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Xenobiotics can interact with cytochromes P450 (CYPs), resulting in drug–drug interactions, but CYPs can also contribute to drug–disease interactions, especially in the case of inflammation, which downregulates CYP activities through pretranscriptional and posttranscriptional mechanisms. Interleukin‐6 (IL‐6), a key proinflammatory cytokine, is mainly responsible for this effect. The aim of our study was to develop a physiologically based pharmacokinetic (PBPK) model to foresee the impact of elevated IL‐6 levels in combination with drug interactions with esomeprazole on CYP3A and CYP2C19. Data from a cohort of elective hip surgery patients whose CYP3A and CYP2C19 activities were measured before and after surgery were used to validate the accurate prediction of the developed models. Successive steps were to fit models for IL‐6, esomeprazole, and omeprazole and its metabolite from the literature and to validate them. The models for midazolam and its metabolite were obtained from the literature. When appropriate, a correction factor was applied to convert drug concentrations from whole blood to plasma. Mean ratios between simulated and observed areas under the curve for omeprazole/5‐hydroxy omeprazole, esomeprazole, and IL‐6 were 1.53, 1.06, and 0.69, respectively, indicating an accurate prediction of the developed models. The impact of IL‐6 and esomeprazole on the exposure to CYP3A and CYP2C19 probe substrates and respective metabolites were correctly predicted. Indeed, the ratio between predicted and observed mean concentrations were

BACKGROUND: Dexamethasone is widely used for the prevention of postoperative nausea and vomiting (PONV) but little is known about its efficacy for the treatment of established PONV.OBJECTIVE: To test the antiemetic efficacy of intravenous dexamethasone for the treatment of established PONV in adults undergoing surgery under general anaesthesia and to determine whether there is dose-responsiveness.DESIGN: The DexPonv trial is a multicentre, placebo-controlled, randomised, double-blind, dose-finding study. Inclusion of patients was between September 2012 and November 2017. Follow-up for PONV symptoms was for 24 h. Thirty days postoperatively, patients were contacted by study nurses for any information on postoperative bleeding and infection.SETTING: Four public hospitals in Switzerland.PATIENTS: A total of 803 adults scheduled for elective surgery without any antiemetic prophylaxis signed the consent form; 714 were included. Among those, 319 had PONV and 281 patients were eventually randomised (intention to treat population and safety set). The per protocol set consisted of 260 patients.INTERVENTIONS: Patients with PONV symptoms (including retching) were randomised to a single intravenous dose of dexamethasone 3, 6 or 12 mg or matching placebo.MAIN OUTCOME MEASURES: The primary endpoint was the absence of further nausea or vomiting (including retching), within 24 h after administration of the study drug.RESULTS: Dexamethasone was ineffective during the first 24 h, whatever the dosage, compared to placebo, even when the model was adjusted for known risk factors (P = 0.170). There were no differences in the time to treatment failure or the quality of sleep during the first night. There was a positive correlation between the dose of dexamethasone and blood glucose concentrations (P CONCLUSION: This randomised trial failed to show antiemetic efficacy of any of the tested intravenous regimens of dexamethasone for the treatment of established PONV in adults undergoing surgery under general anaesthesia.TRIAL REGISTRATION: clinicaltrials.gov (NCT01975727).

La population pédiatrique est considérée comme vulnérable, et la prise en charge de la douleur nociceptive y est parfois complexe mais essentielle. Depuis 2013, la prescription de codéine est restreinte chez les enfants en raison du risque de dépression respiratoire parfois fatale lié à l’activité variable du cytochrome P450 (CYP) 2D6 qui bioactive la codéine en morphine. Les options thérapeutiques approuvées chez l’enfant sont limitées, et pour nombre de prescripteurs, le tramadol est devenu l’alternative de choix à la codéine. Le tramadol est cependant, comme la codéine, un promédicament opioïde qui doit être bioactivé par le CYP2D6. Il est donc également soumis à une importante variabilité de sa réponse et expose les enfants aux mêmes risques de complications respiratoires. La décision de traiter par tramadol doit prendre en compte les comédications, les comorbidités du patient, le type de douleur et les conditions de surveillance. Les soignants et les parents doivent être informés des risques liés à l’administration du tramadol, notamment la variabilité interindividuelle, les risques d’interactions médicamenteuses et les signes de surdosage. Dans les situations de douleurs récurrentes, une approche personnalisée, avec adaptation des doses et sélection du médicament antalgique en fonction de l’activité du CYP2D6, est certainement la méthode la plus sûre. Lorsque l’activité du CYP2D6 n’est pas connue, la prescription de tramadol reste envisageable si le traitement est initié à la dose minimale efficace, titré sous surveillance et administré sous une forme posologique adaptée à l’enfant. Chez l’enfant de moins de 12 ans et en présence de facteurs de risque de dépression respiratoire, la morphine reste une option prudente, puisque son métabolisme ne dépend pas du CYP2D6.

Background and objective Having to deal on a daily routine with prescriptions in adults with intellectual disability (ID), we systematically reviewed the literature on the specificities of pain interventions in that population, focusing on medication and trying to gather practical information on appropriate pain treatments. Given the scarcity of the literature on the topic, we also discussed the pharmacological considerations to be taken into account when prescribing analgesic drugs in that vulnerable population. Databases and data treatment Articles on pain and ID were searched in the Medline and Google scholar electronic databases using the key words "Intellectual Disability," "Developmental Disability" and specific keywords for pharmacological and non-pharmacological pain interventions. Preset outcomes about pharmacological treatment specificity, efficacy and safety were then collected. Results One hundred and fifty-two articles were found and 16 were retained based on our inclusion and exclusion criteria. Of the 16 articles, five were topical reviews. Among the 11 remaining articles, five discussed pharmacological interventions, four considered non-pharmacological interventions and two discussed both. As anticipated, the literature matching our specific outcomes about the pharmacological treatment of pain was scarce and for the most part not designed to answer the questions of specificity, efficacy and safety of pain treatment in adults with ID. Conclusion The specificity of analgesic treatments in adults with ID is a totally unexplored domain. In the absence of clinical guidelines, pharmacological facts-such as inter-individual variability in drug response, pharmacokinetic and pharmacodynamic interactions, frequent co-morbidities and ease of administration-must be systematically integrated, when prescribing in the population of adults with ID. Significance This review synthesizes the state of research on pain interventions in adults with ID and is one of the rare articles addressing the specificities of analgesic prescriptions in this population.

BACKGROUND Busulfan (Bu) is one of the conditioning regimen components for pediatric hematopoietic stem cell transplantation. Bu therapeutic drug monitoring (TDM) is essential for a successful treatment outcome and toxicity evasion. Dried blood spot (DBS) sampling is a rapid and simple method for Bu TDM, compared with conventional plasma sampling. This study evaluated the feasibility of using the DBS method for Bu TDM. The hematocrit (Hct) and conditioning day were also examined for their impact on the DBS method's performance. METHODS Venous blood collected from 6 healthy volunteers was diluted, using their plasma into 4 samples of varying Hct values. Each sample was spiked with Bu calibrators (300, 600, and 1400 ng/mL), prepared using DBS and dried plasma spot (DPS) sampling and analyzed using a validated liquid-chromatography tandem-mass spectrometry method. Clinical blood samples (n = 153) from pediatric patients (n = 15) treated with Bu (mainly from doses 1, 2, 5, and 9) were used to prepare paired volumetric DBS and DPS samples. A Bland-Altman plot and Deming regression were used to define the agreement between the paired DBS and DPS measurements. Passing-Bablok regression analyses investigated the effects of Hct and conditioning day on the linearity between both methods. RESULTS In vitro analyses showed good agreement between DBS and DPS measurements, with a mean difference of -5.4% and a 95% confidence interval on the limits of agreement of -15.3% to 4.6%. Clinical samples showed good correlation (Pearson correlation coefficient = 0.96; slope = 1.00) between the DBS and DPS methods. The DBS method met the clinical acceptance limits for clinical samples, with a bias

Background Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) is the most toxic congener of a family of structurally and mechanistically related persistent organic pollutants whose effects are mediated through the aryl hydrocarbon receptor (AhR). Induction of CYP1A1/2 by TCDD through the AhR depends on the magnitude and the duration of exposure. We aimed to assess CYP1A2 activity after acute and chronic exposure to TCDD. The Maincy cohort is a sample population from Melun in the Val-de-Seine region in France that lived for at least 5 years close to a waste incinerator emitting polluted vapours (1974-2002) with high concentrations of dioxins (up to 2000 times the maximal recommended values). Acute exposure to TCDD (Viktor Yushchenko) has been described elsewhere by Sorg et al (Toxicol. Sci. 2012; 125:310-317). Both are rare cases of well-identified source of chronic and acute exposure to TCDD. Methods All subjects underwent a full medical history and physical examination and had a cutaneous examination, and a retro-auricular skin biopsy was taken. A questionnaire was designed and used regarding demographic, personal, environmental and occupational characteristics. CYP1A2 activity was assessed 2 hours after the ingestion of a drink containing caffeine through measurement of the metabolic ratio of paraxanthine (17X) over caffeine (137X) by LC-MS/MS or LC-UV. CYP1A1 expression in skin biopsies was determined by immunohistochemical analysis. Results Forty-seven exposed subjects (age 11-78) and 31 controls were included in the study. Eleven exposed subjects had a history of thyroid disease (23.4%), and 7 (14.8%) had a cancer vs none and 1, respectively, in controls. Nodular skin lesions were found in 13 exposed subjects (27.7%) vs none in controls. Mean CYP1A2 activity of the exposed population was modestly elevated as compared to controls (17X/137X metabolic ratio of 0.475 vs 0.374, P = .051). CYP1A2 was, however, induced (17X/137X, metabolic ratio >0.5) in 27.6% of the exposed cases vs 6.4% of the controls. In contrast, acute dioxin exposure was associated with a strong induction (mean 17X/137X, metabolic ratio of 1.9) still present 29 months after the acute exposure. CYP1A1 was expressed in 59.6% of the skin biopsies (highly expressed in 31.9%) of the Maincy cohort. No correlation between CYP1A2 activity, CYP1A1 expression and clinical manifestations (thyroid disease, cancer, skin lesions) could be demonstrated. Conclusion Higher frequencies of dysthyroidism and cancer were detected in the population exposed chronically to dioxins from a waste incinerator. CYP1A2 was induced in 27.6% of the exposed population, while the magnitude of induction was fourfold higher after acute exposure in the case of Yushchenko.

Background and purpose Individualized assessment of cytochrome P450 2D6 (CYP2D6) activity is usually performed through phenotyping following administration of a probe drug to measure the enzyme's activity. In order to avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-burdensome tools for real-time phenotyping of CYP2D6 could significantly contribute to the expansion of precision medicine. This study focuses on the identification of markers of the CYP2D6 enzyme in human biofluids using a liquid chromatography-high-resolution mass spectrometry-based metabolomic approach. Experimental approach Plasma and urine samples from healthy volunteers were analysed before and after intake of a daily dose of paroxetine 20 mg over seven days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants. Key results In this study, we reported four metabolites of solanidine and two unknown compounds as possible novel CYP2D6 markers. Mean relative intensities of these features were significantly reduced during the inhibition session compared to the control session (n = 37). Semi-quantitative analysis showed that the largest decrease (-85%) was observed for the ion m/z 432.3108 normalized to solanidine (m/z 398.3417). Furthermore, mean relative intensities of these ions were significantly higher in the CYP2D6 normal-ultrarapid metabolizer group (n = 37) compared to the poor metabolizer group (n = 6). Solanidine intensity was more than 15 times higher in CYP2D6-deficient individuals compared to other volunteers. Conclusion and implications The applied untargeted metabolomic strategy identified potential novel markers capable of semi-quantitatively predicting CYP2D6 activity, a promising discovery for personalised medicine.

For the quantification of the pineal hormone melatonin and its metabolite, 6-hydroxymelatonin, in human overnight urine, a single accurate method by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed. Urine samples were deconjugated using β-glucuronidase/arylsulfatase from Helix pomatia before solid phase extraction (SPE) purification. Chromatographic separation was performed using a reverse phase C18 column with a 7-minute gradient elution. Water was used as matrix to prepare the calibration standards, and deuterated analogues of melatonin and 6-hydroxymelatonin were used as internal standards. This newly developed method was validated in terms of linearity, accuracy, repeatability, intermediate precision, recovery, matrix effect, and stability according to the guidelines of the European Medicines Agency. The method was successfully applied to the analysis of overnight urine samples from 12 healthy volunteers, showing significant correlations of urinary melatonin and 6-hydroxymelatonin excretion rates with age. The urinary 6-hydroxymelatonin to melatonin ratio was also established and will be assessed in further studies as a potential endogenous metric of CYP1A2 activity.

Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, is a severe acute respiratory syndrome with an underlying inflammatory state. We have previously demonstrated that acute inflammation modulates cytochromes P450 (CYPs) activity in an isoform‐specific manner. We therefore hypothesized that COVID‐19 might also impact CYP activity, and thus aimed to evaluate the impact of acute inflammation in the context of SARS‐CoV‐2 infection on the six main human CYPs activity. This prospective observational study was conducted in 28 patients hospitalized at the Geneva University Hospitals (Switzerland) with a diagnosis of moderate to severe COVID‐19. They received the Geneva phenotyping cocktail orally during the first 72 hours of hospitalization and after 3 months. Capillary blood samples were collected 2 hours after cocktail administration to assess the metabolic ratios (MRs) of CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. C‐reactive protein (CRP), interleukin 6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) levels were also measured in blood. CYP1A2, CYP2C19, and CYP3A MRs decreased by 52.6% (P = 0.0001), 74.7% (P = 0.0006), and 22.8% (P = 0.045), respectively, in patients with COVID‐19. CYP2B6 and CYP2C9 MRs increased by 101.1% (P = 0.009) and 55.8% (P = 0.0006), respectively. CYP2D6 MR variation did not reach statistical significance (P = 0.072). As expected, COVID‐19 was a good acute inflammation model as mean serum levels of CRP, IL‐6, and TNF‐α were significantly (P

Background Proton pump inhibitors are among the most widely prescribed drugs in the world, but more than half of the indications for prescription are unjustified. The misuse of this therapeutic class has heavy consequences such as additional health costs, adverse drug reactions following long-term use and gastric acid rebound when the proton pump inhibitor is discontinued. Objective The overprescription of proton pump inhibitors is therefore becoming a public health problem, which led us to evaluate their use within the Geneva University Hospitals. Setting Patients hospitalized in two divisions of the department of internal medicine of the Geneva University Hospitals on a single day. Methods This is a register-based cross-sectional study and it collected data about the prescription pattern of proton pump inhibitors by consulting the electronic records of patients included. Main outcome measure To determine if the proton pump inhibitors prescription is made according to the market authorization and the available guidelines. Results Hundred-eighty patients were included. 54% of patients were on proton pump inhibitors, 29% of whom had their treatment initiated at hospital. Of the indications for treatment, 72% were not justified and 63% of the justified indications did not have an adequate dosage. Therefore, in all patients with a proton pump inhibitor at hospital, only 11% had a justified indication with an adequate dose. Finally, 87% of known home prescriptions were renewed on admission and among them, 71% did not have a justified or possibly justified indication according to the guidelines. Conclusion Indication for treatment inside the hospital was not justified in 72% of patients and only 11% had a justified indication with an adequate dosage. Precise guidelines with evidence-based indications and adequate daily doses would help to correctly prescribe proton pump inhibitors. Moreover, patients should benefit from a thorough evaluation of their treatment.

Drug response is subject to an important within- and between-individual variability owing, mainly, to pharmacokinetic and pharmacodynamic factors. Pharmacokinetics includes metabolism by cytochrome P450 (CYP450), major enzymes of phase I reactions that are responsible for the biotransformation of around 60% of the currently approved drugs. CYP450 activity and/or expression are influenced by multiple intrinsic and extrinsic factors, such as drug-drug interactions or genetic polymorphisms. Present phenotyping strategies with xenobiotics used to assess CYP450 activity could be replaced by less invasive procedures using endogenous CYP450 biomarkers. In this work, we review existing knowledge on endobiotics and their ability to characterise variability of the CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes in humans. To date, it appears that there is a lack of clinical data for the majority of the endogenous compounds described in the literature or some important limitations to allow their use in clinical practice. Additional studies are needed to fill the gap or to identify new candidates, in particular through the use of metabolomics. The use of multivariate models is also a very promising approach to enhance prediction by combining several endogenous phenotyping metrics and other covariates.

Contexte: Les patients atteints de cancer sont soumis à divers traitements pharmacologiques (antinéoplasiques, analgésiques, antinauséeux et/ou anticoagulants principalement). Le risque d’augmenter la morbidité et la mortalité au travers des interactions médicamenteuses engendrées existe et est souvent prédictible. Des programmes informatisés d’aide à la détection d’interactions médicamenteuses sont utiles pour le médecin et le pharmacien, pour limiter ce risque, ils sont cependant nombreux et diffèrent tant par leur disponibilité que par les bases de données utilisées, et leurs limites d’utilisation restent souvent méconnues.Objectif: Évaluer la performance de plusieurs programmes de détection des interactions médicamenteuses.Méthode: Cinq programmes de détection des interactions médicamenteuses fréquemment cités dans la littérature (Compendium®, Thériaque, Epocrates®, Vidal et Lexi- Interact®) ont été évalués par l’analyse de 40 paires médicamenteuses préalablement définies sur la base duStockley’s Drug Interaction, ouvrage de référence. Vingt-trois paires de médicaments sans interaction décrite dans ce dernier ont en outre aussi été choisies. Les médicaments sélectionnés appartenaient principalement à des classes thérapeutiques potentiellement utilisées en oncologie. Des analyses quantitative, semi-quantitative et qualitative ont permis d’évaluer la performance de la détection des interactions à risque mais également la qualité, le contenu et l’ergonomie générale d’utilisation de chaque programme.Résultats: Tous les programmes montraient une bonne performance en termes de spécificité et de valeur prédictive positive (VPP), alors que Compendium® (73 % ; 67 %), Thériaque (68 % ; 63 %) et Vidal (60 % ; 58 %) étaient caractérisés par une sensibilité et une valeur prédictive négative (VPN) basses. L’analyse semi-quantitative a mis en avant le Compendium®, recensant davantage d’informations concernant les délais d’apparition et propositions d’intervention, et Lexi-Interact®, renseignant le plus souvent sur les effets et mécanismes des interactions à risque. Lexi-Interact ® s’est révélé être le programme le plus performant à la détection des interactions néfastes sur tous les paramètres d’intérêt (sensibilité : 98 %, spécificité : 96 %, VPP : 98 %, VPN : 96 %).Conclusion: Tous les programmes testés ont montré une bonne performance, et le Lexi-Interact® s’est révélé être le programme de détection informatisé d’interactions médicamenteuses le plus performant dans les traitements du cancer, avec notamment la meilleure spécificité, sensibilité, VPP et VPN.

Les interventions de massage permettent de diminuer les sensations liées à la douleur et surtout d’améliorer la qualité de vie des personnes confrontées à une douleur chronique. Un effet bénéfique est également relevé auprès des soignants et de l’entourage. Entre 2013 et 2017, des séances de Toucher-massage® ont été prodiguées par des infirmières formées auprès de 136 patients dans un hôpital universitaire suisse. Les commentaires spontanés des patients ont été recueillis à l’issue des séances dans un objectif d’évaluation de la satisfaction des patients et de l’amélioration de la qualité des soins. Une analyse thématique a permis de dégager trois thèmes spécifiques : le bien-être, la complicité et la gratitude. Les résultats obtenus rejoignent ceux de la littérature notamment en ce qui concerne la diminution de l’intensité de la douleur, le soulagement de différents symptômes, les sentiments de proximité avec les soignants et la valorisation de leur rôle.

Acute nociceptive pain management in children is a major public health concern. Effective and safe pain treatment is essential, but safety data cannot be simply extrapolated from adults to children due to pharmacokinetic and pharmacodynamic specificities. In addition, the frequent absence of child-specific data, the difficulty to assess drug tolerability, and the infants' inability to communicate properly and voluntarily report adverse drug reactions make children more vulnerable to safety issues. Awareness of the possible toxicity of analgesics is important but should not lead to suboptimal dosing and underuse of analgesia. A better assessment and individualization of treatment should allow effective prescribing of analgesics in more secure conditions. This article aims to review the safety of acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids in children and the precautions that should be taken.

In this study, we assessed the potential use of the 1β-hydroxy-deoxycholic acid (1β-OH-DCA) to deoxycholic acid (DCA) urinary metabolic ratio (UMR) as a CYP3A metric in ten male healthy volunteers. Midazolam (MDZ) 1 mg was administered orally at three sessions: alone (control session), after pre-treatment with fluvoxamine 50 mg (12 h and 2 h prior to MDZ administration), and voriconazole 400 mg (2 h before MDZ administration) (inhibition session), and after a 7-day pre-treatment with the inducer rifampicin 600 mg (induction session). The 1β-OH-DCA/DCA UMR was measured at each session, and correlations with MDZ metrics were established. At baseline, the 1β-OH-DCA/DCA UMR correlated significantly with oral MDZ clearance (r = 0.652, p = 0.041) and Cmax (r = −0.652, p = 0.041). In addition, the modulation of CYP3A was reflected in the 1β-OH-DCA/DCA UMR after the intake of rifampicin (induction ratio = 11.4, p &lt, 0.01). During the inhibition session, a non-significant 22% decrease in 1β-OH-DCA/DCA was observed (p = 0.275). This result could be explained by the short duration of CYP3A inhibitors intake fixed in our clinical trial. Additional studies, particularly involving CYP3A inhibition for a longer period and larger sample sizes, are needed to confirm the 1β-OH-DCA/DCA metric as a suitable CYP3A biomarker.

Background and Purpose: Individualized assessment of the activity of cytochrome P450 2D6 (CYP2D6), a highly variable drug-metabolizing enzyme, is performed through phenotyping during which a probe drug is administered to measure the enzyme’s activity. In order to avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-invasive tools for real-time phenotyping of CYP2D6 could significantly contribute to the expansion of precision medicine in clinical practice. This study focuses on the identification of endogenous markers of the CYP2D6 enzyme in human biofluids using a liquid chromatography (LC)-high-resolution mass spectrometry (HRMS)-based metabolomics approach. Experimental Approach: Data from a control session were compared to data from an inhibition session. Before the latter, healthy volunteers (extensive and ultrarapid metabolizers) received a daily dose of paroxetine 20 mg over seven days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants. Key Results: In CYP2D6 extensive and ultrarapid metabolizers (n = 37), mean relative intensities of five features were significantly reduced during the inhibition session compared to the control session (fold changes ≤ 0.67, FDR-adjusted P < 0.0001). Furthermore, mean relative intensities of these candidates were significantly higher in the CYP2D6 extensive-ultrarapid metabolizer group (n = 37) compared to the poor metabolizer group (n = 6) (fold changes ≤ 0.67, P < 0.0001). Conclusion and Implications: The applied untargeted metabolomics strategy was able to identify five CYP2D6 endogenous metabolites, a promising discovery for non-invasive phenotyping and personalised medicine.

ObjectivesAdults with an intellectual disability (AWID) are often polymedicated because of somatic and psychiatric health problems. Besides, they may display challenging behaviours, leading to off-label prescription of psychotropic drugs, without efficacy and with numerous adverse effects. In this context, a prescription/deprescription tool (Tool for Optimising Prescription in Intellectual Disability/TOP-ID) was developed to improve the care of AWID. This paper describes how TOP-ID was designed.DesignFour-step consensus-based process involving a review of the literature, eight semistructured interviews and a two-round Delphi process.SettingSeventeen general practices and university and general hospitals from Belgium, France and Switzerland.ParticipantsEighteen French-speaking physicians from different domains of expertise participated in the Delphi process.Primary and secondary outcome measuresFor the Delphi iteration process, consensus was defined as at least a 65% agreement between the experts.ResultsTwo rounds were needed for the Delphi process. Eighty-one items of the tool were submitted to 18 out of 35 recruited French-speaking experts during the first round. Sixty-nine per cent of the items reached a rate of agreement of 65% or more in that round. Thirteen questions were reformulated and resubmitted for the second Delphi iteration round. All of the statements reached a rate of agreement of 65% or more in the second round.ConclusionTOP-ID is the first prescription–deprescription tool developed specifically for AWIDs in French. It is intended to help prescribers document patient care in order to reduce prescription errors and to improve safety. The next steps of the project include the development of an electronic version of TOP-ID and a utility study.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide in both sexes. Despite considerable progress in better understanding the patterns of disease in women, they are still often undertreated and benefit less from evidence-based treatment. Hypertension is a key contributor to CVD and is also one of the most potent risk factors for heart failure in women. Even with the wide variety of available drugs, blood pressure control is globally suboptimal. Current guidelines do not suggest differential treatment of hypertension for women; however, a growing body of research suggests gender dimorphism in the pathophysiology of hypertension and pharmacological response to cardiovascular drugs. The clinical relevance of theses sex-divergent effects of drugs is still under investigation. Owing to the exponential relationship between blood pressure and cardiovascular mortality, even a modest decrease in blood pressure or therapeutic adhesion could be clinically \relevant. In this review, we explore the known pharmacological and pharmacokinetic sex differences with special attention to the main classes of antihypertensive treatment. Current data shows frequently higher drug exposures in women and more frequent adverse drug reactions in all antihypertensive drug groups. As far as cardiovascular prevention is concerned, sex-specific data is often lacking in clinical trials, highlighting the necessity to further study CVD and their treatment in both men and women.

Background Chronic pain is a significant risk factor for suicidal ideation (SI) and suicidal behavior (SB), including a 20%-40% prevalence rate of SI, a prevalence between 5% and 14% of suicide attempts, and a doubled risk of death by suicide in patients with chronic pain compared to controls. In most studies, associations between chronic pain and suicidality are robust, even after adjusting for the effect of sociodemographics and psychiatric comorbidity, and particularly for depressive conditions. A number of specific conditions that can modulate suicidality risk in patients with chronic pain have been investigated, but there is a need for their more specific characterization. Numerous recent studies have shown that demoralization and meaning in life (MiL) constructs affect suicidality as risk and protective factors, respectively. These constructs have been mainly investigated in patients with somatic illness and in community-dwelling individuals who may present with SI or SB independently of a psychiatric diagnosis of depression. However, a paucity of studies investigated them in suicidal patients affected by chronic pain. Objective The primary objective of this project is to investigate the relationship between demoralization and MiL on SI risk in patients with chronic pain. The secondary objectives are (1) to test whether demoralization can occur independently of depression in patients with chronic pain and SI, (2) to examine whether the expected association between demoralization and SI may be explained by a sole dimension of demoralization: hopelessness, (3) to examine whether the presence of MiL, but not the search for MiL, is associated with less SI, and (4) to explore whether previously described MiL profiles (ie, high presence-high search, high presence-low search, moderate presence-moderate search, low presence-low search, and low presence-high search) emerge in our cohort. Methods This project is a single-center, observational, case-control study—the Demoralization and Meaning in Life (DEMiL) study—conducted by the Division of Clinical Pharmacology and Toxicology, the Multidisciplinary Pain Centre, and the Service of Liaison Psychiatry and Crisis Intervention at the Geneva University Hospitals. Self- and hetero-administered questionnaires were conducted among patients and controls, matched by age and gender. The Ethics Committee of the Canton of Geneva approved the scientific utilization of collected data (project No. 2017-02138; decision dated January 25, 2018). Data have been analyzed with SPSS, version 23.0, software (IBM Corp). Results From March 1, 2018, to November 30, 2019, 70 patients and 70 controls were enrolled. Statistical analyses are still in progress and are expected to be finalized in November 2020. To date, we did not observe any unfavorable event for which a causal relationship with the collection of health-related personal data could be ruled out. Results of this study are expected to form the basis for possible prevention and psychotherapeutic interventions oriented toward demoralization and MiL constructs for suicidal patients with chronic pain. Conclusions The interest in exploring demoralization and MiL in chronic pain patients with SI arises from the common clinical observation that experiencing chronic pain often requires a revision of one’s life goals and expectations. Hence, the impact of chronic pain is not limited to patients’ biopsychosocial functioning, but it affects the existential domain as well. The major clinical implications in suicidal patients with chronic pain consist in trying to (1) delineate a more precise and individualized suicide risk profile, (2) improve detection and prevention strategies by investigating SI also in individuals who do not present with a clinically diagnosed depression, and (3) enhance the panel of interventions by broadening supportive or psychotherapeutic actions, taking into consideration the existential condition of a person who suffers and strives to deal with his or her suffering. International Registered Report Identifier (IRRID) DERR1-10.2196/24882

Introduction and Objective Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. Materials and Methods The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. Results A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. Conclusions In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events. Refereed/Peer-reviewed

Objective We aimed to characterize drug exposures during pregnancy where the outcome was known that had benefited from counselling through our Teratology Information Service (TIS) between 1994–2016. Study design This observational study analysed data collected through the drug exposures during pregnancy counselling. Data was analysed descriptively. Results Data from a total of 1’374 pregnant women were collected. Mean age was of 32 years. These women were exposed to more than ten drugs in 1.4 % (N = 19) of cases, with a mean drug intake of two. Analysis of the drugs altogether (N = 3′129) showed that FDA Pregnancy Category C drugs represented 42.9 % (N = 1′342) of drugs and ATC code N (nervous system) represented 36.4 % (N = 1′138). The onset of drug exposure was during the first trimester of pregnancy in 95.1 % (N = 2′982) of patients. Regarding outcomes, the rate of induced abortion was 10.8 % (N = 151), of pregnancy complications was 11.2 % (N = 157) and of malformations was 4.5 % (N = 49). Conclusion Pregnant women counselled by our TIS take a mean of two drugs, ranging from one to 17. Drugs are from FDA Pregnancy Category C and ATC N drugs in most cases, 42.9 % and 36.4 % respectively. The rate of malformation of our cohort was of 4.5 %, close to the estimated spontaneous rate of malformation. This data gives a reassuring aspect of drug exposure in pregnancy but takes into account the outcome at birth only.

Cytochromes P450 (CYP) are subject to important interindividual variability in their activity due to genetic and environmental factors and some diseases. Limited human data support the idea that inflammation downregulates CYP activities. Our study aimed to evaluate the impact of orthopedic surgery (acute inflammation model) on the activity of six human CYP. This prospective observational study was conducted in 30 patients who underwent elective hip surgery at the Geneva University Hospitals in Switzerland. The Geneva phenotyping cocktail containing caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam as probe drugs respectively assessing CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A activities was administered orally before surgery, day 1 (D1) and 3 (D3) postsurgery and at discharge. Capillary blood samples were collected 2 hours after cocktail intake to assess metabolic ratios (MRs). Serum inflammatory markers (CRP, IL‐6, IL‐1β, TNF‐α, and IFN‐γ) were also measured in blood. CYP1A2 MRs decreased by 53% (P

Resume Le syndrome du grele court (SGC) se caracterise par la presence d’un intestin grele fonctionnel dont la longueur est inferieure a 200 cm. L’absorption des medicaments ayant principalement lieu par un processus de diffusion passive, elle peut etre influencee par la surface d’absorption. Ainsi en cas de SGC, des doses plus elevees ou une administration par une autre voie peut s’averer necessaire. La presente revue a pour objectif une mise a jour des donnees de la litterature sur l’absorption des medicaments administres par voie orale en cas de SGC. Malgre une utilisation large de medicaments chez ces patients, et en raison du fait qu’il s’agit d’une maladie rare, une absence de donnees etayees a ce sujet a ete constatee, essentiellement basee sur des rapports de cas ou des etudes de petite taille. Les patients impliques etaient tres heterogenes, rendant difficile l’extrapolation des donnees publiees chez chaque patient individuel, ce qui souligne l’importance d’une anticipation, de la mise en place d’un suivi clinique et/ou biologique pour guider la pharmacotherapie chez ce type de patients.

Prasugrel and clopidogrel are inhibitors of the ADP-P2Y12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection. In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial. A significantly lower exposure to clopidogrel AM [3.2-fold lower area under the concentration–time curve (AUC) and maximum plasma concentration (Cmax)] and prasugrel AM (2.1-fold and 1.7-fold lower AUC and Cmax) were demonstrated in HIV-infected patients treated with boosted ARTs compared with healthy controls; however, a differential impact was observed on platelet inhibition between clopidogrel and prasugrel. Clopidogrel 300 mg induced adequate (although modest) platelet inhibition in all healthy subjects, while platelet inhibition was insufficient in 44% of HIV patients. On the contrary, prasugrel 60 mg induced a potent platelet inhibition in both healthy and HIV-infected subjects. Prasugrel appears to remain an adequate antiplatelet agent in HIV-infected patients and could be preferred to clopidogrel in this context, regardless of the metabolic interaction and inhibition of its bioactivation pathways.

We investigated whether CYP2D6 extensive metabolizers carrying a nonfunctional allele are at higher risk of phenoconversion to poor metabolizers in the presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully-functional alleles and 17 heterozygous carriers of one fully-functional and one nonfunctional allele participated in this trial. Dextromethorphan 5 mg and tramadol 10 mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60 mg (session 2) and paroxetine 20 mg (session 3). A higher rate of phenoconversion to intermediate metabolizers with duloxetine (71% vs. 25%, P = 0.009) and to poor metabolizers with paroxetine (94% vs. 56%, P = 0.011) was observed in heterozygous than homozygous extensive metabolizers. The magnitude of drug-drug interaction between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 vs. 8.5, P < 0.028). Our study suggests that genetic extensive metabolizers may not represent a homogenous population and that available genetic data should be considered when addressing drug-drug interactions in clinical practice.

Resume Contexte Les prescriptions medicamenteuses inappropriees comprennent les sur-prescriptions (prescription d’un medicament non indique), les prescriptions inadaptees (choix de molecules, duree, dose inadaptes, doublon, interactions medicamenteuses potentiellement nefastes, suivi inapproprie) et les sous-prescriptions (omission d’un traitement indique). Elles constituent une cause d’evenements indesirables medicamenteux evitables et sont associees a des allongements de durees d’hospitalisation, une diminution de la qualite de vie, une augmentation de la morbimortalite, ou encore a des surcouts pour les systemes de sante. Les patients geriatriques, souvent polypathologiques et polymediques, sont a haut risque de prescriptions medicamenteuses inappropriees. Depuis une vingtaine d’annee, des outils de detection de ces prescriptions ont ete developpes, afin de diminuer ces erreurs. Objectif Cette revue a pour objectifs d’apporter un apercu comparatif et une analyse critique de ces outils explicites. Sources documentaires et selection des etudes Une recherche systematique de la litterature menee dans les bases de donnees PubMed , Embase , Cochrane Library et Google Scholar , sur la periode janvier 1991–novembre 2015, utilisant la combinaison de mots-cles : « (“inappropriate prescribing” [MeSH Terms] OR “medication errors” [MeSH Terms] AND “potentially inappropriate medications” [MeSH Terms] AND “elderly” [MeSH All field] AND “explicit criteria” [MeSH Terms]) » a permis d’inclure les article rediges en anglais ou en francais, decrivant le developpement d’une nouvelle liste de criteres explicites destinee a la geriatrie. Les caracteristiques, l’organisation et le contenu de ces dernieres sont detailles, ainsi que l’evaluation de leur validite et de leur caractere optimal pour une utilisation en geriatrie. Resultats Quatorze outils ont ete identifies. Une organisation par specialites medicales et pathologies, comme dans les grilles ACOVE, Beers version 5 et STOPP/START permet une utilisation rapide des outils. La faible redondance des criteres entre les outils suggere un manque d’exhaustivite pour certains d’entre eux. Les grilles Mimica, ACOVE, PIEA, et STOPP/START sont les plus exhaustives, seules les trois dernieres abordent les problemes de sous-prescriptions. Enfin, la capacite a detecter et diminuer les prescriptions inappropriees n’a ete evaluee que pour quelques grilles, seule STOPP/START a montre, dans le cadre d’une etude prospective, sa capacite a les diminuer.

Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its Active Metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by Liquid-Liquid Extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma.

Background Rebound cholinergic syndrome is a rare, but well known unwanted phenomenon occurring after abrupt clozapine discontinuation. There have been previous reported cases of cholinergic rebound in the literature; however, these reports described cholinergic rebound following cessation of high doses of clozapine in patients diagnosed with schizophrenia. Here, we report a case of rebound cholinergic syndrome and catatonia in a male patient three days after abrupt discontinuation of 50 mg of clozapine prescribed for type I bipolar affective disorder. Case presentation A 66-year old male of Spanish origin, treated for type I bipolar affective disorder for 15 years and for Crohn disease, was brought to the emergency department because of a sudden onset of mutism, dysphagia and trismus. He was described catatonic and presented hypertension, tachycardia and tachypnea. His body temperature was normal and the laboratory tests were unremarkable at presentation. A head CT and an EEG were in the normal range. While reviewing his history, it appeared the he was on clozapine 50 mg a day, first introduced 2 months ago, during a previous hospitalization for a manic episode resistant to other mood stabilizers. For an unknown reason, the patient’s psychiatrist stopped clozapine three days before the admission and replaced it by risperidone 5 mg and quetiapine 200 mg daily. A cholinergic rebound syndrome was then evoked. The patient’s ability to speak recovered dramatically and fast after the intravenous administration of 2.5 mg of biperiden supporting the diagnosis. Risperidone and quetiapine were also stopped. The patient fully recovered in 20 days after the reintroduction of 50 mg of clozapine and 2.5 mg of biperiden daily. Conclusions This case report underscores that cholinergic rebound syndrome may occur in patients suffering from bipolar affective disorders, being on clozapine as a mood stabilizer. The low dose clozapine does not preclude severe manifestations of the phenomenon. Progressive tapering should therefore be adopted in any case.

Background Chronic pain after major lower back surgery is frequent. We investigated in adults the effect of perioperative low-dose ketamine on neuropathic lower back pain, assessed by the DN4 questionnaire, 6 and 12 months after major lower back surgery. Methods In this single-centre randomized trial, 80 patients received intravenous ketamine 0.25 mg/kg preoperatively, followed by 0.25 mg kg-1 hr-1 intraoperatively, and 0.1 mg kg-1 hr-1 from 1 hr before the end of surgery until the end of recovery room stay; 80 controls received placebo. Results Preoperatively, 47.4% of patients in the ketamine group and 46.3% in the placebo group had neuropathic pain; 10% and 3.8%, respectively, were using strong opioids. At the end of the infusion, the median cumulative dose of ketamine was 84.8 mg (IQR 67.4-106.7) and the median plasma level was 97 ng/ml (IQR 77.9-128.0). At 6 months, 28.8% of patients in the ketamine group and 23.5% in the placebo group had neuropathic pain (absolute difference, 5.2%; 95% CI -10.7 to 21.1; p = .607). At 12 months, 26.4% of patients in the ketamine group and 17.9% in the placebo group had neuropathic pain (absolute difference 8.5%; 95% CI -6.7 to 23.6; p = .319). Conclusions In this patient population with a high prevalence of neuropathic lower back pain undergoing major lower back surgery, a perioperative intravenous low-dose ketamine infusion did not have an effect on the prevalence of neuropathic lower back pain at 6 or 12 months postoperatively. Significance We were unable to show any analgesic benefit of a short-term perioperative ketamine infusion as an adjuvant to multimodal analgesia in patients with a high prevalence of neuropathic lower back pain undergoing major back surgery. Based on these data, the widespread opinion that ketamine is universally analgesic across different pain conditions must be challenged. Prior presentations Abstract presentation at the annual congress of the Swiss Society of Anaesthesiology, 2016, Basel, Switzerland. Clinical trial number and registry url Registered by Dr Christoph Czarnetzki as principal investigator on February 20, 2008 at clinicaltrials.gov (NCT00618423).

The activity of drug-metabolizing enzymes (DME) shows high inter- and intra-individual variability. Genetic polymorphisms, exposure to drugs, and environmental toxins are known to significantly alter DME expression. In addition, the activity of these enzymes is highly age-dependent due to maturation processes that occur during development. Currently, there is a vast choice of phenotyping methods in adults using exogenous probes to characterize the activity of these enzymes. However, this can hardly be applied to children since it requires the intake of non-therapeutic xenobiotics. In addition, sampling may be challenging in the pediatric population for a variety of reasons: limited volume (e.g., blood), inappropriate sampling methods for age (e.g., urine), and metric requiring invasive or multiple blood samples. This review covers the main existing methods that can be used in the pediatric population to determine DME activity, with a particular focus on cytochrome P450 enzymes. Less invasive tools are described, including phenotyping using endogenous probes. Finally, the potential of pediatric model-informed precision dosing using physiologically based pharmacokinetic modeling is discussed.

The aim of this work was to predict the extent of Cytochrome P450 2D6 (CYP2D6)‐mediated drug–drug interactions (DDIs) in different CYP2D6 genotypes using physiologically‐based pharmacokinetic (PBPK) modeling. Following the development of a new duloxetine model and optimization of a paroxetine model, the effect of genetic polymorphisms on CYP2D6‐mediated intrinsic clearances of dextromethorphan, duloxetine, and paroxetine was estimated from rich pharmacokinetic profiles in activity score (AS)1 and AS2 subjects. We obtained good predictions for the dextromethorphan–duloxetine interaction (Ratio of predicted over observed area under the curve (AUC) ratio (R pred/obs) 1.38–1.43). Similarly, the effect of genotype was well predicted, with an increase of area under the curve ratio of 28% in AS2 subjects when compared with AS1 (observed, 33%). Despite an approximately twofold underprediction of the dextromethorphan–paroxetine interaction, an R pred/obs of 0.71 was obtained for the effect of genotype on the area under the curve ratio. Therefore, PBPK modeling can be successfully used to predict gene–drug–drug interactions (GDDIs). Based on these promising results, a workflow is suggested for the generic evaluation of GDDIs and DDIs that can be applied in other situations.

Ticagrelor is a potent antiplatelet drug metabolized by cytochrome (CYP)3A. It is contraindicated in patients with human immunodeficiency virus (HIV) because of the expected CYP3A inhibition by most protease inhibitors, such as ritonavir and an increased bleeding risk. In this study, a physiologically based pharmacokinetic (PBPK) model was created for ticagrelor and its active metabolite (AM). Based on the simulated interaction between ticagrelor 180 mg and ritonavir 100 mg, a lower dose of ticagrelor was calculated to obtain, when coadministered with ritonavir, the same pharmacokinetic (PK) and platelet inhibition as ticagrelor administered alone. A clinical study was thereafter conducted in healthy volunteers. Observed PK profiles of ticagrelor and its AM were successfully predicted with the model. Platelet inhibition was nearly complete in both sessions despite administration of a fourfold lower dose of ticagrelor in the second session. This PBPK model could be prospectively used to broaden the usage of ticagrelor in patients with ritonavir-treated HIV regardless of the CYP3A inhibition.

BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).

Cytochrome P450 (CYP) activity can be assessed using a 'cocktail' phenotyping approach. Recently, we have developed a cocktail (Geneva cocktail) which combines the use of low-dose probes with a low-invasiveness dried blood spots (DBS) sampling technique and a single analytical method for the phenotyping of six major CYP isoforms. We have previously demonstrated that modulation of CYP activity after pre-treatment with CYP inhibitors/inducer could be reliably predicted using Geneva cocktail. To further validate this cocktail, in this study, we have verified whether probe drugs contained in the latter cause mutual drug-drug interactions. In a randomized, four-way, Latin-square crossover study, 30 healthy volunteers received low-dose caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam (a previously validated combination with no mutual drug-drug interactions); fexofenadine alone; bupropion alone; or all seven drugs simultaneously (Geneva cocktail). Pharmacokinetic profiles of the probe drugs and their metabolites were determined in DBS samples using both conventional micropipette sampling and new microfluidic device allowing for self-sampling. The 90% confidence intervals for the geometric mean ratios of AUC metabolite/AUC probe for CYP probes administered alone or within Geneva cocktail fell within the 0.8-1.25 bioequivalence range indicating the absence of pharmacokinetic interaction. The same result was observed for the chosen phenotyping indices, that is metabolic ratios at 2 hr (CYP1A2, CYP3A) or 3 hr (CYP2B6, CYP2C9, CYP2C19, CYP2D6) post-cocktail administration. DBS sampling could successfully be performed using a new microfluidic device. In conclusion, Geneva cocktail combined with an innovative DBS sampling device can be used routinely as a test for simultaneous CYP phenotyping.

Pharmacogenomics is a relatively recent yet rapidly expanding field of study examining how genetic variations influence responses to drugs. Antithrombotic drugs include the anticoagulant and antiplatelet compounds widely prescribed for the treatment and prevention of cardiovascular diseases. However, there is a large variability in response to antithrombotics, and this can modify the benefit/risk ratio of taking such medications. This variability can be explained by clinical factors such as age, sex, and drug-drug interactions, but also by genetic variants. In recent years, several genetic polymorphisms have been associated with variable biological responses to antithrombotics. Relevant polymorphisms related to antithrombotics have included target genes and genes that participate in the drugs' pharmacokinetics. This article provides a comprehensive review of the published literature about the pharmacogenomics of antithrombotic drugs, including well-studied compounds such as vitamin K antagonists (e.g., warfarin, acenocoumarol, and phenprocoumon), aspirin, and clopidogrel, as well as more recently approved compounds such as prasugrel, ticagrelor, and direct oral anticoagulants.

Meme si les evidences sont minces, il est frequent et parfois legitime en pratique d’avoir recours aux opioides chez un patient qui a mal, dont la qualite de vie et la fonction sont alteres par la douleur et qui ne repond pas aux antalgiques non opioides.

Auch wenn die Evidenz dafur dunn ist, ist es in der Praxis eine haufige und in manchen Fallen legitime Vorgehensweise, Opioide bei Schmerzpatienten einzusetzen, deren Lebensqualitat und Funktionsfahigkeit durch die Schmerzen eingeschrankt sind und die auf Nicht-Opioid-Analgetika nicht ansprechen.

This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients.

BackgroundIdentifying patients at high risk of hospital preventable readmission is an essential step towards selecting those who might benefit from specific transitional interventions.ObjectiveDerive and validate a predictive risk score for potentially avoidable readmission (PAR) based on analysis of readmissions, with a focus on medication.Design/setting/participantsRetrospective analysis of all hospital admissions to internal medicine wards between 2011 and 2014. Comparison between patients readmitted within 30 days and non-readmitted patients, as identified using a specially designed algorithm. Univariate and multivariate regression analyses of demographic data, clinical diagnoses, laboratory results, and the medication data of patients admitted during the first period (2011-2013), to identify factors associated with PAR. Using these, derive a predictive score with a regression coefficient-based scoring method. Subsequently, validate this score with a second cohort of patients admitted in 2013-2014. Variables were identified at hospital discharge.ResultsThe derivation cohort included 7,317 hospital stays. Multivariate logistic regressions found significant associations with PAR for: [adjusted OR (95% CI)] hospital length of stay > 4 days [1.3 (1.1-1.7)], admission in previous 6 months [2.3 (1.9-2.8)], heart failure [1.3 (1.0-1.7)], chronic ischemic heart disease [1.7 (1.2-2.3)], diabetes with organ damage [2.2 (1.3-3.8)], cancer [1.4 (1.0-1.9)], metastatic carcinoma [1.9 (1.3-3.0)], anemia [1.2 (1.0-1.5)], hypertension [1.3 (1.1-1.7)], arrhythmia [1.3 (1.0-1.6)], hyperkalemia [1.4 (1.0-1.7)], opioid drug prescription [1.3 (1.1-1.6)], and acute myocardial infarction [0.6 (0.4-0.9)]. The PAR-Risk Score, derived from these results, demonstrated fair discriminatory and calibration power (C-statistic = 0.699; Brier Score = 0.069). The results for the validation cohort's operating characteristics were similar (C-statistic = 0.687; Brier Score = 0.064).ConclusionThis study identified routinely-available factors that were significantly associated with PAR. A predictive score was derived and internally validated.

The current use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic processes, and each of these components, in addition to pain perception and processing, seem to be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After usual dose, drug toxicity, as well as inefficacy, can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. Thus, cytochrome P450 (CYP)2D6 polymorphism influences codeine and tramadol analgesic effects, CYP2C9 has an impact on the disposition of some nonsteroidal anti-inflammatory drugs, and opioid receptor polymorphism (118A>G) may reduce morphine potency. Moreover, drug interaction mimics genetic deficiency and contributes to the variability in response to analgesics. This two-part review summarizes the available data on the pharmacokinetic–pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes (CYP and uridine diphosphate glucuronosyltransferase), drug transporters (multidrug resistance proteins, multidrug resistance-associated proteins, organic anion-transporting polypeptides, and serotonin transporters), relevant drug targets (such as µ-opioid receptor, serotonin receptor and cyclooxygenases) and other nonopioid biological systems, on currently prescribed central and peripheral analgesics.

on therapeutic outcomes. This has been demonstrated for codeine [7,8], tramadol [9,10] and oxycodone [11,12], when activated by CYP2D6 into their active moieties, morphine, O-desmethyltramadol and oxymorphone, respectively, in terms of pharmacokinetic and pharmacodynamic consequences. In the case of reduced or absent CYP2D6 activity such as in poor metabolizers (PMs) for CYP2D6 (7–10% of Caucasians), reduced or absent metabolite formation and reduced analgesic effects have been observed. After major abdominal surgery, nonresponse rates to tramadol were fourfold higher amongst PMs than other CYP2D6 genotypes [10]. A cohort study demonstrated that children undergoing ineffective pain treatment of sickle cell crisis with codeine were more likely to have reduced CYP2D6 activity [13]. Inversely, ultrarapid metabolizers (UMs) for CYP2D6, with increased enzymatic activity, experienced quicker analgesic effects but were prone to higher μ-opioid-related toxicity after tramadol [14] or oxycodone in the experimental pain setting [12]. Furthermore, case reports have highlighted the risks of codeine use in pediatrics and breastfed neonates in association with the UM genotype [6,15]. The dual serotoninergic and adrenergic inhibitor antidepressants, such as venlafaxine, and the tricyclics used in the treatment of neuropathic pain are also metabolized by CYP2D6. The PM phenotype has been associated with higher risks of tricyclics toxicity [16]. Inversely, UMs may experience reduced effects due to subtherapeutic plasma levels [17]. However, even though dose adjustments according to CYP2D6 (and CYP2C19) have been published for antidepressants, these guidelines relate to psychiatric doses [18] and no investigations in the neuropathic pain setting have been published Over the last decade, the knowledge of genetic modulators of pain and antinociception has increased so that individualized pre-emptive pain therapy adjusted to the patient’s genetic background could move closer to reality [1]. Indeed, in the field of oncology, it is now established that the choice of treatment and/or dose adjustment according to a patient’s genetic make-up is associated with better therapeutic outcomes [2]. In current clinical practice in pain medicine, individual patients are given their own analgesic trial, depending on pain intensity and origin, at a standardized dose followed by individual titration until expected outcomes are achieved. The trial and error approach is progressively adjusted, according to the physician’s experience with patients with related pain or disease conditions. However, studies have shown that doses of opioids administered may vary as much as 40-fold in the clinical setting [3]. Moreover, a significant proportion of patients will experience side effects or inadequate analgesia. The heterogeneity observed in response to pain medication might be due to the underlying disease itself or compliance, but also to the genetic background of the individual. Studies have reported genetic variations in drug absorption, distribution, metabolism and elimination that might ultimately have an impact on the efficacy/safety ratio of a particular drug [4–6]. Evidence for the influence of genetic polymorphisms of drug-metabolizing enzymes, such as cytochromes P450 (CYP), on the response to various analgesics is now established. A prototypical example is illustrated by prodrug opioids that need to be bioactivated by CYP2D6 into active metabolites, with genetic polymorphisms of CYP2D6 having a profound impact “Gene–drug interactions are still poorly understood and there is a need for prospective highly powered studies in phenotyped populations to evaluate the cost–effectiveness of pre-emptive drug selection and dosage according to the genotypic and phenotypic data.”

Antidepressants are widely administered to chronic pain patients, but there is large interindividual variability in their efficacy and adverse effect rates that may be attributed to genetic factors. Studies have attempted to determine the impact of genetic polymorphisms in enzymes and transporters that are involved in antidepressant pharmacokinetics, for example, cytochrome P450 and P-gp. The impacts of genetic polymorphisms in the targets of antidepressants, such as the serotonin receptor or transporter, the noradrenaline transporter and the COMT and monoamine oxydase enzymes, have also been described. This manuscript discusses the current knowledge of the influence of genetic factors on the plasma concentrations, efficacy and adverse effects of the major antidepressants used in pain management.

OBJECTIVE Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach. METHODS From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5. RESULTS We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent. CONCLUSIONS The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02438072.

Cytochrome P450 (CYP) 2D6 metabolizes a wide range of xenobiotics and is characterized by a huge interindividual variability. A recent clinical study highlighted differential magnitude of CYP inhibition as a function of CYP2D6 genotype. The aim of this study was to investigate the effect of CYP2D6 genotype on the inhibition of dextromethorphan O-demethylation by duloxetine and paroxetine in human liver microsomes (HLMs). The study focused on genotypes defined by the combination of two fully functional alleles (activity score 2, AS 2, n = 6), of one fully functional and one reduced allele (activity score 1.5, AS 1.5, n = 4) and of one fully functional and one non-functional allele (activity score 1, AS 1, n = 6), which all predict extensive metabolizer phenotype. Kinetic experiments showed that maximal reaction velocity was affected by CYP2D6 genotype, with a decrease in 33% of Vmax in AS 1 HLMs compared to AS 2 (P = 0.06). No difference in inhibition parameters Ki , KI and kinact was observed neither with the competitive inhibitor duloxetine nor with the time-dependent inhibitor paroxetine. Among the genotypes tested, we found no difference in absolute CYP2D6 microsomal levels with ELISA immunoquantification. Therefore, our results suggest that genotype-sensitive magnitude of drug-drug interactions recently observed in vivo is likely to be due to differential amounts of functional enzymes at the microsomal level rather than to a difference in inhibition potencies across genotypes, which motivates for further quantitative proteomic investigations of functional and variant CYP2D6 alleles.