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1.
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-142550.2.
Lin Pan Paula Belloni Han Ting Ding Jianshuang Wang Christopher M. Rubino Wendy S. Putnam 《Advances in therapy》2017,34(9):2071-2082
Introduction
Pirfenidone film-coated tablets were developed to offer an alternative to the marketed capsule formulation. This study assessed the bioequivalence of the tablet and capsule formulations under fed and fasted states.Methods
A Phase I, open-label, randomized, four-treatment-period, four-sequence, crossover pharmacokinetics study (NCT02525484) was conducted. Each subject received an 801-mg single dose of pirfenidone as three 267-mg capsules or one 801-mg tablet under fasted and fed conditions. Pirfenidone plasma C max, AUC0–t and AUC0–∞ were used to assess bioequivalence.Results
Forty-four subjects were randomized to treatment. The 801-mg tablet in the fasted state met bioequivalence criteria [90% confidence intervals (CI) 80.00–125.00%] for the GLSM ratios of natural log-transformed C max, AUC0–t and AUC0–∞. Under fed conditions, the 801-mg tablet met the bioequivalence criteria for AUC0–t and AUC0–∞, but slightly exceeded the bioequivalence criteria for the C max (90% CI of 108.26–125.60%). The tablet C max was approximately 17% higher than that of the capsules. In the fed state, the tablet C max, and both AUC0–t and AUC0–∞ were reduced by 39% and 17%, respectively, relative to the fasted state. The tablet and capsules had acceptable tolerability profiles.Conclusions
The pirfenidone 801-mg tablet met bioequivalence criteria when compared with three 267-mg capsules in the fasted state. The tablet C max was slightly higher relative to capsules in the fed state, but this is not expected to have a clinically meaningful impact on the benefit–risk profile of pirfenidone.Funding
This work was supported by F. Hoffmann-La Roche Ltd.3.
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, NCT02548806.4.
Introduction
Clopacin® (Acino Pharma AG) is a proprietary, besylate salt and lactose-free formulation of the widely-used anti-platelet treatment, clopidogrel. This study aimed to evaluate the bioequivalence of Clopacin® with the originator as reference drug, using a guideline-compliant trial design: open-labeled, randomized, single-dose (clopidogrel 75 mg tablet), two-period, crossover trial in 48 healthy male volunteers, with a 7 day wash-out period.Methods
Plasma samples were collected at intervals and extracted before quantifying clopidogrel concentrations using a fully validated LC–MS/MS method. Bioequivalence of Clopacin® and the reference drug was established by comparison of the primary pharmacokinetic parameters, C max, AUC0–t, and AUC0–∞.Results
The parameter values were similar for the two products (analysis of variance) and provided Clopacin/reference ratios (least squares means) of >90% and 90% confidence intervals (CIs 84.64–105.50%, 90.43–111.22%, 88.75–110.71%, respectively) that were well within the limits set for defining bioequivalence, according to international guidelines. The respective Clopacin® and reference drug values for mean time to maximal plasma clopidogrel concentration (t max) were 0.83 and 0.91 h, and for terminal elimination half-life were 3.99 and 3.51 h. The intra-subject coefficients of variability for maximal plasma clopidogrel concentration (C max), area under the plasma clopidogrel concentration versus time curve, at 48 h (AUC0–t) and extrapolated to infinity (AUC0–∞) were 32.2%, 30.2%, and 28.9% (least square means), respectively, and the respective power values were 99.5%, 97.1%, and 95.3%.Conclusion
This bioequivalence study provided robust clopidogrel pharmacokinetic data that established the bioequivalence of Clopacin® and the reference originator drug.Funding
Acino Pharma AG (formerly Cimex AG)5.
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.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.
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.
Tomohiro Kusawake James J. Keirns Donna Kowalski Martin den Adel Dorien Groenendaal-van de Meent Akitsugu Takada Yoshiaki Ohtsu Masataka Katashima 《Advances in therapy》2017,34(12):2625-2637
Introduction
Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella–zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants.Methods
Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5–2400 mg) or daily (300 or 600 mg/day) for 7 days.Results
Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUCinf) and C max. After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUCinf increased by about 90%. In the bioavailability study, AUCinf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported.Conclusion
Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUCinf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated.Funding
Astellas Pharma.Trial registration
ClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).9.
Introduction
Mifepristone, a competitive glucocorticoid receptor antagonist approved for Cushing syndrome, and ketoconazole, an antifungal and steroidogenesis inhibitor, are both inhibitors of and substrates for cytochrome P450 (CYP3A4). This study evaluated the pharmacokinetic effects of concomitant ketoconazole, a strong CYP3A4 inhibitor, on mifepristone.Methods
In an open-label, two-period, single-center study, healthy adult men received mifepristone 600 mg orally daily for 12 days (period 1) followed by mifepristone 600 mg daily plus ketoconazole 200 mg orally twice daily for 5 days (period 2). Serial pharmacokinetic blood samples were collected predose and over 24 h postdose on days 12 (period 1) and 17 (period 2). A cross-study comparison (using data on file) further examined whether systemic exposure to mifepristone plus ketoconazole exceeded the exposure following mifepristone 1200 mg orally administered for 7 days.Results
Sixteen subjects were enrolled and 14 completed the study. Concomitant administration with ketoconazole increased the systemic exposure to mifepristone, based on geometric least squares mean ratios, by 28% for C max and 38% for AUC0–24. This increase was 85% and 87% of the exposure observed following mifepristone’s highest label dose of 1200 mg/day for C max and AUC0–24, respectively. Adverse events (AEs) were reported in 56.3% (9/16) of subjects during administration of mifepristone alone and in 57.1% (8/14) during combination with ketoconazole. No serious AEs were reported.Conclusion
Systemic exposure to mifepristone increased following multiple doses of mifepristone 600 mg daily plus ketoconazole 200 mg twice daily. Little to no increase in AEs occurred. Dose adjustment of mifepristone may be needed when given with ketoconazole.Funding
Corcept Therapeutics.10.
Tomohiro Kusawake Martin den Adel Dorien Groenendaal-van de Meent Alberto Garcia-Hernandez Akitsugu Takada Kota Kato Yoshiaki Ohtsu Masataka Katashima 《Advances in therapy》2017,34(11):2466-2480
Introduction
Amenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants.Methods
Two studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80–1.25.Results
Interactions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C max and the area under the plasma concentration–time curve from time zero to infinity (AUCinf) were 1.30 (90% CI 1.17–1.45) and 2.58 (90% CI 2.32–2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37–0.49) and 0.17 (90% CI 0.15–0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUCinf and C max were 0.53 (90% CI 0.47–0.61) and 0.63 (90% CI 0.50–0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C max increased and mean AUCinf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits.Conclusion
These findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a cytochrome P450 3A4 inducer) can interact with midazolam; however, no interaction between amenamevir and (S)-warfarin was observed, indicating that amenamevir is not an inducer of cytochrome P450 2C9.Funding
Astellas Pharma.Trial registration
EudraCT2007-002227-33 (study 15L-CL-008), EudraCT2007-002228-14 (study 15L-CL-009), EudraCT2007-002761-13 (study 15L-CL-010), and EudraCT2007-002779-14 (study 15L-CL-018).11.
Ji Wang Jie-Jun Cheng Kai-Yi Huang Zhi-Guo Zhuang Xue-Bin Zhang Jia-Chang Chi Xiao-Lan Hua Jian-Rong Xu 《Abdominal imaging》2016,41(3):545-552
Purpose
The aim of this study was to develop a quantitative measurement of perfusion reduction using color-coded digital subtraction angiography (ccDSA) to monitor intra-procedural arterial stasis during TACE.Materials and methods
A total number of 35 patients with hepatocellular carcinoma who had undergone TACE were enrolled into the study. Pre- and post-two-dimensional digital subtraction angiography scans were conducted with same protocol and post-processed with ccDSA prototype software. Time-contrast-intensity (CI[t]) curve was obtained by region-of-interest (ROI) measurement on the generated ccDSA image. Quantitative 2D perfusion parameters time to peak, area under the curve (AUC), maximum upslope, and contrast intensity peak (CI-Peak) derived from the ROI-based CI[t] curve for pre- and post-TACE were evaluated to assess the reduction of antegrade blood flow and tumor blush. Relationships between 2D perfusion parameters, subjective angiographic chemoembolization endpoint (SACE) scale, and clinical outcomes were analyzed.Results
Area normalized AUC and CI-Peak revealed significant reduction after the TACE (P < 0.0001). AUCnorm decreased from pre-procedure of 0.867 ± 0.242 to 0.421 ± 0.171 (P < 0.001) after completion of TACE. CI-Peaknorm was 0.739 ± 0.221 before TACE and 0.421 ± 0.174 (P < 0.001) after TACE. Tumor blood supply time slowed down obviously after embolization. A perfusion reduction either from AUCnorm or CI-Peaknorm ranging from 30% to 40% was associated with SACE level III and a reduction ranging from 60% to 70% was equivalent to SACE level IV. For intermediate reduction (SACE level III), better tumor response was found after TACE rather than a higher reduction (SACE level IV).Conclusion
ccDSA application provides an objective approach to quantify the perfusion reduction and subjectively evaluate the arterial stasis of antegrade blood flow and tumor blush caused by TACE.12.
Yuuichi Sakurai Madoka Shiino Hiroyuki Okamoto Akira Nishimura Koki Nakamura Setsuo Hasegawa 《Advances in therapy》2016,33(9):1519-1535
Introduction
Vonoprazan (TAK-438) is a novel potassium-competitive acid blocker that inhibits gastric H+, K+-ATPase. The objectives of this study were to evaluate the influence of triple therapy with vonoprazan–amoxicillin–clarithromycin or vonoprazan–amoxicillin–metronidazole on the pharmacokinetics of each component of the triple therapies (primary) and to evaluate the safety and tolerability of vonoprazan-based triple therapies (secondary) in healthy adults.Methods
In this single-center, phase 1, open-label, randomized, four-way crossover study, Helicobacter pylori-negative, healthy Japanese male subjects were randomly assigned to 1 of 4 treatment sequences in two cohorts (12 subjects per cohort). Each treatment sequence comprised four treatment periods separated by a washout period of 7 or 14 days. Pharmacokinetic parameters for vonoprazan, amoxicillin, clarithromycin and metronidazole in single therapy or triple therapies were assessed. All adverse events were recorded.Results
Compared with single therapy, triple therapy with vonoprazan–amoxicillin–clarithromycin increased the area under the plasma concentration–time curve from time 0–12 h (AUC0-12) and maximum plasma concentration (C max) of plasma vonoprazan free base by 1.846- and 1.868-fold, respectively, and increased the AUC0-12 and C max of plasma clarithromycin by 1.450- and 1.635-fold, respectively. Triple therapy with vonoprazan–amoxicillin–metronidazole had no influence on the pharmacokinetics of vonoprazan or metronidazole. The pharmacokinetics of amoxicillin was not influenced by vonoprazan-based triple therapies. Seven adverse events were reported. Two subjects discontinued because of an adverse event (rash, liver function test abnormal); both events were considered to be study drug-related.Conclusion
In healthy Japanese male subjects, triple therapy with vonoprazan–amoxicillin–clarithromycin increased vonoprazan and clarithromycin exposure. The safety and tolerability profile of triple therapy with vonoprazan–amoxicillin–clarithromycin or vonoprazan–amoxicillin–metronidazole was favorable in this population.Funding
Takeda Pharmaceutical Company Ltd.Trial registration
JapicCTI-153102.13.
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.15.
Xiao-feng Xiong Li-li Fan Hong-xia Wu Min Zhu De-yun Cheng 《Advances in therapy》2018,35(12):2201-2213
Introduction
Tiotropium bromide has been widely used in clinical practice, while theophylline is another treatment option for chronic obstructive pulmonary disease (COPD). However, only a few relevant studies have investigated the long-term outcomes and efficacy of both in patients with COPD. We evaluated the effects of tiotropium and low-dose theophylline on stable COPD patients of groups B and D.Methods
Eligible participants (n?=?170) were randomized and received either tiotropium 18 µg once daily with theophylline 100 mg twice daily (Group I) or tiotropium 18 µg once daily (Group II) for 6 months. COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scores and pulmonary function tests were measured before randomization and during the treatment.Results
After 6 months of treatment, the CAT scores in both groups decreased significantly (11.41?±?3.56 and 11.08?±?3.05, p?<?0.0001). The changes of CAT (p?=?0.028) and mMRC scores (p?=?0.049) between the two groups differed after 1 month of treatment. In Group I, forced expiratory flow after 25% of the FVC% predicted (MEF25% pred) was significantly improved after 3 months (4.84?±?8.73%, p?<?0.0001) and 6 months (6.21?±?8.65%, p?<?0.0001). There was a significant difference in small airway function tests (MEF50% pred, MEF25% pred, and MMEF% pred) between the two groups after 6 month of treatment (p?=?0.003, p?<?0.0001, and p?=?0.021, respectively).Conclusions
Tiotropium combined with low-dose theophylline significantly improved the symptoms and general health of patients with stable COPD of groups B and D after 6 months of follow-up. Additionally, this therapy also improved the indicators of small airway function.Trial Registration
Chinese Clinical Trial Registry (Registry ID: ChiCTR1800019027).16.
Ralph Kickuth Hanno Hoppe Bettina Saar Daniel Inderbitzin Jürgen Triller Susanne Raessler Jürgen Gschossmann 《Abdominal imaging》2016,41(9):1782-1792
Purpose
To evaluate the efficacy of superselective transcatheter arterial embolization (TAE) in the treatment of acute peripancreatic bleeding complications.Methods
During a 9-year period, 44 patients with acute bleeding of the peripancreatic arteries underwent TAE in our institution. Thirty-eight patients were treated using microcatheters and 6 patients with a diagnostic catheter. Embolic agents included coils (n = 38), polyvinyl alcohol (PVA) particles (n = 2), isobutyl cyanoacrylate (n = 2), coils plus PVA particles (n = 1), and coils plus isobutyl cyanoacrylate (n = 1). Outcome measures included technical success, clinical success, and the rate of complications.Results
Identified bleeding sources included gastroduodenal artery (n = 14), splenic artery (n = 9), pancreaticoduodenal artery (n = 6), common hepatic artery (n = 5), superior mesenteric artery branches (n = 4), proper hepatic artery (n = 3), and dorsal/transverse pancreatic artery (n = 3). Technical success with effective control of active bleeding was achieved in 41/44 patients (93 %). Clinical success attributed to TAE alone was documented in 40/44 patients (91 %). The rate of major complications was 2 % including death in one patient.Conclusions
Superselective TAE allows effective, minimally invasive control of acute peripancreatic bleeding complications with a low rate of therapeutically relevant complications.17.
Purpose
To introduce a new diagnostic parameter: the linear combination of apparent integrated backscatter and spectral centroid shift.Methods
Ultrasonic backscatter measurements were performed at the calcanei of 1262 volunteers in vivo. The hip and spine bone mineral densities of the volunteers were measured using dual X-ray absorptiometry. The apparent integrated backscatter and spectral centroid shift were calculated. A new diagnostic parameter, i.e., the linear combination of apparent integrated backscatter and spectral centroid shift, was introduced and its correlation to bone mineral density was analyzed.Results
The results show that the combination of apparent integrated backscatter and spectral centroid shift is significantly correlated to bone mineral density (R = 0.73–0.84, n = 1262, p < 0.05), and that this correlation is more significant than the correlation between the apparent integrated backscatter and bone mineral density or the correlation between spectral centroid shift and bone mineral density (R = 0.48–0.69, p < 0.05).Conclusion
The combination of apparent integrated backscatter and spectral centroid shift can provide the complementary information of attenuation of the two parameters and predict more information about cancellous bone, and may be employed to assess cancellous bone status.18.
Harumi Koibuchi Yasutomo Fujii Yoshikazu Hirai Takashi Mochizuki Kohji Masuda Kazuhiko Kotani Toshiyuki Yamada Nobuyuki Taniguchi 《Journal of Medical Ultrasonics》2018,45(1):25-29
Purpose
The purpose of this study was to clarify the effect of ultrasonic irradiation on biofilm produced by Staphylococcus epidermidis (S. epidermidis), which causes central venous catheter-related infections.Materials and methods
Staphylococcus epidermidis (S. epidermidis, ATCC 35984 RP 62A) was used in this study. First, biofilm was prepared from S. epidermidis on the bottom of the upper left well of a 6-well plate. Next, the biofilm was irradiated for 24 h with 1-MHz ultrasound (US) in the continuous wave mode to serve as the US irradiation group. The acoustic power irradiated below the bottom of the well was 3.8 mW. As a control (non-US irradiation group), non-irradiated biofilm on the bottom of a 6-well plate was incubated at 37 °C in an atmosphere of 5.0% CO2. After US irradiation, the bottoms of the wells were stained with 0.1% crystal violet for 60 s. To extract the crystal violet, 99.5% ethanol was added to the wells, and the extracted solutions were measured at an absorbance of 595 nm.Result
The absorbance of the US irradiation group was significantly less than that of the non-US irradiation group (p < 0.01).Conclusion
US irradiation can decrease the amount of S. epidermidis biofilm when the duration of US irradiation is sufficiently long even if the acoustic intensity is low.19.
Ryosuke Arakawa Lars Farde Junya Matsumoto Naoki Kanegawa Igor Yakushev Kai-Chun Yang Akihiro Takano 《Molecular imaging and biology》2018,20(2):183-187
Purpose
Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BPND) of [11C]raclopride in NHP.Procedures
Three cynomolgus monkeys underwent two to three PET measurements with [11C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BPND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region.Results
In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman’s ρ = ? 0.79, p = 0.03), but not with BPND (ρ = ? 0.25, p = 0.55).Conclusions
These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BPND in consecutive PET measurements.20.
Damien Cressier Martine Dhilly Thang T. Cao Pham Fabien Fillesoye Fabienne Gourand Auriane Maïza André F. Martins Jean-François Morfin Carlos F. G. C. Geraldes Éva Tóth Louisa Barré 《Molecular imaging and biology》2016,18(3):334-343