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1.
Dagmar Kubitza Stefan Willmann Michael Becka Kirstin Thelen Guy Young Leonardo R. Brandão Paul Monagle Christoph Male Anthony Chan Gili Kennet Ida Martinelli Paola Saracco Anthonie W. A. Lensing 《Thrombosis journal》2018,16(1):31
Background
The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.Methods
This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.Results
Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.Conclusions
Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.Trial registration
ClinicalTrials.gov number, NCT01145859.2.
Anthony Chan Anthonie W. A. Lensing Dagmar Kubitza Grahaem Brown Dolores Elorza Marta Ybarra Jacqueline Halton Sebastian Grunt Gili Kenet Damien Bonnet Amparo Santamaria Paola Saracco Tina Biss Francesco Climent Philip Connor Joseph Palumbo Kirstin Thelen William T. Smith Amy Mason Ivet Adalbo Scott D. Berkowitz Eva Hurst Jeroen van Kesteren Guy Young Paul Monagle 《Thrombosis journal》2018,16(1):29
Background
Venous thromboembolism (VTE) in young children is not well documented.Methods
Clinicians from 12 institutions retrospectively evaluated the presentation, therapeutic management, and outcome of VTE in children younger than 2 years seen in 2011–2016. Feasibility of recruiting these children in EINSTEIN-Jr. phase III, a randomized trial evaluating rivaroxaban versus standard anticoagulation for VTE, was assessed.Results
We identified 346 children with VTE, of whom 227 (65.6%) had central venous catheter-related thrombosis (CVC-VTE), 119 (34.4%) had non-CVC-VTE, and 156 (45.1%) were younger than 1 month. Of the 309 children who received anticoagulant therapy, 86 (27.8%) had a short duration of therapy (i.e. <?6 weeks for CVC-VTE and?<?3 months for non-CVC-VTE) and 17 (5.5%) had recurrent VTE during anticoagulation (n?=?8, 2.6%) or shortly after its discontinuation (n?=?9, 2.9%). A total of 37 (10.7%) children did not receive anticoagulant therapy and 4 (10.5%) had recurrent VTE.The average number of children aged <?0.5 years and 0.5–2 years who would have been considered for enrolment in EINSTEIN-Jr is approximately 1.0 and 0.9 per year per site, respectively.Conclusions
Young children with VTE most commonly have CVC-VTE and approximately one-tenth and one-fourth received no or only short durations of anticoagulant therapy, respectively. Recurrent VTE rates without anticoagulation, during anticoagulation or shortly after its discontinuation seem comparable to those observed in adults. Short and flexible treatment durations could potentially increase recruitment in EINSTEIN-Jr. phase III.3.
Anthonie W. A. Lensing Christoph Male Guy Young Dagmar Kubitza Gili Kenet M. Patricia Massicotte Anthony Chan Angelo C. Molinari Ulrike Nowak-Goettl Ákos F. Pap Ivet Adalbo William T. Smith Amy Mason Kirstin Thelen Scott D. Berkowitz Mark Crowther Stephan Schmidt Victoria Price Martin H. Prins Paul Monagle 《Thrombosis journal》2018,16(1):34
Background
Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20?mg once-daily.Methods
EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20?mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18?years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3?months with the option to continue treatment in 3-month increments, up to a total of 12?months. However, based on most common current practice, children younger than 2?years with catheter-related thrombosis will have a main treatment period of 1?month with the option to prolong treatment in 1-month increments, up to a total of 3?months.Conclusions
EINSTEIN-Jr will compare previously established 20?mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.Trial registration
Clinicaltrials.gov NCT02234843, registered on 9 September 2014.4.
Anne-Laure Sennesael Anne-Sophie Larock Jonathan Douxfils Laure Elens Gabriel Stillemans Martin Wiesen Max Taubert Jean-Michel Dogné Anne Spinewine François Mullier 《Thrombosis journal》2018,16(1):28
Background
Serious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.Methods
This analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.Results
Rivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C?>?T, 2677G?>?T, 3435 C?>?T and rs4148738 single nucleotide polymorphisms (SNP).Conclusions
Rivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.5.
Introduction
The aim of this study was to evaluate the cost-effectiveness of rivaroxaban and apixaban versus enoxaparin for the universal prophylaxis of venous thromboembolism (VTE) and associated long-term complications in Chinese patients after total hip replacement (THR).Methods
A decision model, which included both acute VTE (represented as a decision tree) and the long-term complications of VTE (represented as a Markov model), was developed to assess the economic outcomes of the three prophylactic strategies for Chinese patients after THR. Transition probabilities for acute VTE were derived from two randomized controlled studies, RECORD1 and ADVANCE3, of patients after THR. The transition probabilities of long-term complications after acute VTE, utilities, and costs were derived from the published literature and local healthcare settings. One-way and probabilistic sensitivity analyses (PSA) were performed to test the uncertainty concerning the model parameters. The quality-adjusted life years (QALYs) and direct medical costs were reported over a 5-year horizon, and incremental cost-effectiveness ratios (ICERs) were also calculated.Results
Thromboprophylaxis with apixaban was estimated to have a higher cost (US $178.70) and more health benefits (0.0025 QALY) than thromboprophylaxis with enoxaparin over a 5-year time horizon, which resulted in an ICER of US $71,244 per QALY gained and was more than three times the GDP per capita of China in 2014 (US $22,140). Owing to the higher cost and lower generated QALYs, rivaroxaban was inferior to enoxaparin among post-THR patients. The sensitivity analyses confirmed these results.Conclusions
The analysis found that apixaban was not cost-effective and that rivaroxaban was inferior to enoxaparin. This finding indicates that compared with enoxaparin, the use of apixaban for VTE prophylaxis after THR does not represent a good value for the cost at the acceptable threshold in China; in addition, the cost of rivaroxaban was higher with lower QALYs.6.
Introduction
Bacterial vaginosis (BV) is a serious infection that is the most common vaginal infection in women of childbearing potential. SYM-1219 is a novel, granule formulation containing 2 g of secnidazole that is being developed as a single, oral dose to treat women with BV. Because many of the women diagnosed with BV use hormonal contraception, the effect of SYM-1219 on the pharmacokinetics (PK) of commonly prescribed oral contraceptive drugs, ethinyl estradiol (EE2), and norethindrone (NET) was evaluated.Methods
This two-period, randomized, open-label study examined effects in 54 healthy female subjects. During the first period of the study, each subject received EE2 0.035-mg/NET 1-mg tablets. During the second period of the study, subjects were randomized to receive either EE2 0.035-mg/NET 1-mg tablets with concomitant 2-g SYM-1219 or 2-g SYM-1219 followed by EE2 0.035-mg/NET 1-mg tablets 1 day later. The PK of EE2 and NET were analyzed for 24 h following administration.Results
Coadministration of SYM-1219 and EE2/NET, either on the same day or 1 day apart, had no clinically relevant effects on the bioavailability of EE2 or NET. The combined use of SYM-1219 with EE2/NET was well tolerated. Taken together, these results indicate that contraceptive efficacy should be maintained during coadministration of SYM-1219 and EE2/NET.Conclusion
SYM-1219 is a valuable single-dose treatment option for women with BV that will not interfere with combined oral contraceptive methods.Funding
Symbiomix Therapeutics.7.
Ruth Plummer Henk M. Verheul Filip Y. F. L. De Vos Karin Leunen L. Rhoda Molife Christian Rolfo Peter Grundtvig-Sørensen Jacques De Grève Sylvie Rottey Guy Jerusalem Antoine Italiano James Spicer Luc Dirix Carsten Goessl Joseph Birkett Stuart Spencer Maria Learoyd Christopher Bailey Emma Dean 《Advances in therapy》2018,35(11):1945-1964
Introduction
The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.Methods
During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1–5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10–13, 20 mg qd days 14–26; cohort 2, anastrozole 1 mg qd days 10–19; cohort 3, letrozole 2.5 mg qd days 10–38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B.Results
Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) Cmax,ss and AUC0–τ decreased by 20% (90% CI 0.71–0.90) and 27% (0.63–0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean Cmax,ss and AUC0–τ increased by 13% (1.06–1.22) and 16% (1.11–1.21), respectively]; however, the 90% CI fell within the 0.7–1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.Conclusions
The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.Funding
AstraZeneca.Clinical Trial Registration
NCT02093351.8.
Kazuaki Enya Ben T. Saji Takuya Kato Hiroyuki Okamoto Emiko Koumura 《Advances in therapy》2018,35(8):1181-1190
Introduction
Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients.Methods
In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg.Results
Mean maximum plasma concentration (Cmax) of azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (Tmax) of unchanged azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC0–24) and 0 h to infinity (AUC0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to azilsartan occurred during the study.Conclusion
Our data suggest that pediatric patients weighing less than 50 kg may have? approximately 2-fold greater exposure to azilsartan than those weighing at least 50 kg at the same dose. Exposure to azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose.Trial Registration
ClinicalTrials.gov identifier, NCT02451150.Funding
Takeda Pharmaceutical Co. Ltd.9.
Silvia Natoli Marzia Lazzari Roberta Carpenedo Elisa Palombo Maria Beatrice Silvi Massimo Mammucari Mario Dauri 《Advances in therapy》2016,33(6):1025-1032
Introduction
Oxycodone is one of the most commonly used opioid analgesics in the clinical management of pain. The present retrospective analysis aimed to determine the dose of oxycodone that could achieve effective control of moderate pain when combined with a fixed dose of acetaminophen, and the time required to reach a clinically relevant reduction in intensity of pain.Methods
Data of patients treated with a combination of oxycodone (5, 10, and 20 mg) and acetaminophen (325 mg) were evaluated for gender, current disease condition, basal pain intensity, total daily dose, days of controlled pain at the initial low dose, and pain intensity after treatment using a numeric pain rating scale.Results
Data from a total of 491 patients were assessed; of these 93.5% of patients experienced persistent non-cancer pain and had an average baseline pain score of 5.68 ± 1.35. For the overall population, the pain score was reduced to 2.49 ± 1.71 with a mean dose of 8.68 ± 4.96 mg oxycodone after 21.60 ± 6.12 days of treatment with the combination. Almost 97% of the patients who reported relief of pain received 1.61 ± 0.67 doses of oxycodone 5 mg combined with 325 mg of acetaminophen.Conclusion
A low-dose combination of oxycodone with acetaminophen can be effective in the management of moderate pain and may help in reducing the treatment-associated adverse reactions and drug dependence.Funding
Sponsorship for article processing charges was provided by Molteni Farmaceutici, Florence, Italy.10.
N. López-Vilanova J. Pavía M. A. Duch A. Catafau D. Ros S. Bullich 《Molecular imaging and biology》2017,19(2):305-314
Purpose
Human dosimetry studies play a central role in radioligand development for positron emission tomography (PET). Drawing regions of interest (ROIs) on the PET images is used to measure the dose in each organ. In the study aspects related to ROI delineation methods were evaluated for two radioligands of different biodistribution (intestinal vs urinary).Procedures
PET images were simulated from a human voxel-based phantom. Several ROI delineation methods were tested: antero-posterior projections (AP), 3D sub-samples of the organs (S), and a 3D volume covering the whole-organ (W). Inter- and intra-operator variability ROI drawing was evaluated by using human data.Results
The effective dose estimates using S and W methods were comparable to the true values. AP methods overestimated (49 %) the dose for the radioligand with intestinal biodistribution. Moreover, the AP method showed the highest inter-operator variability: 11 ± 1 %.Conclusions
The sub-sampled organ method showed the best balance between quantitative accuracy and inter- and intra-operator variability.11.
Bérangère Vasseur Alain Dufour Laetitia Houdas Helen Goodwin Kathryn Harries Neslihan Yesiltas Emul Simon Hutchings 《Advances in therapy》2017,34(8):2022-2032
Introduction
The clonidine mucoadhesive buccal tablet (MBT) is a novel delivery system resulting in high and sustained concentrations of clonidine in the oral cavity. In a phase II clinical trial, clonidine MBT reduced the incidence of severe oral mucositis (OM) compared to placebo in head and neck cancer patients undergoing chemoradiation. This study compared the pharmacokinetics (PK), safety and tolerability of clonidine MBT with a reference oral tablet (OT).Methods
This was a randomised, three-period, single-dose crossover study in 36 healthy subjects aged 18–50 years. Eligibility was assessed within 14 days of the first dose. IMP was administered in the fasted state on day 1 of each treatment period. PK samples were collected up to 24 h (saliva)/96 h (blood) for measurement of the clonidine concentration. Safety and tolerability were evaluated at specified times throughout the study. A washout period of at least 7 days was observed between administrations.Results
Clonidine MBT (50 and 100 µg) applied to the upper gum resulted in a dose-proportional increase in saliva (C max and AUC0–t ) and plasma (Cmax and AUC0–inf) clonidine levels. Clonidine MBT was considered to mimic a continuous release of clonidine in plasma, significantly decreasing the C max and AUC and increasing the T max when compared with the reference clonidine HCl tablets. Clonidine MBT exhibited high and prolonged concentrations in saliva where concentrations with the clonidine HCl tablet were negligible. Clonidine MBT exhibited a favourable safety profile with significantly fewer subjects reporting AEs (dry mouth and fatigue) and a reduction in blood pressure when compared to the reference clonidine HCl tablets.Conclusion
Clonidine MBT is well tolerated and exhibits proportional saliva and plasma PK over the 50–100-µg dose level. The MBT results in higher saliva concentrations and lower systemic exposure than OT, which was associated with a trend towards fewer adverse events and less dry mouth, fatigue and hypotensive effect.Funding
Onxeo SA.Trial Registration
ClinicalTrials.gov identifier, NCT02548806.12.
Objective
To compare the safety and estimate the response profile of olanzapine, a second-generation antipsychotic, to haloperidol in the treatment of delirium in the critical care setting.Design
Prospective randomized trialSetting
Tertiary care university affiliated critical care unit.Patients
All admissions to a medical and surgical intensive care unit with a diagnosis of delirium.Interventions
Patients were randomized to receive either enteral olanzapine or haloperidol.Measurements
Patient’s delirium severity and benzodiazepine use were monitored over 5 days after the diagnosis of delirium.Main results
Delirium Index decreased over time in both groups, as did the administered dose of benzodiazepines. Clinical improvement was similar in both treatment arms. No side effects were noted in the olanzapine group, whereas the use of haloperidol was associated with extrapyramidal side effects.Conclusions
Olanzapine is a safe alternative to haloperidol in delirious critical care patients, and may be of particular interest in patients in whom haloperidol is contraindicated.13.
Danielle Armas Robert J. Holt Nils F. Confer Gregg C. Checani Mohammad Obaidi Yuli Xie Meg Brannagan 《Advances in therapy》2018,35(2):199-209
Introduction
Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR.Methods
This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences.Results
All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC0–t, AUC0–∞, and Cmax were all within the 80–125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated.Conclusion
Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water).Funding
Horizon Pharma, Inc.14.
Alexander?T.?Cohen Anthony?Maraveyas Jan?Beyer-Westendorf Agnes?Y.?Y.?Lee Lorenzo?G.?Mantovani Miriam?Bach 《Thrombosis journal》2018,16(1):21
Background
Around 20% of venous thromboembolism (VTE) cases occur in patients with cancer. Current guidelines recommend low molecular weight heparin (LMWH) as the preferred anticoagulant for VTE treatment. However, some guidelines state that vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) are acceptable alternatives for long-term therapy in some patients if LMWHs are not available. LMWHs and VKAs have a number of drawbacks that can increase the burden on patients. DOACs, such as rivaroxaban, can ameliorate some burdens and may offer an opportunity to increase patient satisfaction and health-related quality of life (HRQoL). The Cancer-associated thrOmboSIs – patient-reported outcoMes with rivarOxaban (COSIMO) study is designed to provide real-world information on treatment satisfaction in patients with active cancer who switch from LMWH or VKA to rivaroxaban for the treatment of acute VTE or to prevent recurrent VTE.Methods
COSIMO is a prospective, non-interventional, single-arm cohort study that aims to recruit 500 patients in Europe, Canada and Australia. Adults with active cancer who are switching to rivaroxaban having received LMWH/VKA for the treatment and secondary prevention of recurrent VTE for at least the previous 4 weeks are eligible. Patients will be followed for 6 months. The primary outcome is treatment satisfaction assessed as change in the Anti-Clot Treatment Scale (ACTS) Burdens score at week 4 after enrolment compared with baseline. Secondary outcomes include treatment preferences, measured using a discrete choice experiment, change in ACTS Burdens score at months 3 and 6, and change in HRQoL (assessed using the Functional Assessment of Chronic Illness Therapy – Fatigue questionnaire). COSIMO will collect data on patients’ medical history, patterns of anticoagulant use and incidence of bleeding and thromboembolic events. Study recruitment started in autumn 2016.Conclusions
COSIMO will provide information on outcomes associated with switching from LMWH or VKA therapy to rivaroxaban for the treatment or secondary prevention of cancer-associated thrombosis in a real-life setting. The key goal is to assess whether there is a change in patient-reported treatment satisfaction. In addition, COSIMO will facilitate the evaluation of the safety and effectiveness of rivaroxaban in preventing recurrent VTE in this patient population.Trial registration
NCT02742623. Registered 19 April 2016.15.
Background
Children and adolescents with severe hemophilia commonly suffer from acute and chronic pain as a consequence of hemophilia-related bleeding. Intervention-related pain also plays a major role. Despite its high prevalence in this patient group, hemophilia-related pain is not always adequately addressed and sufficiently treated.Objectives
This paper discusses how to improve pain management for children and adolescents (0–18 years) with hemophilia and which specific features in this population should influence decisions in pain management.Materials and methods
An expert panel discussed challenges in pain treatment in children and adolescents with hemophilia. Recommendations are based on evidence and clinical experience.Result
Pain management in children with hemophilia needs improvement. Children with hemophilia are at risk of developing chronic pain and of suffering traumatization due to insufficient pain management. Pain therapy can be challenging in these children as both their age and the underlying disease limit the options in particular in pain medication. The expert panel developed recommendations to improve pain management in children with hemophilia.16.
Emily Dotson Brooke Crawford Gary Phillips Jeffrey Jones 《Supportive care in cancer》2016,24(3):1125-1129
Purpose
Rituximab is a chimeric monoclonal antibody approved to treat B cell non-Hodgkin’s lymphoma (NHL). Infusion reactions among NHL patients are common during the first exposure but decrease with subsequent infusions. We sought to assess the safety and feasibility of a rituximab rapid infusion protocol in the outpatient treatment area of a comprehensive cancer center.Patients and methods
Patients with indolent and intermediate B cell NHL were invited to enroll in this prospective, single-institution study if they had received the first dose of rituximab according to the manufacturer-labeled standard titration schedule without grade >2 infusion reaction. The subsequent infusion proceeded without the use of steroid premedication at 100 mg/h administered over 15 min, with the remaining dose given over 45 min. Time savings between rapid infusion and standard titration were calculated.Results
Fifty patients received 60-min rituximab infusions during the second drug administration. No infusion-related reactions of any grade were observed with the rapid infusion protocol (0 %, one-sided 97.5 % CI 0–7.1 %). The mean time for the rapid rituximab infusion was 62.4 min (95 % CI 61.2–63.6). When compared to the standard second dose infusion recommendation, a mean time of 94.2 min (95 % 90–98.4) was saved with rapid infusion. Nursing surveys demonstrated 100 % satisfaction with the rapid infusion protocol.Conclusions
Subsequent rituximab infusions can be safely administered over 60 min and without steroid premedication in an experienced outpatient infusion center when patients are appropriately screened. The faster infusions can reduce resource utilization and increase nursing satisfaction.Trial Registration
NCT0120677717.
Jane J. Keating Olugbenga T. Okusanya Elizabeth De Jesus Ryan Judy Jack Jiang Charuhas Deshpande Shuming Nie Philip Low Sunil Singhal 《Molecular imaging and biology》2016,18(2):209-218
Purpose
During lung surgery, identification of surgical margins is challenging. We hypothesized that molecular imaging with a fluorescent probe to pulmonary adenocarcinomas could enhance residual tumor during resection.Procedures
Mice with flank tumors received a contrast agent targeting folate receptor alpha. Optimal dose and time of injection was established. Margin detection was compared using traditional methods versus molecular imaging. A pilot study was then performed in three humans with lung adenocarcinoma.Results
The peak tumor-to-background ratio (TBR) of murine tumors was 3.9. Fluorescence peaked at 2 h and was not improved beyond 0.1 mg/kg. Traditional inspection identified 30 % of mice with positive margins. Molecular imaging identified an additional 50 % of residual tumor deposits (p?<?0.05). The fluorescent probe visually enhanced all human tumors with a mean TBR of 3.5.Conclusions
Molecular imaging is an important adjunct to traditional inspection to identify surgical margins after tumor resection.18.
Marjorie Paris Colombini Priscilla Bento Matos Cruz Derogis Valdir Fernandes de Aranda João Carlos de Campos Guerra Nelson Hamerschlak Cristóvão Luis Pitangueiras Mangueira 《Thrombosis journal》2017,15(1):21
Background
Rivaroxaban is a direct oral anticoagulant designed to dispense with the necessity of laboratory monitoring. However, monitoring rivaroxaban levels is necessary in certain clinical conditions, especially in the critical care setting.Methods
This is a diagnostic accuracy study evaluating sensitivity and specificity of prothrombin time (PT), activated partial thromboplastin time (aPTT), and Dilute Russell viper venom time (dRVVT), to evaluate the hemorrhagic risk in patients taking rivaroxaban. The study used a convenience sample of 40 clinically stable patients using rivaroxaban to treat deep vein thrombosis or atrial fibrillation admitted in a private hospital in Brazil, compared to a group of 60 healthy controls. The samples from patients were collected two hours after the use of the medication (peak) and two hours before the next dose (trough).Results
The correlation with the plasmatic concentration measured by anti-FXa assay was higher for PT and dRVVTS. The PT and aPTT tests presented higher specificity, while dRVVT was 100% sensible.Conclusions
There was a strong correlation between the tests and the plasma concentration of the drug. Additionally, our results demonstrated the potential use of dRVVT as a screening test in the emergency room and the need of a second test to improve specificity.19.
David J. W. Knight Dale Gardiner Amanda Banks Susan E. Snape Vivienne C. Weston Stig Bengmark Keith J. Girling 《Intensive care medicine》2009,35(5):854-861
Objective
To investigate the effect of enteral Synbiotic 2000 FORTE® (a mixture of lactic acid bacteria and fibre) on the incidence of ventilator associated pneumonia (VAP) in critically ill patients.Design
Prospective, randomised, double blind, placebo controlled trial.Setting
Tertiary referral centre, general Adult Intensive Care Unit (ICU).Patients and participants
259 enterally fed patients requiring mechanical ventilation for 48 h or more were enrolled.Intervention
All patients were enterally fed as per a standard protocol and randomly assigned to receive either synbiotic 2000 FORTE® (twice a day) or a cellulose-based placebo for a maximum of 28 days.Measurements and results
Treatment group (n = 130) was well matched with placebo group (n = 129) for age (mean 49.5 and 50 years, respectively) and APACHE II score (median 17 for both). Oropharyngeal microbial flora and colonisation rates were unaffected by synbiotics. The overall incidence of VAP was lower than anticipated (11.2%) and no statistical difference was demonstrated between groups receiving synbiotic and placebo in the incidence of VAP (9 and 13%, P = 0.42), VAP rate per 1,000 ventilator days (13 and 14.6, P = 0.91) or hospital mortality (27 and 33%, P = 0.39), respectively.Conclusions
Enteral administration of Synbiotic 2000 FORTE® has no statistically significant impact on the incidence of VAP in critically ill patients.20.
David M. Kwartowitz Fuad N. Mefleh G. Hamilton Baker 《International journal of computer assisted radiology and surgery》2017,12(10):1839-1844