Environmental impact of intravenous versus oral administration materials for acetaminophen and ketoprofen in a French university hospital: an eco-audit study using a life cycle analysis.

PURPOSE: The combination of acetaminophen with a nonsteroidal anti-inflammatory drug is the cornerstone of perioperative multimodal analgesia. These drugs can be administered intravenously or orally as premedication, consistent with the concept of pre-emptive and preventive analgesia. We aimed to assess the environmental impact of their intravenous and oral administration in a French university hospital. METHODS: We carried out a life cycle assessment to determine the amount of greenhouse gas emissions and depletion of water resources resulting from the oral vs intravenous administration of 1 g acetaminophen and 50 mg ketoprofen. We assessed two schemes of intravenous administration, depending on the use of the same or a different infusion set for each drug. RESULTS: At our centre, the intravenous administration of both drugs was associated with the emission of 444-556 g CO2 equivalent (CO2e), and with 9.8-12.2 L of water waste. The oral administration of both drugs generated 8.36 g of CO2e emissions and consumed 1.16 L of water. At a national level, the switch from intravenous to oral premedication of the drugs could avoid the emission of 2,900-3,700 tons of CO2e and the waste of 58,000-74,000 m3 of water each year. CONCLUSION: This eco-audit indicates that oral administration of acetaminophen and ketoprofen results in significantly lower carbon emissions and water consumption than intravenous administration. These findings highlight the importance of using the oral route for most patients, limiting intravenous administration for those with specific needs because of higher environmental impact and cost.

RéSUMé: OBJECTIF: L'association de l'acétaminophène et d'un anti-inflammatoire non stéroïdien constitue la pierre angulaire de l'analgésie multimodale périopératoire. Ces médicaments peuvent être administrés par voie intraveineuse ou orale en prémédication, conformément au concept d'analgésie préemptive et préventive. Notre objectif était d'évaluer l'impact environnemental de leur administration intraveineuse et orale dans un hôpital universitaire français. MéTHODE: Nous avons réalisé une analyse du cycle de vie pour déterminer la quantité d'émissions de gaz à effet de serre et l'épuisement des ressources en eau résultant de l'administration orale vs intraveineuse de 1 g d'acétaminophène et de 50 mg de kétoprofène. Nous avons évalué deux schémas d'administration intraveineuse, en fonction de l'utilisation du même dispositif de perfusion ou d'un dispositif différent pour chaque médicament. RéSULTATS: Dans notre centre hospitalier, l'administration intraveineuse des deux médicaments a été associée à l'émission de 444 à 556 g d'équivalent CO2 (CO2e) et de 9,8 à 12,2 L d'eaux usées. L'administration orale des deux médicaments a généré 8,36 g de CO2e et consommé 1,16 L d'eau. Au niveau national, le passage de la prémédication intraveineuse à la prémédication orale des médicaments pourrait éviter l'émission de 2900 à 3700 tonnes de CO2e et l'épargne de 58 000 à 74 000 m3 d'eau chaque année. CONCLUSION: Cet éco-audit indique que l'administration orale d'acétaminophène et de kétoprofène entraîne une réduction significative des émissions de carbone et de la consommation d'eau par rapport à une administration par voie intraveineuse. Ces résultats soulignent l'importance d'utiliser la voie orale pour la plupart des patient·es, limitant l'administration intraveineuse pour celles et ceux qui ont des besoins spécifiques en raison de l'impact environnemental et du coût plus élevés.

Integrated clinical pharmacy activities into the pediatric kidney graft pathway / Activités de pharmacie clinique intégrées dans le parcours du patient de greffe rénale pédiatrique

The pediatric renal graft pathway is at risk of care discontinuation, even though therapeutic adherence is essential. The objective is to evaluate the integration of clinical pharmacy activities into this care pathway. This feasibility study is divided into three stages: structuring, implementing and evaluation. In pre-transplant, immediate and remote post-transplant, interviews were proposed as well as the pharmaceutical analysis of medication prescriptions. In 8 months duration, 32 patients were included. All patients included in pre-transplant and immediate post-transplant benefited from the activities. At M0, all the prescriptions analyzed resulted in at least one problem detected. Half of the transplanted patients benefited from M1 maintenance, one patient from M3 maintenance and no M6 follow-up could be carried out. This work concludes with the good feasibility and integration of clinical pharmacy activities within the care pathway.

Le parcours de greffe rénale pédiatrique est à risque de rupture de soins car les patients sont polymédiqués alors même que l'adhésion thérapeutique est essentielle. L'objectif est d'évaluer l'intégration d'activités de pharmacie clinique dans ce parcours de soins. Cette étude de faisabilité se décline en trois étapes : structuration, mise en œuvre et évaluation. En pré-greffe, post-greffe immédiate et post-greffe à distance, des entretiens ont été proposés ainsi que l'analyse pharmaceutique des prescriptions médicamenteuses. En huit mois, 32 patients ont été inclus. Tous les patients inclus en pré-greffe et en post-greffe immédiate ont bénéficié des activités. À M0, toutes les prescriptions analysées ont abouti à au moins un problème détecté. La moitié des patients greffés ont bénéficié de l'entretien à M1, un patient de l'entretien à M3 et aucun suivi à M6 n'a pu être réalisé. Ce travail conclut à la bonne faisabilité et intégration des activités de pharmacie clinique au sein du parcours de soins.

Population Pharmacokinetic Modeling and Dosing Simulations of Tobramycin in Pediatric Patients with Cystic Fibrosis.

Initial dosing and dose adjustment of intravenous tobramycin in children with cystic fibrosis (CF) is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our children's CF center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the ratios of maximal concentration to the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC24/MIC) were considered efficacy targets. Trough concentration (Cmin) was considered the safety target. A total of 2,884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area, and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation in the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/pharmacodynamics (PD) simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MICs of ≥10 for MICs up to 2 mg/liter in most patients. The AUC24/MIC target was associated with higher dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend performing tobramycin therapeutic drug monitoring (TDM), model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial.

Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.

Efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial.

Hereditary hemorrhagic telangiectasia is a rare vascular genetic disease. Epistaxis is the most frequent and disabling manifestation, and timolol appears to be a new therapeutic option as non-selective beta-blockers have in vitro and in vivo anti-angiogenic properties. Our main objective was to evaluate the efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. This study is a single-center, randomized, phase 2, double-blind placebo-controlled study with an allocation ratio of 1:1. It was proposed to patients with hereditary hemorrhagic telangiectasia monitored at the French Reference Center, and we included patients aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis. The treatment was self-administered by the patient with a posology of one spray (50 µL) of timolol 0.5% or placebo in each nostril twice a day for 28 consecutive days. The primary efficacy endpoint was mean monthly epistaxis duration, assessed by monitoring epistaxis grids. A total of 58 patients were randomized and treated. The baseline characteristics were similar in the 2 groups. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 26 patients receiving the drug in comparison with the placebo group (p = 0.54). Toxicity was low and no severe adverse events were reported. One limitation is that we included all HHT patients with nosebleeds and did not take into account history of nasal surgery or nasal crusts. Timolol, administered by nasal spray at a dose of 0.25 mg in each nostril twice a day for 28 consecutive days, did not improve epistaxis in patients with hereditary hemorrhagic telangiectasia at 4 months after the beginning of the treatment.

Radiochemical purity of technetium-99m-nanocolloid rhenium sulphide is not influenced by heating.

Despite a mistake during the preparation of technetium-99m (Tc)-nanocolloid rhenium sulphide (Nanocis) because of lack of heating, the apparent radiochemical purity (RCP) of this product was correct. The objectives of this study were to evaluate the impact of absence of heating on the RCP of Tc-nanocolloid rhenium sulphide and the effect of heating on particle size. Five Tc-Nanocis were prepared according to the manufacturer's instructions and five others were realized without any heating step. Quality controls were performed for each preparation. To evaluate the effect of heating on particle size, preparations were filtered through a 0.22 µm sterilizing membrane filter before and after 30 min of heating. The radioactivity was measured before and after the filtration. The results showed that absence of heating does not influence the apparent RCP of Tc-nanocolloid of rhenium sulphide. In terms of the particle size, 72% of particles had a diameter less than 0.22 µm before heating, as opposed to 21% after heating. To conclude, this study underlines a problem of quality control of the Tc-nanocolloid rhenium sulphide preparation, which cannot detect a lack of heating and can lead to the release of preparations that would not be suitable for scintigraphy.

Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial.

BACKGROUND: Epistaxis is the most frequent and disabling manifestation of hereditary hemorrhagic telangiectasia (HHT). The efficacy of intravenous bevacizumab (an anti-vascular endothelial growth factor monoclonal antibody) for epistaxis has been shown. However, the efficacy of intranasal bevacizumab has yet to be evaluated. OBJECTIVE: To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT. DESIGN, SETTING, AND PARTICIPANTS: Randomized, multicenter, placebo-controlled, phase 2/3 clinical trial with dose selection at an intermediate analysis and prespecified stopping rules (nonbinding stopping for futility). Patients aged 18 years or older with a diagnosis of HHT were recruited from 5 French centers from April 2014 to January 2015 with a 6-month follow-up after the end of treatment. Participants had a history of self-reported nosebleeds with a monthly duration of more than 20 minutes in at least the 3 months prior to inclusion corroborated by epistaxis grids completed during the same preinclusion period. INTERVENTIONS: Eighty consecutive HHT patients were randomized and treated in the phase 2 study, with 4 parallel groups in a 1:1:1:1 ratio. One group received placebo (n = 21); the other 3 received bevacizumab nasal spray. Each bevacizumab group received a different dose of the drug (25 mg [n = 20], 50 mg [n = 20], or 75 mg [n = 19] per treatment) in 3 doses 14 days apart for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, and 225 mg in each treatment group. MAIN OUTCOMES AND MEASURES: Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment. RESULTS: Of the 80 patients who were randomized (mean age, 60.47 [SD, 10.61] years; 37 women [46.25%]), 75 completed the study. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1-436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8-406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8-327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3-291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee. CONCLUSIONS AND RELEVANCE: In patients with HHT, a bevacizumab nasal spray treatment of 3 administrations at 14-day intervals with doses of 25 mg, 50 mg, or 75 mg per spray, compared with a placebo, did not reduce monthly epistaxis duration in the 3 consecutive months immediately after the end of treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02106520.

The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an estimated prevalence of about 1/3000, independent of ethnicity, race, or gender. Attention Deficit Hyperactivity like Disorder (ADHD)-like characteristics are often reported in patients with NF1. We hypothesised that learning disabilities in NF1 children were related to ADHD symptoms. Treatment with methylphenidate (MPD) has improved learning disabilities in ADHD by acting on neurotransmitters. Our objective was to evaluate its efficacy on ADHD-like symptoms in neurofibromatosis type 1 children (7-12 years). METHODS: This was a randomised, double blind, placebo controlled, and crossover trial comparing 0.5 to 0.8 mg/kg/d of MPD as it is indicated for ADHD to placebo in NF1 children with ADHD-like symptoms. Children aged 7 to 12 years were eligible when their IQ was between 80 and 120. The total follow-up was 9 weeks including 4 weeks for each period and 1 week wash out. Fifty subjects (25 for each period) were required for testing the primary study hypothesis. The main outcome was an improvement in scores on the simplified Conners' Parent Rating Scale. RESULTS: Thirty-nine patients were included between April 2004 and December 2010. Twenty participants received MPD and 19 placebo during the first period. They all completed the trial. MPD decreased the simplified Conners by 3.9 points (±1.1, p = 0. 0003). CONCLUSIONS: This is the first randomised controlled trial showing the short-term benefit of MPD on simplified Conners scores in NF1 children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00169611.