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1.
Nancy M. Albert Dana A. Drzayich Antol Richard W. DeClue Adrianne Waldman Casebeer Yong Li Stephen Stemkowski Chun-Lan Chang 《Advances in therapy》2017,34(10):2345-2359
Introduction
Factors associated with mortality for patients with heart failure and reduced ejection fraction (HFrEF) are known; however, the association between initial pharmacotherapy (IPT) and mortality is unclear in real-world settings.Methods
Using a retrospective design and claims database, 14,359 Medicare patients with HFrEF from August 2010 to July 2015 were identified. Index date was first HF claim. IPT was mono- or combo-angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), beta-blocker (BB), hydralazine–nitrate (HN), and aldosterone antagonist (AA) within 1 year post-index. A multivariable time-dependent Cox model estimated associations between IPT and 2-year all-cause mortality.Results
Patients’ median age was 76 (70–82) years; 45.1% were female. Within 1 month post-index, 61.4% had IPT, 6.1% started after the first month, and 32.4% had no IPT in the first year. Of IPTs, 47.5% were mono-vasodilators (ACEI, ARB or HN), 23.3% mono-vasodilator + BB, 16.9% mono-BB, and 3.5% triple therapy [(ACEI or ARB) + BB + (HN or AA)]. Two-year mortality rate was 27.9%. Compared to mono-vasodilator therapy, patients initiating triple therapy had 29.3% lower risk of 2-year mortality; those on mono-BB or no IPT had higher mortality risk.Conclusion
IPT was associated with decreased 2-year mortality risk. Timely consideration of triple IPT therapies may be warranted once HFrEF diagnosis is confirmed.Funding
Novartis Pharmaceuticals Corp. located in East Hanover, NJ, USA.2.
Background
The study was performed to reveal the effect of an individualized personal outpatient therapy program, based on a multidisciplinary assessment, on pain and health-related quality of life in patients with chronic pain.Methods
Fifty patients were prospectively evaluated before and 3 months after establishment of an individualized outpatient therapy program. Health-related quality of life, pain and pain-related disability, depression and motivation to adopt self-management of chronic pain were assessed. Therapy adherence was tested with a structured interview.Results
Only marginal improvements were observed in terms of pain and health-related quality of life. Therapy adherence varied between the different therapies.Conclusions
An individualized personal outpatient therapy program has only marginal effects on pain and health-related quality of life in patients with chronic pain.3.
Daniel Du 《Advances in therapy》2018,35(8):1169-1180
Introduction
Nicotine replacement therapy (NRT) benefits smokers who wish to quit; nicotine gum represents one NRT. New formulations of nicotine gum have been developed to consider consumer preferences and needs. A new mint-flavored nicotine gum with a different texture was developed that may provide a more appealing taste and chewing experience. This study evaluated this new nicotine gum (2 and 4 mg strengths) for bioequivalence versus the original flavor sugar-free nicotine gum at corresponding dosages.Methods
All subjects randomized in this crossover study received a single dose of all treatments, i.e., 2 and 4 mg doses of test and reference gums, separated by 2–7 days of washout between treatments. Subjects’ maximal plasma nicotine concentration (Cmax) and extent of nicotine absorption (AUC0–t) following the administration of each treatment were calculated from plasma nicotine concentrations. Ratios of test/reference for Cmax and AUC0–t were calculated to evaluate bioequivalence between the two products.Results
Both 2 and 4 mg doses of the new mint-flavored nicotine gum were bioequivalent to the dose-matched reference product as determined by the ratio of the geometric means and their 90% confidence intervals for Cmax and AUC0–t as well as secondary pharmacokinetic parameters. The safety profiles of the test and reference gums were similar; all treatments were well tolerated.Conclusions
A new mint-flavored nicotine gum with modified taste and texture is bioequivalent to the original flavor sugar-free nicotine gum at both the 2 and 4 mg dosage strengths and has a similar safety profile.Funding
GlaxoSmithKline.Trial Registration
ClinicalTrials.gov identifier NCT01847443.4.
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
NCT02093351.5.
Anna Theodorou-Kanakari Spyridon Karampitianis Vasiliki Karageorgou Eleni Kampourelli Efstathios Kapasakis Panagiotis Theodossiadis Irini Chatziralli 《Advances in therapy》2018,35(10):1510-1518
Introduction
The purpose of this review is to present the current and emerging treatment alternatives for Leber’s hereditary optic neuropathy (LHON), emphasizing the most recent use of idebenone and stem cells or gene therapy.Methods
A comprehensive literature review was performed at the PubMed database regarding the various treatment modalities for LHON.Results
Treatment modalities for LHON include nutritional supplements, activators of mitochondrial biogenesis, brimonidine, and symptomatic and supportive treatment, but nowadays attention is being paid to idebenone and gene therapy or stem cells.Conclusion
The treatment of LHON remains challenging, given the nature of the disease and its prognosis.6.
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.7.
Objective
Imbalance of the renal medullary oxygen supply/demand relationship can cause hypoxic medullary damage and ischaemic acute renal failure (ARF). The use of mannitol for prophylaxis/treatment of clinical ischaemic ARF is controversial and the effect of mannitol on renal oxygenation in man has not yet been investigated. We evaluated the effects of mannitol on renal oxygen consumption (RVO2), renal blood flow (RBF) and glomerular filtration rate (GFR) in postoperative patients.Design
Prospective interventional study.Setting
University hospital cardiothoracic ICU.Patients
Ten uncomplicated mechanically ventilated and sedated postcardiac surgery patients with preoperatively normal renal function.Interventions
Mannitol infusion (225 mg/kg + 75 mg/kg/h) and combined mannitol and furosemide infusion (0.25 mg/kg + 0.25 mg/kg/h).Measurements and results
Systemic haemodynamics were evaluated by a pulmonary artery catheter. RBF and GFR were measured by the renal vein thermodilution technique and by renal extraction of 51Cr–EDTA, respectively. Mannitol increased urine flow (60%), GFR (20%) and filtration fraction (FF) (20%) with no change in RBF. This was accompanied by an increase in renal sodium reabsorption (18%), RVO2 (19%) and renal oxygen extraction (21%). When combined with mannitol, furosemide normalised sodium reabsorption, RVO2, renal oxygen extraction with no change in RBF, while GFR and FF were still elevated compared to control.Conclusions
In patients with normal renal function, mannitol increases GFR, which increases tubular sodium load, sodium reabsorption and RVO2 after cardiac surgery. The lack of effect on RBF, indicates that mannitol impairs the renal oxygen supply/demand relationship. Furosemide normalised renal oxygenation when combined with mannitol.8.
Lindsay E. Kelderhouse Sakkarapalayam Mahalingam Philip S. Low 《Molecular imaging and biology》2016,18(2):201-208
Purpose
Although current therapies for many inflammatory/autoimmune diseases are effective, a significant number of patients still exhibit only partial or negligible responses to therapeutic intervention. Since prolonged use of an inadequate therapy can result in both progressive tissue damage and unnecessary expense, methods to identify nonresponding patients are necessary.Procedures
Four murine models of inflammatory disease (rheumatoid arthritis, ulcerative colitis, pulmonary fibrosis, and atherosclerosis) were induced, treated with anti-inflammatory agents, and evaluated for inflammatory response. The mice were also injected intraperitoneally with OTL0038, a folate receptor-targeted near-infrared dye that accumulates in activated macrophages at sites of inflammation. Uptake of OTL0038 in inflamed lesions was then correlated with clinical measurements of disease severity.Results
OTL0038 accumulated at sites of inflammation in all four animal models. More importantly, changes in lesion-associated OTL0038 preceded changes in clinical symptoms in mice treated with all anti-inflammatory drugs examined.Conclusion
OTL0038 has the ability to predict responses to multiple therapies in four murine models of inflammation.9.
Manabu Kato Hitoshi Ishizuka Takashi Taguchi Kazuhito Shiosakai Emi Kamiyama Michio Sata Takafumi Yoshida 《Advances in therapy》2018,35(8):1239-1250
Introduction
The pharmacokinetics, safety, and tolerability of DS-8500a (a G protein receptor 119 agonist) up to 100 mg have been investigated in healthy Japanese adults. The objective of this study was to evaluate the effects of hepatic or renal impairment on the pharmacokinetics of a single 25-mg oral dose of DS-8500a.Methods
This single-center, open-label study enrolled subjects into eight groups according to hepatic function (normal; mild or moderate impairment) and renal function [normal; mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]. Drug concentrations were measured by liquid-chromatography tandem mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. Adverse events (AEs) were evaluated for safety.Results
The hepatic and renal groups enrolled 15 and 30 subjects, respectively. Pharmacokinetic parameters of DS-8500a were comparable between the normal hepatic function and mild hepatic impairment groups, but the mean area under the concentration–time curve (AUC) was 1.37-fold higher, and the half-life was longer in the moderate hepatic impairment group compared with the normal hepatic function group. The maximum concentration (Cmax) and AUC values were 0.704- and 0.609-fold lower, respectively, in the ESRD group compared with the values in the other renal impairment groups; no clear differences in AUC and time to Cmax were observed in the normal function and mild, moderate, and severe renal impairment groups. There was no relationship between apparent total body clearance and estimated glomerular filtration rate. The incidence of AEs was similar among all groups.Conclusion
DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD.Trial registration
Japic CTI-No. 163135.Funding
Daiichi Sankyo Co. Ltd., Tokyo, Japan.10.
Ivan Urits Abra H. Shen Mark R. Jones Omar Viswanath Alan D. Kaye 《Current pain and headache reports》2018,22(2):10
Purpose of Review
Complex regional pain syndrome (CRPS) refers to a chronic pain condition that is characterized by progressively worsening spontaneous regional pain without dermatomal distribution. The symptomatology includes pain out of proportion in time and severity to the inciting event. The purpose of this review is to present the most current information concerning epidemiology, diagnosis, pathophysiology, and therapy for CRPS.Recent Findings
In recent years, discovery of pathophysiologic mechanisms of CRPS has led to significant strides in the understanding of the disease process.Summary
Continued elucidation of the underlying pathophysiological mechanisms will allow for the development of more targeted and effective evidence-based therapy protocols. Further large clinical trials are needed to investigate mechanisms and treatment of the disorder.11.
Casey Quinn Qiufei Ma Amber Kudlac Stephen Palmer Beth Barber Zhongyun Zhao 《Advances in therapy》2017,34(2):495-512
Introduction
Advances in the treatment of metastatic melanoma have been achieved in recent years: immunotherapies and targeted therapies have demonstrated survival benefits over older agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF), dacarbazine, and glycoprotein peptide vaccine (gp100) in pivotal phase 3 trials. It is important to compare therapies to guide the treatment decision-making process, and establishing the relationship between older agents can strengthen the networks of evidence for newer therapies. We report the outcome of an indirect comparison of GM-CSF, dacarbazine, and gp100 in metastatic melanoma through meta-analysis of absolute treatment effect.Methods
A systematic literature review identified trials for inclusion in the meta-analysis. A valid network meta-analysis was not feasible: treatment-specific meta-analysis was conducted. A published algorithm was used to adjust overall survival estimates from trials of GM-CSF, dacarbazine, and gp100 for heterogeneity in baseline prognostic factors. Survival estimates were compared in three patient groups: stage IIIB–IV M1c, stage IIIB–IV M1a, and stage IV M1b/c.Results
One trial of GM-CSF, four of dacarbazine, and one of gp100 were included in the analysis. After adjusting for differences in baseline prognostic factors, median overall survival (OS) in all patient groups was longer for those receiving GM-CSF than for those receiving dacarbazine or gp100. The observed survival over time for GM-CSF was similar to the adjusted survival for dacarbazine and greater than for gp100 in all patient groups.Conclusion
The relative treatment effect of GM-CSF, dacarbazine, and gp100 has been reliably estimated by adjusting for differences in baseline prognostic factors. Results suggest that OS with GM-CSF is at least as good as with dacarbazine and greater than with gp100. Given the role of these agents as controls in phase 3 trials of new immunotherapies and targeted agents, these results can be used to contextualize the efficacy of newer therapies.Funding
Amgen Inc.12.
Eric Sheldon Martin Schwickart Jing Li Keunpyo Kim Sarah Crouch Shaista Parveen Chris Kell Claire Birrell 《Advances in therapy》2016,33(2):225-251
Introduction
The anti-IgE therapy omalizumab is currently licensed for the treatment of moderate to severe allergic asthma and chronic idiopathic urticaria. Owing to limitations in the use of omalizumab, a need exists for optimized anti-IgE therapies to broaden clinical indications and patient populations, and to improve dosing schedules. The objective of this phase I, randomized, placebo/omalizumab-controlled, first-in-human, dose-escalation study was to evaluate the pharmacokinetics, pharmacodynamics, and safety of the high-affinity, anti-IgE therapy MEDI4212 in non-Japanese and Japanese subjects with atopy and/or diagnostic IgE ≥30 IU/mL.Methods
Subjects with atopy and/or baseline IgE ≥30 IU/mL were randomized to a single dose of subcutaneous (5, 15, 60, 150, or 300 mg) or intravenous (300 mg) MEDI4212, subcutaneous omalizumab, or placebo. Following administration, pharmacokinetic, pharmacodynamic [IgE (free and total), and cellular FcεRI expression], and safety assessments were made.Results
MEDI4212 rapidly suppressed free serum IgE to a greater extent than omalizumab; however, recovery of free IgE to baseline in MEDI4212-dosed subjects was rapid when compared with the slow and gradual recovery seen in omalizumab-dosed individuals. The loss of IgE suppression corresponded with a rapid decrease of serum MEDI4212. FcεRI expression on dendritic cells and basophils was reduced following MEDI4212 dosing. MEDI4212 was well tolerated by subjects; adverse events were generally of low severity and no subjects discontinued due to adverse events.Conclusions
The increased potency of MEDI4212 may be of clinical interest for individuals with high-diagnostic IgE levels where more extensive IgE suppression is required for clinical response. However, the modest duration of free IgE suppression below the target concentration noted with MEDI4212 in this study suggests limited potential for dosing schedule advantages over omalizumab.Funding
MedImmune.Trial registration
ClinicalTrials.gov identifier, NCT01544348.13.
Hiroaki Ito Shigeru Furuta Hidetaka Sasaki Toyomitsu Yoshida Yuichi Takano Toshifumi Hibi 《Advances in therapy》2009,26(8):749-761
Introduction
The pharmacokinetics and safety of Asacol® (Tillotts Pharma AG, Ziefen, Switzerland), which has been used worldwide to treat ulcerative colitis and Crohn’s disease, were studied in Japanese healthy male volunteers.Methods
Drug plasma concentrations and urinary and fecal excretions after a single dose (400–4800 mg) and multiple doses (3600 mg/day for 7 days) were investigated.Results
All adverse events were “not serious.” The peak plasma concentration (Cmax) was reached at 12.3–18.0 hours after a single dose, and the Cmax and area under the plasma concentration-time curve (AUC) of mesalazine and its N-acetyl metabolite were proportional to the doses. The Cmax and AUC in non-Japanese subjects reported in the literature were closely correlated to findings in Japanese subjects, and external excretions were also similar in the Japanese and non-Japanese subjects.Conclusions
Asacol was safe and well tolerated in this Japanese population, and the non-Japanese clinical data could be extrapolated to the Japanese population.14.
Ippei Ikushima Lene Jensen Anne Flint Tomoyuki Nishida Jeppe Zacho Shin Irie 《Advances in therapy》2018,35(4):531-544
Introduction
Semaglutide is a glucagon-like peptide-1 analogue for once-weekly subcutaneous treatment of type 2 diabetes. This trial compared the pharmacokinetics, pharmacodynamics, and safety of semaglutide in Japanese and Caucasian subjects.Methods
In this single-center, double-blind, parallel-group, 13-week trial, 44 healthy male subjects (22 Japanese, 22 Caucasian) were randomized within each race to semaglutide 0.5 mg (n = 8), 1.0 mg (n = 8), placebo 0.5 mg (n = 3) or 1.0 mg (n = 3). The primary endpoint was semaglutide exposure at steady state [area under the curve (AUC0–168h)].Results
Steady-state exposure of semaglutide was similar for both populations: AUC0–168h estimated race ratio (ERR), Japanese/Caucasian: 0.5 mg, 1.06; 1.0 mg, 0.99; maximum concentration (Cmax) ERR: 0.5 mg, 1.06; 1.0 mg, 1.02. Exposure after the first dose (0.25 mg) was slightly higher in Japanese versus Caucasian subjects (AUC0–168h ERR 1.11; Cmax ERR 1.14). Dose-dependent increases in AUC0–168h and Cmax occurred in both populations. Accumulation was as expected, based on the half-life (t1/2, ~ 1 week) and dosing interval of semaglutide. Significant body weight reductions were observed with semaglutide 0.5 mg and 1.0 mg in Japanese (both p ≤ 0.05) and Caucasian (both p ≤ 0.05) subjects versus placebo. No new safety issues were identified.Conclusions
The pharmacokinetic, pharmacodynamic, and safety profiles of semaglutide were similar in Japanese and Caucasian subjects, suggesting that no dose adjustment is required for the clinical use of semaglutide in Japanese subjects.Funding
Novo Nordisk A/S, Denmark.Trial registration
ClinicalTrials.gov identifier NCT02146079. Japanese trial registration number JapicCTI-142550.15.
Introduction
To present short-term safety and efficacy data of men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) treated with Aquablation.Methods
Men with LUTs secondary to BPH (60–150 cc) underwent Aquablation treatment from February 2016 to December 2017 across 17 investigational sites in the USA from two contemporary investigational device exemption (IDE) studies called WATER (NCT02505919) and WATER II (NCT03123250).Results
One hundred seven males with mean age of 67.3?±?6.5 years were treated with Aquablation; mean prostate volume was 99.4?±?24.1 cc. The pooled results show that large prostates have an average procedure time of less than 36 min and discharge on average 1.6?±?1 days. The IPSS decreased by 16.7?±?8.1 points at 3 months and Qmax increased by 11.2?±?12.4 ml/s. The Clavien-Dindo (CD) grade 2 or higher event rate at 3 months was 29%. A non-hierarchical breakdown for CD events yielded 18% grade 2 and 19% grade 3 or higher.Conclusion
Men with LUTS secondary to BPH (60–150 cc) in a pooled analysis were treated safely and effectively with Aquablation up to 3 months postoperatively.Trial Registration
ClinicalTrials.gov identifiers, NCT02505919 and NCT03123250.Funding
PROCEPT BioRobotics.16.
Karlsson S Varpula M Ruokonen E Pettilä V Parviainen I Ala-Kokko TI Kolho E Rintala EM 《Intensive care medicine》2007,33(3):435-443
Objective
To determine the incidence and outcome of severe sepsis in the adult Finnish population and to evaluate how treatment guidelines in severe sepsis are applied in clinical practice.Study design
A prospective study in 24 closed multidisciplinary ICUs in 21 hospitals (4 university and 17 tertiary hospitals) in Finland.Patients
All 4,500 consecutive ICU admission episodes were screened for severe sepsis during a 4-month period (1 November 2004 – 28 February 2005). The referral population was 3,743,225.Results
The severe sepsis criteria were fulfilled in 470 patients, who had472 septic episodes. The incidence of severe sepsis in the ICUs in Finland was 0.38/1000 in the adult population (95% confidence interval 0.34–0.41). The mean ICU length of stay was 8.2?±?8.1?days. ICU, hospital, and 1-year mortality rates were 15.5%, 28.3%, and 40.9%, respectively. Respiratory failure requiring ventilation support was the most common organ failure (86.2%); septic shock was present in 77% and acute renal failure in 20.6% of cases. Activated protein C was given to only 15 of the 55 patients with indication (27%) and low-dose corticosteroids to 150 of 366 (41%) patients with septic shock.Conclusions
This prospective study found the incidence of ICU-treated severe sepsis in Finland to be 0.38 per 1,000 of the population. The ICU and hospital mortalities were also lower than earlier reported in United States or Australia. Evidence-based sepsis therapies were not used as often as recommended.17.
Andrew Conway Morris Deepankar Datta Manu Shankar-Hari Jacqueline Stephen Christopher J. Weir Jillian Rennie Jean Antonelli Anthony Bateman Noel Warner Kevin Judge Jim Keenan Alice Wang Tony Burpee K. Alun Brown Sion M. Lewis Tracey Mare Alistair I. Roy Gillian Hulme Ian Dimmick Adriano G. Rossi A. John Simpson Timothy S. Walsh 《Intensive care medicine》2018,44(5):627-635
Purpose
Cellular immune dysfunctions, which are common in intensive care patients, predict a number of significant complications. In order to effectively target treatments, clinically applicable measures need to be developed to detect dysfunction. The objective was to confirm the ability of cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients.Methods
Multi-centre, prospective observational cohort study of critically ill patients in four UK intensive care units. Serial blood samples were taken, and three cell surface markers associated with immune cell dysfunction [neutrophil CD88, monocyte human leucocyte antigen-DR (HLA-DR) and percentage of regulatory T cells (Tregs)] were assayed on-site using standardized flow cytometric measures. Patients were followed up for the development of secondary infections.Results
A total of 148 patients were recruited, with data available from 138. Reduced neutrophil CD88, reduced monocyte HLA-DR and elevated proportions of Tregs were all associated with subsequent development of infection with odds ratios (95% CI) of 2.18 (1.00–4.74), 3.44 (1.58–7.47) and 2.41 (1.14–5.11), respectively. Burden of immune dysfunction predicted a progressive increase in risk of infection, from 14% for patients with no dysfunction to 59% for patients with dysfunction of all three markers. The tests failed to risk stratify patients shortly after ICU admission but were effective between days 3 and 9.Conclusions
This study confirms our previous findings that three cell surface markers can predict risk of subsequent secondary infection, demonstrates the feasibility of standardized multisite flow cytometry and presents a tool which can be used to target future immunomodulatory therapies.Trial registration
The study was registered with clinicaltrials.gov (NCT02186522).18.
Daniel Rutrick Dan J. Stein Ganesan Subramanian Brian Smith Maurizio Fava Gregor Hasler Jang-Ho Cha Fabrizio Gasparini Toni Donchev Magdalena Ocwieja Donald Johns Baltazar Gomez-Mancilla 《Advances in therapy》2017,34(2):524-541
Introduction
To determine if mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale–Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive–compulsive disorder (OCD) resistant to SSRI treatment.Methods
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study. Patients remained on their SSRI treatment and mavoglurant or placebo was added on. Non-smoking men and women aged 18–65 years primarily diagnosed with OCD according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria were randomized (1:1) to mavoglurant or placebo groups. After 50 patients were randomized, an interim analysis was conducted to determine whether the study should be continued. The primary outcome measure was absolute change in Y-BOCS from baseline at week 17. Safety was assessed by recording adverse events (AEs) and serious adverse events (SAEs).Results
Interim analysis led to a decision to terminate the study. In total 38 (76.0%) participants completed 17 weeks of treatment and 37 (74.0%) completed the study. There was no significant difference in least squares (LS) mean change from baseline at week 17 in Y-BOCS total score for mavoglurant compared with placebo groups [?6.9 (1.75) vs. ?8.0 (1.78), respectively; LS mean difference 1.1; 95% CI ?3.9, 6.2; p = 0.671]. The incidence of AEs was higher in the mavoglurant compared with the placebo group (80.8% vs. 70.8%, respectively).Conclusion
This study of mavoglurant in OCD was terminated because of the lack of efficacy at interim analysis. The study did not support the use of an antagonist of mGluR5 receptors for OCD treatment.Trial Registration
The study was registered with ClinicalTrials.gov: NCT01813019.Funding
This study was sponsored by Novartis Pharma AG, Basel, Switzerland.19.
Mariana Vigiola Cruz Jenna N. Luker Bonnie C. Carney Kathleen E. Brummel-Ziedins Maria-Cristina Bravo Thomas Orfeo Jason H. Chen Lauren T. Moffatt Jeffrey W. Shupp 《Thrombosis journal》2017,15(1):31
Background
A functional coagulation assay was used to investigate the extrinsic pathway of coagulation on citrated whole blood samples from healthy adult male Sprague Dawley rats using the mini cup and pin system.Methods
Reference values for coagulation parameters from forty-three animals were calculated using data obtained from the ROTEM® delta hemostasis analyzer with the EXTEM test.Results
The following ranges, presented as the 2.5–97.5 percentiles, were established: CT [18–77], CFT [20–80], α [73–86], MCF [53–70], and ML [1–22], along with others.Conclusions
These reference ranges can be used in future studies in rats to identify clinically significant coagulopathies.20.