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1.
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).2.
Tomohiro Kusawake Donna Kowalski Akitsugu Takada Kota Kato Masataka Katashima James J. Keirns Michaelene Lewand Kenneth C. Lasseter Thomas C. Marbury Richard A. Preston 《Advances in therapy》2017,34(12):2612-2624
Introduction
Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.Methods
These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.Results
In the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated.Conclusion
The findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5–2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearanceFunding
Astellas Pharma.3.
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.4.
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.5.
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 NCT01847443.6.
Matthieu Jabaudon Raiko Blondonnet Bruno Pereira Rodrigo Cartin-Ceba Christoph Lichtenstern Tommaso Mauri Rogier M. Determann Tomas Drabek Rolf D. Hubmayr Ognjen Gajic Florian Uhle Andrea Coppadoro Antonio Pesenti Marcus J. Schultz Marco V. Ranieri Helena Brodska Ségolène Mrozek Vincent Sapin Michael A. Matthay Jean-Michel Constantin Carolyn S. Calfee 《Intensive care medicine》2018,44(9):1388-1399
Purpose
The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury.Methods
We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume.Results
Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01–1.38; P?=?0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02–1.07; P?=?0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07–3.64; P?=?0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher VT.Conclusions
Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).7.
Jeffrey E. Edwards Lise Eliot Andrew Parkinson Sharon Karan Leigh MacConell 《Advances in therapy》2017,34(9):2120-2138
Introduction
Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug–drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters.Methods
Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin).Results
OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs.Conclusion
In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin).Funding
Intercept Pharmaceuticals, Inc.8.
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
NCT02093351.9.
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-142550.10.
Introduction
This study aimed to compare the efficacy and safety of two mesalazine formulations in the treatment of Chinese patients with ulcerative colitis (UC) in the remission phase.Methods
In this multicenter, single-blind, randomized controlled study conducted from November 2010 to August 2012, 251 patients with UC from 18 hospitals were enrolled. The patients were randomized to treatment with mesalazine modified-release tablets (MR group, n = 126) or other enteric-coated tablets (EC group, n = 125), at 800 mg three-times daily for 48 weeks. The primary efficacy parameter was the rate of non-emergence of bloody stool. If the lower limit of the 95% confidence interval (CI) of the primary efficacy measure was over ?10%, the modified-release tablets were considered non-inferior to the enteric-coated tablets. The secondary efficacy parameters included the period of non-emergence of bloody stool and the period of non-recurrence of UC. The incidences of adverse events and adverse drug reactions were compared between the two groups.Results
At 48 weeks of maintenance treatment, the rates of non-emergence of bloody stool were 82.99% (95% CI 73.53–92.45%) and 73.30% (95% CI 64.04–82.56%) in the MR and EC groups, respectively, and the difference between the two groups was 9.69% (95% CI ?1.15–20.53%). There was no significant difference in the period of non-emergence of bloody stool and the period of non-recurrence of UC between the two groups (P > 0.05). The incidences of adverse events were 48.78% (60/123) and 48.00% (60/125) in the MR and EC groups, respectively (P = 0.902). The incidences of adverse drug reactions were 16.26% (20/123) and 13.60% (17/125) in the MR and EC groups, respectively (P = 0.556).Conclusion
Mesalazine modified-release tablets were non-inferior to the enteric-coated tablets and may be considered an effective and safe treatment alternative for the maintenance of remission in Chinese patients with UC.Trial registration
ClinicalTrials.gov identifier: NCT01257399.Funding
Tillotts Pharma AG.11.
Mohd H. Abdul-Aziz Helmi Sulaiman Mohd-Basri Mat-Nor Vineya Rai Kang K. Wong Mohd S. Hasan Azrin N. Abd Rahman Janattul A. Jamal Steven C. Wallis Jeffrey Lipman Christine E. Staatz Jason A. Roberts 《Intensive care medicine》2016,42(10):1535-1545
Purpose
This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic/pharmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis.Methods
This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation.Results
A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p < 0.043) than IB participants. PK/PD target attainment rates were higher in the CI arm at 100 % fT >MIC than the IB arm on day 1 (97 versus 70 %, p < 0.001) and day 3 (97 versus 68 %, p < 0.001) post-randomisation. There was no difference in 14-day or 30-day survival between the treatment arms.Conclusions
In critically ill patients with severe sepsis not receiving RRT, CI demonstrated higher clinical cure rates and had better PK/PD target attainment compared to IB dosing of beta-lactam antibiotics. Continuous beta-lactam infusion may be mostly advantageous for critically ill patients with high levels of illness severity and not receiving RRT. Malaysian National Medical Research Register ID: NMRR-12-1013-14017.12.
Jürgen W. A. Sijbesma Xiaoyun Zhou David Vállez García Martin C. Houwertjes Janine Doorduin Chantal Kwizera Bram Maas Peter Meerlo Rudi A. Dierckx Riemer H. J. A. Slart Philip H. Elsinga Aren van Waarde 《Molecular imaging and biology》2016,18(5):715-723
Purpose
Small animal positron emission tomography (PET) can be used to detect small changes in neuroreceptor availability. This often requires rapid arterial blood sampling. However, current catheterization procedures do not allow repeated blood sampling. We have developed a procedure which allows arterial sampling on repeated occasions in the same animal.Procedures
Eleven male Wistar rats were two times catheterized via a superficial branch of a femoral artery and scanned with [11C]MPDX and blood sampling. PET images were co-registered to a magnetic resonance imaging (MRI) template. Regional tracer distribution volumes (V T) in the brain were calculated by the Logan analysis. The procedure was repeated after 1 week.Results
Surgery was successful in 90 % of the cases, and discomfort was minor. The V T data showed small differences between test and retest, low between subject variability, and a strong agreement between and within subjects.Conclusion
Repeated quantitative imaging with a high reproducibility is possible with this approach.13.
Audrey De Jong Jeanne Cossic Daniel Verzilli Clément Monet Julie Carr Mathieu Conseil Marion Monnin Moussa Cisse Fouad Belafia Nicolas Molinari Gérald Chanques Samir Jaber 《Intensive care medicine》2018,44(7):1106-1114
Purpose
The relation between driving pressure (plateau pressure-positive end-expiratory pressure) and mortality has never been studied in obese ARDS patients. The main objective of this study was to evaluate the relationship between 90-day mortality and driving pressure in an ARDS population ventilated in the intensive care unit (ICU) according to obesity status.Methods
We conducted a retrospective single-center study of prospectively collected data of all ARDS patients admitted consecutively to a mixed medical-surgical adult ICU from January 2009 to May 2017. Plateau pressure, compliance of the respiratory system (Crs) and driving pressure of the respiratory system within 24 h of ARDS diagnosis were compared between survivors and non-survivors at day 90 and between obese (body mass index?≥?30 kg/m2) and non-obese patients. Cox proportional hazard modeling was used for mortality at day 90.Results
Three hundred sixty-two ARDS patients were included, 262 (72%) non-obese and 100 (28%) obese patients. Mortality rate at day 90 was respectively 47% (95% CI, 40–53) in the non-obese and 46% (95% CI, 36–56) in the obese patients. Driving pressure at day 1 in the non-obese patients was significantly lower in survivors at day 90 (11.9?±?4.2 cmH2O) than in non-survivors (15.2?±?5.2 cmH2O, p?<?0.001). Contrarily, in obese patients, driving pressure at day 1 was not significantly different between survivors (13.7?±?4.5 cmH2O) and non-survivors (13.2?±?5.1 cmH2O, p?=?0.41) at day 90. After three multivariate Cox analyses, plateau pressure [HR?=?1.04 (95% CI 1.01–1.07) for each point of increase], Crs [HR?=?0.97 (95% CI 0.96–0.99) for each point of increase] and driving pressure [HR?=?1.07 (95% CI 1.04–1.10) for each point of increase], respectively, were independently associated with 90-day mortality in non-obese patients, but not in obese patients.Conclusions
Contrary to non-obese ARDS patients, driving pressure was not associated with mortality in obese ARDS patients.14.
Purpose
The purpose of this cohort study was to investigate the association of adjuvant chemotherapy with quality of life (QoL), survival, and recurrence over the 24 months following diagnosis in stage II colon cancer patients.Methods
Overall, 453 patients were recruited from North Carolina from 2009 to 2011 and interviewed with a closed-ended survey detailing quality of life, health behaviors, treatment, and cancer recurrence at three times points: diagnosis, 12-, and 24-months post-diagnosis; mortality was obtained via the National Death Index.Results
In sum, 265 patients received chemotherapy. Receipt of chemotherapy exhibited an inverse association with total Functional Assessment of Cancer Treatment (FACT)-General (P?<?0.01), FACT-Colorectal (P?<?0.01), physical (P?<?0.01), emotional (P?=?0.02), and functional (P?<?0.01) well-being; the inverse association between receiving chemotherapy and emotional well-being persisted for Caucasians but not African Americans (P interaction?=?0.049). Those who received chemotherapy demonstrated significantly higher odds of cancer recurrence (odds ratio (OR) 2.74; 95 % confidence interval (CI) 1.18, 6.35) and all-cause mortality (OR: 1.95; 95 % CI: 1.05, 3.62).Conclusions
In this study, stage II colon cancer patients who received chemotherapy treatment were more likely to have poor QoL, recurrence, and all-cause mortality after 24 months compared to those who did not receive chemotherapy. Future research focusing on subtypes of chemotherapy treatment, as well as a longer follow-up period, is needed.15.
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.16.
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-153102.17.
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.18.
Introduction
This study compared the efficacy and safety of two mesalazine formulations in the treatment of Chinese patients with mildly to moderately active ulcerative colitis (UC).Methods
In this multicenter, single-blind, randomized controlled study of 251 patients with active UC conducted from November 2010 to January 2012, subjects were randomized to treatment with mesalazine modified-release tablets (MR group, n = 123) or enteric-coated tablets (EC group, n = 128) at 800 mg three-times daily for 8 weeks. The primary efficacy measure was the decrease in UC Disease Activity Index (UCDAI) at final evaluation. If the 95% confidence interval (CI) lower limit of the difference of the decrease in UCDAI between groups was over ?1.0, mesalazine modified-release tablets were considered non-inferior to mesalazine enteric-coated tablets. The change in UCDAI in patients with mild and moderate (UCDAI 3–5 and 6–8 at enrollment, respectively) UC was analyzed. Secondary efficacy measures were remission and efficacy rates. Incidences of adverse drug reactions (ADRs) were calculated.Results
The decreases in UCDAI at final evaluation were 2.84 and 2.56 in the MR and EC groups, respectively, with a difference of 0.27 between groups (95% CI ?0.34, 0.88). The remission rates were 48.33% (58/120) and 55.65% (69/124), and the efficacy rates were 63.33% (76/120) and 66.94% (83/124) in the MR and EC groups, respectively (all P > 0.05). In patients with mild UC, the decreases in UCDAI were 2.16 and 2.05 in the MR and EC groups, respectively, while in patients with moderate UC they were 3.49 and 3.03, respectively (all P > 0.05). The incidences of ADRs in the MR and EC groups were 6.61% (8/121) and 10.24% (13/127), respectively (P > 0.05). No serious ADRs were reported during the study.Conclusion
Mesalazine modified-release tablets are non-inferior to enteric-coated tablets and are an effective and safe treatment option in Chinese patients with mildly to moderately active UC.Trial registration
ClinicalTrials.gov identifier: NCT01257386.Funding
Tillotts Pharma AG.19.
Susanna W. L. de Geus Leonora S. F. Boogerd Rutger-Jan Swijnenburg J. Sven D. Mieog Willemieke S. F. J. Tummers Hendrica A. J. M. Prevoo Cornelis F. M. Sier Hans Morreau Bert A. Bonsing Cornelis J. H. van de Velde Alexander L. Vahrmeijer Peter J. K. Kuppen 《Molecular imaging and biology》2016,18(6):807-819
Purpose
The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma.Procedures
The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)—score and immunohistochemical analysis in normal pancreatic tissue (n?=?9), pancreatic (n?=?137), and periampullary (n?=?28) adenocarcinoma.Results
Integrin αvβ6, carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p?<?0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients.Conclusions
The results of this study show that integrin αvβ6, CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.20.
Jay K. Pahade David Juice Lawrence Staib Gary Israel Dan Cornfeld Kisha Mitchell Jeffrey Weinreb 《Abdominal imaging》2016,41(7):1270-1284