ -2Bzim, TN-2Bzim) differ in the cationic charge, the number of vinylbenzimidazolium branches and the nature of the triaryl core. Using microscopy, we demonstrated that the cationic derivatives accumulate in mitochondria but do not reach mtDNA. Under depolarisation of the mitochondrial membrane, TP-2Bzim and TP1+ -2Bzim translocate to the nucleus in direct correlation with their strong DNA affinity. This reversible phenomenon emphasizes that these probes can be used to monitor ΔΨm variations.

Assessment of drug-drug interaction in an elderly human immunodeficiency virus population: Comparison of 3 expert databases.

AIMS: Polypharmacy increase the risk of drug-drug interactions (DDIs) in the elderly population living with human immunodeficiency virus (HIV). Several expert databases can be used to evaluate DDIs. The aim of the study was to describe actual DDIs between antiretroviral drugs and comedications in an elderly population and to compare grading of the DDIs in 3 databases. METHODS: All treatments of HIV-infected subjects aged 65 years and older were collected in 6 French HIV centres. Summary of Product Characteristic (SPC), French DDI Thesaurus (THES), and Liverpool HIV DDI website (LIV) were used to define each DDI and specific grade. DDIs were classified in yellow flag interaction (undefined grade in SPC and THES or potential weak interaction in LIV), amber flag interaction (to be considered/precaution of use in SPC and THES and potential interaction in LIV) and red flag interaction (not recommended/contraindication in SPC and THES and do not administer/contraindication in LIV). RESULTS: Among 239 subjects included, 60 (25.1%) had at least 1 DDI for a total of 126 DDIs: 23/126 red flag DDIs were identified in 17 patients. All these 23 DDIs were identified in LIV. THES and SPC missed 6 and 1 red flag DDIs, respectively. Seven of 23 red flag DDIs were identified in the 3 databases concomitantly. CONCLUSION: Polypharmacy is frequent in this elderly HIV population leading to DDI in a quarter of the subjects. The discrepancies between databases can be explained by differences in analysis methods. A consensus between databases would be helpful for clinicians.

Fluorescent Biosensor for Detection of the R248Q Aggregation-Prone Mutant of p53.

The p53 tumour suppressor and guardian of the genome undergoes missense mutations that lead to functional inactivation in 50 % of human cancers. These mutations occur mostly in the DNA-binding domain of the protein, and several of these result in conformational changes that lead to amyloid-like protein aggregation. Herein, we describe a fluorescent biosensor that reports on the R248Q mutant of p53 in vitro and in living cells, engineered through conjugation of an environmentally sensitive probe onto a peptide derived from the primary aggregation segment of p53. This biosensor was characterised both in vitro and by means of fluorescence microscopy following facilitated delivery into cultured cells. It is shown that this biosensor preferentially reports on the p53 R248Q mutant in the PC9 lung cancer cell line compared with other lung cancer cell lines harbouring either wild-type or no p53.

Selectivity of Terpyridine Platinum Anticancer Drugs for G-quadruplex DNA.

Guanine-rich DNA can form four-stranded structures called G-quadruplexes (G4s) that can regulate many biological processes. Metal complexes have shown high affinity and selectivity toward the quadruplex structure. Here, we report the comparison of a panel of platinum (II) complexes for quadruplex DNA selective recognition by exploring the aromatic core around terpyridine derivatives. Their affinity and selectivity towards G4 structures of various topologies have been evaluated by FRET-melting (Fluorescence Resonance Energy Transfert-melting) and Fluorescent Intercalator Displacement (FID) assays, the latter performed by using three different fluorescent probes (Thiazole Orange (TO), TO-PRO-3, and PhenDV). Their ability to bind covalently to the c-myc G4 structure in vitro and their cytotoxicity potential in two ovarian cancerous cell lines were established. Our results show that the aromatic surface of the metallic ligands governs, in vitro, their affinity, their selectivity for the G4 over the duplex structures, and platination efficiency. However, the structural modifications do not allow significant discrimination among the different G4 topologies. Moreover, all compounds were tested on ovarian cancer cell lines and normal cell lines and were all able to overcome cisplatin resistance highlighting their interest as new anticancer drugs.

Diabetes knowledge in adolescents with type 1 diabetes and their parents and glycemic control.

OBJECTIVE: To evaluate diabetes knowledge and skills (DKS) in adolescents (>10 year) with type 1 diabetes (T1D) and their parents, and its effect on glycemic control. METHODS: A ready-to-use program and a standardized questionnaire comprising 50 true-false questions based on this program, were elaborated by a National Committee, to help dispensing education at diagnosis of T1D. The questionnaire was completed by 2933 T1D patients (49% girls, 51% boys; 14.1 ± 2.5 year), 2180 mothers and 798 fathers, in 115 pediatric centers. Associations between DKS score (number of correct answers), glycated hemoglobin (HbA1c) and sociofamilial characteristics were assessed. RESULTS: DKS score increased with age, and was higher in girls than in boys and in mothers than in fathers; it correlated strongly between adolescents and their own parents; it was higher when adolescents had previously participated in diabetes camp and when parents had higher academic levels. HbA1c decreased significantly with parents' higher DKS score and academic level, and when both parents lived together. Mean adolescent DKS score was significantly higher in patients with HbA1c below 8% or 8.5% than for patients with HbA1c above these thresholds. CONCLUSION: A large survey in T1D children and adolescents and their parents showed associations between DKS and glycemic control, and the major role of sociofamilial factors.

Identification of human telomerase assembly inhibitors enabled by a novel method to produce hTERT.

Telomerase is the enzyme that maintains the length of telomeres. It is minimally constituted of two components: a core reverse transcriptase protein (hTERT) and an RNA (hTR). Despite its significance as an almost universal cancer target, the understanding of the structure of telomerase and the optimization of specific inhibitors have been hampered by the limited amount of enzyme available. Here, we present a breakthrough method to produce unprecedented amounts of recombinant hTERT and to reconstitute human telomerase with purified components. This system provides a decisive tool to identify regulators of the assembly of this ribonucleoprotein complex. It also enables the large-scale screening of small-molecules capable to interfere with telomerase assembly. Indeed, it has allowed us to identify a compound that inhibits telomerase activity when added prior to the assembly of the enzyme, while it has no effect on an already assembled telomerase. Therefore, the novel system presented here may accelerate the understanding of human telomerase assembly and facilitate the discovery of potent and mechanistically unique inhibitors.

TP-2Rho Is a Sensitive Solvatochromic Red-Shifted Probe for Monitoring the Interactions between CDK4 and Cyclin†D.

Understanding the intricate steps of protein kinase regulation requires characterization of protein-protein interactions between the catalytic subunit, its regulatory partners and the substrate. Fluorescent probes are useful tools with which to study such interactions and to gain insight into their affinities and specificities. Solvatochromic probes, which display changes in their fluorescence emission in response to changes in the polarity of the medium, are particularly attractive. Here we describe conjugation of a switchable fluorescent dye, TP-2Rho, to peptide and protein derivatives of cyclin-dependent kinase 4 (CDK4) and its application to characterization of the interactions between the catalytic subunit of this kinase, its regulatory partner cyclin D1 and a peptide substrate. We demonstrate the sensitivity of TP-2Rho in relation to of those other dyes used for monitoring peptide-protein and protein-protein interactions. Moreover, we show that TP-Rho-labelled peptides can be introduced into living cells to probe endogenous CDK4/cyclin D.

[Pregnancy outcome after preconceptional exposure to methotrexate for ectopic pregnancy]. / Méthotrexate pour grossesse extra-utérine : quels risques en cas de nouvelle grossesse ?

INTRODUCTION: Methotrexate (MTX) is a known teratogenic drug used off-label in the treatment of ectopic pregnancies (EP). As MTX polyglutamated derivatives remains into the cells during several weeks, it is recommended to avoid conception during 3 to 6 months following MTX therapy. We report the follow-up of pregnancies after preconceptional exposure to MTX for EP. MATERIAL/METHODS: Prospective cases of pregnancy occurring within 3 months after MTX injection for an EP recorded in the Terappel database were analyzed. RESULTS: Data were obtained on 52 pregnant women. The median age of patients was 28 (18-38), and the median gestational age at inclusion was 7 weeks after last menstrual period (3-22). The time between the last MTX injection and conception ranged from 12 days to 13 weeks and the total MTX dose was between 40 to 210mg. Out of 45 pregnancies with known outcome, there were 39 live births (87%), 3 spontaneous abortions (6.7%) occurring 63 to 94 days after MTX administration, 2 elective terminations, and 1 medical termination after premature rupture of membranes, oligohydramnios and arthrogryposis (48mg of MTX 9 and 8 weeks before conception). Two additional cases of major malformations were observed among 40 examinable babies or fetuses: tetralogy of Fallot (MTX 6 weeks before conception), and cerebral ventriculomegaly with normal karyotype (50mg of MTX 9 to 13 weeks before conception). The resulting rate of major malformations was 7.5% (95% CI: 1.6-20.4). DISCUSSION/CONCLUSION: Although this prospective study shows a major malformation rate higher than expected in the general population, the observed malformations are not consistent with the typical pattern of methotrexate embryopathy. However, the case of tetralogy of Fallot is reminiscent of previously published cases with MTX exposure during early pregnancy. Owing to the small sample size, more powerful studies are needed to confirm or refute these findings.

Thrombocytopenic Purpura Associated with Dietary Supplements Containing Citrus Flavonoids.

We report a case of thrombocytopenic purpura associated with the intake of two dietary supplements containing mainly citrus flavonoids. This is the first case to be notified to the French Agency for Food, Environmental and Occupational Health Safety (ANSES). It addresses the importance of an accurate medication history interview for each patient.

Changes in insulin therapy regimens over 10 yr in children and adolescents with type 1 diabetes attending diabetes camps.

OBJECTIVE: To describe the changes in insulin therapy regimens of children and adolescents with type 1 diabetes over 10 yr and their correlation with hemoglobin A1c (HbA1c). RESEARCH DESIGN AND METHODS: The study included 7206 children and adolescents (age 12.8 ± 2.7 yr, more than 1 yr of diabetes duration) admitted in summer camps between 1998 and 2007 (707-896/yr). Based on injection times (breakfast, lunch, afternoon, dinner, bedtime) and insulin types (short, long and premixed; human or analog), 786 different therapeutic combinations were classified in six main types of regimens. The distribution of the different regimens and their correlation with HbA1c were evaluated as a function of year and age. RESULTS: Over 10 yr, basal bolus increased from 13 to 52% and the pump from <1 to 13%, regimens with two to three injections per day decreased from 50 to 25%, those with only premixed insulins from 33 to 7%, and diverse regimens from 9 to 1%. HbA1c was significantly higher with premixed insulin only, but there were no differences between the other regimens throughout the follow-up. Mean yearly HbA1c (8.21-8.45%) did not show any significant decrease, but the percentage of patients with HbA1c > 9 and 10% decreased significantly, in those treated with two to three injections and the pump, not with basal bolus or premixed only regimens. CONCLUSION: A major trend in intensifying insulin treatment in children and adolescents with type 1 diabetes was accompanied by modest improvements in HbA1c. No insulin regimen has shown any better results, except over premixed insulins.

Suspicion of fenofibrate-related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a case report.

We describe a DRESS syndrome induced by fenofibrate. This side effect, rarely described with fenofibrate, should be known by clinicians to stop it immediately and avoid serious complications.

Cross-reactivity among and between macrolides, lincosamides, and streptogramins: Study on the French pharmacovigilance database.

BACKGROUND: Hypersensitivity reactions (HSR) are reported for the macrolides, lincosamides, and streptogramins (MLS) antibiotic family. Data about cross-reactivity among and between MLS remain scarce or controversial. OBJECTIVES: The aim of this study was to provide an overview of hypersensitivity cross-reactions among MLSs based on data extracted from the French National Pharmacovigilance Database (FPVD). METHODS: Cases of HSR to MLSs reported between January 1985 and December 2019 were extracted from the FPVD using standardized MedDRA queries (SMQ). Cases including an allergological test involving multiple MLSs and giving at least one positive result were included. RESULTS: Of the 8394 cases reviewed, 149 were included. HSR mainly involved pristinamycin (n = 83; 53.2%) and spiramycin (n = 31; 19.9%). HSR to MLS was immediate in 54 cases and delayed in 94 cases. Skin tests represented the majority of the allergological tests performed (n = 728; 84.7%), followed by reintroduction tests (n = 79; 9.2%). Eighty-six cross-reactivities among MLS were identified in 62 cases (41.6%). All the 25 explorations performed for streptogramins showed cross-reactivities, but only 30/253 among macrolides (11.9%). Cross-reactivities between the three MLS were observed in 31/322 (9.6%) of the allergological explorations. CONCLUSION: This study highlights the possibility of cross-reactivity among and between MLSs. Dermatologists and allergologists managing patients with HSR to MLSs should be aware of a risk of cross-reactivity among the macrolides and between the different classes of MLS and to perform MLSs allergological testing before recommending an alternative antibiotic, especially in severe drug hypersensitivity from the MLS family.

Adverse drug effect in the context of drug shortage: the CIRUPT prospective study from the French pharmacovigilance network.

OBJECTIVES: Drug shortages are of increasing concern to worldwide public health. The consequences of drug shortages for patient safety have been little studied, especially from a pharmacovigilance point of view. In this context, the network of French pharmacovigilance centres conducted the CIRUPT study (Conséquences Iatrogènes des RUPTures de stock/iatrogenic consequences of drug shortages) based on a prospective campaign of adverse effects occurring in the context of drug shortage notifications. METHODS: All notifications involving a shortage drug submitted to the French pharmacovigilance centres between 1 January 2020 and 30 June 2021 were collected and registered in the French national pharmacovigilance database with the standardised high level term 'product supply and availability issues' and with predefined keywords in the narrative section. RESULTS: 224 cases were included, involving mainly adverse drug reactions (ADRs) (n=131/224, 59%) and medication errors (n=51/224, 23%); 29% of the cases were serious. The most represented classes of shortage drugs were: vaccines (n=78/224, 35%); drugs for acid-related disorders (H2-receptor antagonists) (n=27/224, 12%); antineoplastic agents (n=17/224, 8%); and antiepileptics (n=15/224, 7%). In 82% of cases, the involved shortage drug was the subject of information delivered to health professionals by the National Agency for the Safety of Medicines and Health Products. Drug shortages were associated with an ADR related to replacement drugs in 59% (n=131/224) of the cases, drug inefficacy in 18% (n=41/224), and/or an aggravation of the underlying disease in 11% (n=25/224). CONCLUSIONS: From a pharmacovigilance point of view, a large diversity of anatomical therapeutic classes is involved and the risk related to drug shortages is not limited to drugs registered on 'major therapeutic interest or essential drug' lists. Information from health agencies is not sufficient to avoid the risks, and further strategies should be developed.

Ultrabright two-photon excitable red-emissive fluorogenic probes for fast and wash-free bioorthogonal labelling in live cells.

Fluorogenic bioorthogonal reactions are promising tools for tracking small molecules or biomolecules in living organisms. Two-photon excitation, by shifting absorption towards the red, significantly increases the signal-to-noise ratio and decreases photodamage, while allowing imaging about 10 times deeper than with a confocal microscope. However, efficient two-photon excitable fluorogenic probes are currently lacking. We report here the design and synthesis of fluorogenic probes based on a two-photon excitable fluorophore and a tetrazine quenching moiety. These probes react with bicyclo[6.1.0]no-4-yn-9ylmethanol (BCN) with a good to impressive kinetic rate constant (up to 1.1 × 103 M-1 s-1) and emit in the red window with moderate to high turn-on ratios. TDDFT allowed the rationalization of both the kinetic and fluorogenic performance of the different probes. The best candidate displays a 13.8-fold turn-on measured by quantifying fluorescence intensities in live cells under one-photon excitation, whereas a value of 3 is sufficient for high contrast live-cell imaging. In addition, live-cell imaging under two-photon excitation confirmed that there was no need for washing to monitor the reaction between BCN and this probe since an 8.0-fold turn-on was measured under two-photon excitation. Finally, the high two-photon brightness of the clicked adduct (>300 GM) allows the use of a weak laser power compatible with in vivo imaging.

Renal Safety Profile of BCR-ABL Tyrosine Kinase Inhibitors in a Real-Life Setting: A Study Based on Vigibase®, the WHO Pharmacovigilance Database.

BACKGROUND: Alongside their BCR-ABL specificity, TKIs used in chronic myeloid leukemia also target other tyrosine kinases expressed in the kidney such as PDGFR, c-KIT, SRC, and VEGFR, which may result in specific renal adverse drug reaction (ADR). To evaluate the renal safety profile in real-life conditions, a case/non-case study was performed on VigiBase®, the WHO global safety database. METHODS: From 7 November 2001 to 2 June 2021, all cases in which the involvement of imatinib, dasatinib, nilotinib, bosutinib, and ponatinib was suspected in the occurrence of renal ADR were extracted from VigiBase®. Disproportionality analyses were assessed using the reporting odds ratio. RESULTS: A total of 1409 cases were included. Imatinib accounts for half of the reported cases. A signal of disproportionate reporting (SDR) of renal failure and fluid retention was found for the five TKIs. Only dasatinib and nilotinib were related to an SDR for nephrotic syndrome. Nilotinib and ponatinib were related to an SDR for renal artery stenosis, while dasatinib was related to an SDR for thrombotic microangiopathy. No SDR for tubulointerstitial nephritis was observed. CONCLUSION: This study identified a new safety signal, nephrotic syndrome, for nilotinib and highlights the importance of post-marketing safety surveillance.

Recommendations for age-appropriate education of children and adolescents with diabetes and their parents in the European Union.

Education is the keystone of diabetes care, and structured self-management education is the key to a successful outcome. Existing guidelines provide comprehensive guidance on the various aspects of education and offer general and organizational principles of education, detailed curricula at different ages and stages of diabetes, and recommendations on models, methods, and tools to attain educative objectives. The International Society for Pediatric and Adolescent Diabetes guidelines give the most elaborate and detailed descriptions and recommendations on the practice of education, which other national guidelines address on specific aspects of education and care. The aim of the work package on education developed by Better Control in Paediatric and Adolescent Diabetes in the European Union: Working to Create Centers of Reference (SWEET) project was not to generate new guidelines but to evaluate how the existing guidelines were implemented in some pediatric diabetes reference centers. The SWEET members have completed a questionnaire that elaborates on the many aspects of delivery of education. This survey highlights a profound diversity of practices across centers in Europe, in terms of organization as well as the practices and the content of initial and continuing education. A toolbox is being developed within SWEET to facilitate exchanges on all aspects of education and to establish a process of validation of materials, tools, written structured age-adjusted programs, and evaluation procedures for the education of children and adolescents with diabetes.