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1.
Vaishali Sahasrabudhe Steven G. Terra Anne Hickman Didier Saur Sangeeta Raje Haihong Shi Kyle Matschke Susan Zhou David L. Cutler 《Clinical therapeutics》2018,40(10):1701-1710
Purpose
Ertugliflozin, an oral, highly selective inhibitor of the sodium-glucose cotransporter 2, is approved in the United States and the European Union for the treatment of adults with type 2 diabetes mellitus. Hepatic impairment may affect, to varying degrees, the absorption, metabolism, and excretion of drugs and may be associated with a lower plasma protein binding compared with that in healthy individuals. This study was conducted to assess the effect of hepatic impairment on the pharmacokinetic (PK), safety, and tolerability profiles of ertugliflozin after administration of a single, 15-mg oral dose.Methods
This was a Phase I, open-label, single-dose study in healthy individuals (n?=?8) and those with moderate hepatic impairment (n?=?8). Eligible participants were men or women aged 18 to 75years with a body mass index of 18.0 to 40.5 kg/m2. Healthy individuals had normal hepatic function; patients with hepatic impairment had a Child-Pugh score of 7 to 9 points (moderate hepatic impairment). Blood samples were collected before dosing and during 96hours after dosing for evaluation of PK parameters. Adverse events were monitored throughout the study.Findings
The adjusted least squares geometric meanratios for total ertugliflozin AUC0–∞ and Cmax inpatients with moderate hepatic impairment comparedwith healthy individuals were 87.4% (90% CI, 68.1%–112.2%) and 78.7% (90% CI, 65.7%–94.2%), respectively. The AUC0–∞ and Cmax for unbound ertugliflozin were also similar between patients with moderate hepatic impairment and healthy individuals. Mean half-life estimates for ertugliflozin were similar (14.6vs 13.8 hours) in patients with moderate hepatic impairment and healthy individuals. The number of participants with all-causality treatment-emergent adverse events was similar for both groups (2 of 8 patients with moderate hepatic impairment and 3 of 8 healthy individuals).Implications
Moderate hepatic impairment had no clinically relevant effect on the PK and safety profiles of ertugliflozin. The results of this study support a recommendation for no dose adjustment of ertugliflozin in patients with mild or moderate hepatic impairment. Ertugliflozin was well tolerated when administered tohealthy individuals and patients with moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02115347. 相似文献2.
Yong Kyun Kim Dong-Hwan Lee Jaehyun Jeon Hang-Jea Jang Hyeon-Kuk Kim Kyubok Jin Sung-Nam Lim Sung Sook Lee Bong Soo Park Yang Wook Kim Jae-Gook Shin Sungmin Kiem 《Clinical therapeutics》2018,40(8):1384-1395
Purpose
The aim of this study was to investigate the population pharmacokinetic (PK) profile of meropenem in Korean patients with acute infections.Methods
The study included 37 patients with a creatinine clearance ≤50 or >50 mL/min who received a 500- or 1000-mg dose of meropenem, respectively, infused intravenously over 1 hour every 8 hours. Blood samples were collected before and at 1, 1.5, and 5 hours after the start of the fourth infusion. The population PK analysis was conducted by using nonlinear mixed effect modeling software (NONMEM). Monte-Carlo simulations were performed to identify optimal dosing regimens.Findings
Thirty-seven subjects completed the study. Meropenem PK variables were well described by using a one-compartment model. The typical values (relative SE) for weight-normalized clearance (CL) and Vd were 0.266 L/h/kg (12.29%) and 0.489 L/kg (11.01%), respectively. Meropenem CL was significantly influenced by the serum creatinine level, which explained 11% of the interindividual CK variability. The proposed equation to estimate meropenem CL in Korean patients was as follows: CL (L/h)?=?0.266?×?weight?×?[serum creatinine/0.74]–1.017. The simulation results indicate that the current meropenem dosing regimen may be suboptimal in patients infected with normal or augmented renal function.Implications
Prolonged infusions of meropenem over at least 2 hours should be considered, especially in patients with augmented renal function and those infected with pathogens for which the minimum inhibitory meropenem concentration is >1 μg/mL. Our results suggest an individualized meropenem dosing regimen for patients with abnormal renal function and those infected with pathogens with decreased in vitro susceptibility. 相似文献3.
Robert Wilson Emily Jarvis Mickael Montembault J. Nicole Hamblin Edith M. Hessel Anthony Cahn 《Clinical therapeutics》2018,40(8):1410-1417
Purpose
Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.Methods
This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 μg) and repeat (200 μg for 10 days) doses of inhaled nemiralisib in parts A (n?=?12) and B (n?=?12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (n?=?6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days.Findings
21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma Cmax dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma Cmax and AUC0–24 values were 174.3 pg/mL (96.9–313.3) and 694.6 pg·h/mL (503.5–958.2) for 100 μg and 398.9 pg/mL (318.3–500.1) and 1699.6 pg·h/mL (1273.3–2268.7) for 200 μg, respectively. Repeat dosing for 10 days showed exposures ～2- to 4-fold higher than on the single dose (peak, trough, and AUC0–24 levels), achieving steady-state by day 6. Mean AUC0–24 was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non–drug-related adverse events were observed; neither was serious or resulted in withdrawal.Implications
Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that ～23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325. 相似文献4.
Hailan Wu Shengxin Xie Jicheng Yu Yuancheng Chen Jufang Wu Beining Guo Zhenghai Zhu Ying Zhou Zhiqiang Wang Jing Zhang 《Clinical therapeutics》2018,40(9):1548-1555
Purpose
The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole.Methods
A single-center, open, multidose trial was conducted in 16 patients with intra-abdominal anaerobic infection. Patients received levornidazole at 500mg q12h by intravenous infusion for 3 to 7days. The plasma samples collected before and after the last dose were analyzed by the LC-MS/MS method to determine the concentration of levornidazole. The PK parameters of levornidazole were calculated, and the PK profiles of levornidazole after the dosing regimen of 750mg q24h for 7days were simulated based on the linear PK profile of levornidazole. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment (PTA) of both dosing regimens at steady-state against Bacteroides fragilis.Findings
After administration of the last dose of 500mg of levornidazole, the mean (SD) Cmax_ss, AUC0-12, and t1/2 of levornidazole were 24.0 (5.37) μg/mL, 176.59 (29.22) μg·h/mL, and 11.03 (1.34) hours, respectively. The mean (SD) CLss and Vss of levornidazole were 2.90 (0.47) L/h and 45.90 (7.44) L, respectively. The mean (SD) distribution volume of central compartment (V1) and distribution volume of peripheral compartment (V2) were 26.71 (8.51) L and 19.21 (10.86) L, respectively. On the basis of simulation, the accumulation ratio of levornidazole in the 750mg q24h dosing regimen was 30.2% lower than the value in the 500mg q12h dosing regimen. Forthe 2 dosing regimens, the Cmax_ss, AUC0–τ, AUC0–∞, CLss, and Vss did not produce a significant difference between patients and healthy volunteers (P > 0.05). The cumulative fraction of response of levornidazole against B fragilis was >90%, and the probability of target attainment after both dosing regimens was >90%, when the MIC was ≤1 μg/mL.Implications
No significant differences were found in the PK profiles of levornidazole at steady state between the patients with intra-abdominal anaerobic infection and healthy volunteers. The clinical conventional 750mg q24h regimen can achieve similar clinical and microbiological efficacies against anaerobic in the patients after the 500mg q12h regimen. 相似文献5.
Kristina S. Boye Reema Mody Jianmin Wu Maureen J. Lage Fady T. Botros Brad Woodward 《Clinical therapeutics》2018,40(8):1396-1407
Purpose
The aims of this study were to use real-world treatment results to compare changes in estimated glomerular filtration rate (eGFR) and glycosylated hemoglobin (HbA1c) among patients with type 2 diabetes who initiated treatment with dulaglutide or insulin glargine and to determine the proportions of patients with renal impairment who initiate each treatment.Methods
The study used data from the Practice Fusion electronic health records database from October 2013 through June 2017. Adults with type 2 diabetes who initiated dulaglutide or insulin glargine therapy and had multiple recorded serum creatinine and/or HbA1c laboratory test results were included in the study. The dulaglutide cohort (n?=?1222) was matched to the insulin glargine cohort (n?=?13,869) using Mahalanobis distance matching with propensity score calipers. Multivariable analyses of the matched cohorts of individuals with serum creatinine results (n?=?1183 dulaglutide and 1183 insulin glargine) examined the association between intent-to-treat therapy and changes in eGFR. In addition, multivariable analyses were also conducted on a subset of these patients who also had recorded HbA1c tests (n?=?1088 dulaglutide and 1088 insulin glargine) to examine the association between changes in HbA1c during the 1 year postperiod.Findings
Among patients who initiated dulaglutide therapy, only 0.9% of patients had an index eGFR <30 and ≥15 mL/min/1.73 m2 and 0.1% had an index eGFR <15 mL/min/1.73 m2. In contrast, 4.1% of insulin glargine–treated patients had an index eGFR <30 and ≥15 mL/min/1.73 m2 and 1.2% had an index eGFR <15 mL/min/1.73 m2. Compared with patients who initiated therapy with insulin glargine, initiation of dulaglutide therapy was associated with a significantly smaller decrease in eGFR (?0.4 vs ?0.9 mL/min/1.73 m2; P?=?0.0024), a significantly smaller likelihood of having a 30% or greater reduction in eGFR (3.3% vs 4.1%; P < 0.0001), and a significantly larger reduction in HbA1c (?0.5% vs ?0.2%; P < 0.0001).Implications
In clinical practice, the use of dulaglutide was relatively more limited in patients with a higher degree of renal impairment compared with use of insulin glargine. However, initiation of dulaglutide therapy, compared with insulin glargine therapy, was associated with a significantly smaller decrease in eGFR and a larger reduction in HbA1c during the 1 year postperiod. 相似文献6.
Mi-Kyeong Kim Sook Young Lee Hae-Sim Park Ho Joo Yoon Sang-Ha Kim Young Joo Cho Kwang-Ha Yoo Soo-Keol Lee Hee-Kyoo Kim Jung-Won Park Heung-Woo Park Jin-Hong Chung Byoung Whui Choi Byung-Jae Lee Yoon-Seok Chang Eun-Jung Jo Sang-Yeub Lee You Sook Cho Choon-Sik Park 《Clinical therapeutics》2018,40(7):1096-1107.e1
Purpose
The aim of this study was to evaluate the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma compared with the efficacy and safety of montelukast alone.Methods
This study was a 4-week, randomized, multicenter, double-blind, Phase III trial. After a 1-week placebo run-in period, the subjects were randomized to receive montelukast (10 mg/day, n?=?112) or montelukast (10 mg/day)/levocetirizine (5 mg/day) (n?=?116) treatment for 4 weeks. The primary efficacy end point was mean daytime nasal symptom score. Other efficacy end points included mean nighttime nasal symptom score, mean composite symptom score, overall assessment of allergic rhinitis by both subjects and physicians, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, asthma control test score, and the frequency of rescue medication used during the treatment period.Findings
Of 333 patients screened for this study, 228 eligible patients were randomized to treatment. The mean (SD) age of patients was 43.32 (15.02) years, and two thirds of subjects were female (66.67%). The demographic characteristics were similar between the treatment groups. Compared with the montelukast group, the montelukast/levocetirizine group reported significant reductions in mean daytime nasal symptom score (least squares mean [SE] of combination vs montelukast, –0.98 [0.06] vs –0.81 [0.06]; P?=?0.045). For all other allergic rhinitis efficacy end points, the montelukast/levocetirizine group showed greater improvement than the montelukast group. Similar results were observed in overall assessment scores and in FEV1, FVC, FEV1/FVC, and asthma control test score changes from baseline for the 2 treatment groups. Montelukast/levocetirizine was well tolerated, and the safety profile was similar to that observed in the montelukast group.Implications
The fixed-dose combination of montelukast and levocetirizine was effective and safe in treating perennial allergic rhinitis in patients with asthma compared with montelukast alone. ClinicalTrials.gov identifier: NCT02552667. 相似文献7.
Robert M. Rifkin Sundar Jagannath Brian G.M. Durie Mohit Narang Howard R. Terebelo Cristina J. Gasparetto Kathleen Toomey James W. Hardin Lynne Wagner Kejal Parikh Safiya Abouzaid Shankar Srinivasan Amani Kitali Faiza Zafar Rafat Abonour 《Clinical therapeutics》2018,40(7):1193-1202.e1
Purpose
Maintenance therapy after autologous stem cell transplantation (ASCT) improves clinical outcomes in multiple myeloma (MM), but the effect of continued treatment with lenalidomide-only maintenance, or any maintenance, on health care resource utilization (HCRU) is largely unknown.Methods
Here we present an analysis of HCRU and clinical outcomes in a cohort of patients from the Connect MM registry, the largest, ongoing, observational, prospective US registry of patients with symptomatic newly diagnosed MM. In this study, patients with newly diagnosed MM who completed induction and single ASCT without subsequent consolidation received lenalidomide-only maintenance (n?=?180), any maintenance (n?=?256), or no maintenance (n?=?165). HCRU (hospitalization, surgery/procedures, and concurrent medications [growth factors, bisphosphonates, or neuropathic pain medication]) was assessed starting from 100 days post-ASCT for up to 2 years.Findings
Although the rates of hospitalization per 100 person-years were similar across groups at the end of years 1 and 2, the median duration of hospitalization was numerically longer with no maintenance. The rates of use of growth factors, bisphosphonates, and neuropathic pain medication were generally similar in all 3 groups. The receipt of any maintenance was associated with significantly reduced use of neuropathic pain medications during year 1. Of note, lenalidomide-only maintenance was associated with significantly longer progression-free survival (54.5 vs 30.4 months; hazard ratio [HR]?=?0.58; 95% CI, 0.43–0.79; P?=?0.0005) and overall survival (OS) (median OS not reached in either group; HR?=?0.45; 95% CI, 0.28–0.73; P?=?0.001) compared with no maintenance. Likewise, the group treated with any maintenance had significantly longer median progression-free survival (44.7 vs 30.4 months; HR?=?0.62; 95% CI, 0.47–0.82; P?=?0.0008) and OS (median OS not reached in either group; HR?=?0.50; 95% CI, 0.33–0.76; P?=?0.001) than did the group that did not receive maintenance.Implications
These findings suggest that in this largely community-based study population, post-ASCT maintenance therapy, including lenalidomide-only maintenance, improves clinical outcomes without negatively affecting HCRU. ClinicalTrials.gov identifier: NCT01081028. 相似文献8.
Xiaojiao Li Hong Chen Junqi Niu Guiling Chen Gong Shen Benedetta Massetto Diana M. Brainard Xiaoxue Zhu Hong Zhang Yanhua Ding 《Clinical therapeutics》2018,40(9):1556-1566
Purpose
The purpose of this study was to investigate the safety, tolerability, and pharmacokinetic profile of sofosbuvir and its metabolites after a single dose of sofosbuvir 400mg and once daily dosing of sofosbuvir 400mg for 7days in healthy Chinese subjects.Methods
This Phase I, open-label, single- and multiple-dose study enrolled 14 Chinese subjects aged 18 to 45years with an approximately even distribution of healthy male (n?=?9) and nonpregnant, nonlactating female subjects (n?=?5). Subjects received a single oral dose of sofosbuvir 400mg (one tablet) (morning, fasted conditions; single-dose treatment). After a 3-day washout, subjects received oral sofosbuvir 400mg (one tablet) (morning, fasted) for 7days (multiple dose treatment).Findings
No significant accumulation of sofosbuvir, GS-566500, or GS-331007 was observed. Steady state of the major metabolite GS-331007 was achieved after 4days of consecutive dosing with sofosbuvir 400mg once daily. Sofosbuvir was generally well tolerated.Implications
Overall, this study supports the further evaluation of sofosbuvir 400mg in the Chinese population. The pharmacokinetic properties of sofosbuvir, GS-556500, and GS-311007 were found to be broadly similar in healthy Chinese subjects compared with non-Chinese subjects in previous sofosbuvir studies. ChinaDrugTrials.org.cn identifier: CTR20150249. 相似文献9.
Cheng-zi Zuo Yi Gong Xiang-yu Hou Yi-fan Zhang Wen-xing Peng Rong-hua Zhu Da-fang Zhong Xiao-yan Chen 《Clinical therapeutics》2018,40(8):1347-1356
Purpose
Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters.Methods
In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8 days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200 mg/d over 6 days followed by concurrent dosing of imrecoxib 100 mg and fluconazole 200 mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4′-hydroxymethyl metabolite [M1] and 4′-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72 hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study.Findings
All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0–t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0–t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments.Implications
Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxib?+?fluconazole/imrecoxib) for AUC0–t was 1.72 (90% CI, 1.41–2.11) and for Cmax it was 1.88 (90% CI, 1.59–2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors. 相似文献10.
Guilherme Loures Penna Fernanda M. Fialho Pedro Kurtz André M. Japiassú Marcelo Kalichsztein Gustavo Nobre Nivaldo Ribeiro Villela Eliete Bouskela 《Journal of critical care》2013
Purpose
The goal of this study was to explore possible microcirculatory alterations by changing sedative infusion from propofol to midazolam in patients with septic shock.Materials and Methods
Patients (n = 16) were sedated with propofol during the first 24 hours after intubation, then with midazolam, following a predefined algorithm. Systemic hemodynamics, perfusion parameters, and microcirculation were assessed at 2 time points: just before stopping propofol and 30 minutes after the start of midazolam infusion. Sublingual microcirculation was evaluated by sidestream dark-field imaging.Results
The microvascular flow index and the proportion of perfused small vessels were greater when patients were on midazolam than when on propofol infusion (2.8 [2.4-2.9] vs 2.3 [1.9-2.6] and 96.4% [93.7%-97.6%] vs 92.7% [88.3%-94.7%], respectively; P < .005), and the flow heterogeneity index was greater with propofol than with midazolam use (0.49 [0.2-0.8] vs 0.19 [0.1-0.4], P < .05). There were no significant changes in systemic hemodynamics and perfusion parameters either during propofol use or during midazolam infusions. Data are presented as median (25th-75th percentiles).Conclusions
In this study, sublingual microcirculatory perfusion improved when the infusion was changed from propofol to midazolam in patients with septic shock. This observation could not be explained by changes in systemic hemodynamics. 相似文献11.
Purpose
Morphine ARER is a novel oral, abuse-deterrent, extended-release (ER) formulation of morphine sulfate with physical and chemical properties that deter misuse and abuse by nonoral routes of administration. Here we evaluate the relative bioavailability of morphine ARER and extended-release morphine.Methods
This single-dose, 2-treatment, 2-period, 2-sequence, randomized crossover study in healthy adult subjects compared the relative bioavailability of morphine ARER 100 mg to that of ER morphine 100 mg in the fasted condition. At 12 and 1.5 hours before dosing and 12 hours after dosing, all subjects received a 50-mg oral naltrexone tablet to minimize opioid-related side effects. Pharmacokinetic parameters including the AUC0–t, AUC0–∞, and Cmax of morphine and its metabolite morphine-6-glucuronide (M6G) were determined at various times up to 48 hours postdose. The bioequivalence of morphine ARER and ER morphine was determined using an ANOVA of the least-squares mean values of morphine and M6G bioavailability.Findings
Forty-nine subjects completed the study. Both morphine ARER and ER morphine exhibited peak plasma morphine and M6G concentrations of ～30 ng/mL and ～200 ng/mL, respectively, at 3 hours postdose. The 90% CIs of the ln-transformed values of morphine AUC0–t, AUC0–∞, and Cmax were within the 80% to 125% range for bioequivalence. M6G values also indicated bioequivalence of morphine ARER and ER morphine. The most common adverse events were nausea and somnolence.Implications
These data show that, in these subjects, morphine ARER was bioequivalent to ER morphine, a treatment for pain with well-established efficacy and safety profiles. 相似文献12.
Min Yang Yong Luo Tao Liu Xiaolong Zhong Jiao Yan Qi Huang Jie Tao Qingjuan He Mingyang Guo Yonghe Hu 《Clinical therapeutics》2018,40(10):1752-1764.e1
Purpose
Cardiovascular and diabetic complications are the main causes of death in patients with rheumatoid arthritis (RA). Puerarin has potential protective effects against subclinical atherosclerosis and insulin resistance, but the clinical evidence is still not sufficient to draw definitive conclusions. Therefore, we performed the clinical trial to assess the effect of puerarin on carotid intima-media thickness (CIMT) in RA.Methods
This is an open, controlled, randomized, and parallel-group comparison study of 119 patients with a definite diagnose of active RA. All 119 consecutive patients with RA receiving routine antirheumatic care were randomized to receive treatment with (n?=?60; 16 males and 44 females; mean age, 52.97 years; 95% CI, 49.78–56.15 years) or without (n?=?59; 17 males and 42 females; mean age, 54.05 years; 95% CI, 50.03–58.07 years) 400mg of puerarin. The effects of both interventions on CIMT, homeostasis model assessment of insulin resistance (HOMA-IR) value, and possible adverse events were assessed and compared at entry, 12 weeks, and 24 weeks. The collected data were processed and assessed using ANCOVA, paired t test, repeated-measure ANOVA, one-way ANOVA, Pearson's χ2 test, Fisher exact test, Kaplan-Meier survival analysis, Pearson correlation, and LOESS (locally weighted smoothing) regression analysis.Findings
No significant adverse effects occurred concerning the use of puerarin, and both interventions were generally well tolerated in all the patients. A tiny but significant decrease of CIMT was observed in puerarin-treated patients at 24 weeks (?0.003 mm; 95% CI, ?0.005 to ?0.001vs 0.019 mm; 95% CI, ?0.002 to 0.040; P < 0.001). At 24 weeks, insulin resistance was indicated with more pronounced improvement in the puerarin group versus the control group (homeostasis model assessment, ?0.40; 95% CI, ?0.47 to ?0.33vs ?0.05; 95% CI, ?0.08 to ?0.01; P < 0.001). Correlation analysis indicated an interaction between the parallel reductions in CIMT and insulin resistance in the puerarin group (r?=?0.878, P < 0.001) but not in the control group.Implications
In the study, 24 weeks of treatment with 400mg of puerarin exerted a significant effect against CIMT progression in patients with active RA, which may be associated with the improvement of insulin resistance. Puerarin holds promise as a drug candidate for the prevention and treatment of cardiometabolic comorbidities in patients with active RA. However, more strictly designed trials, such as double-blind and placebo-controlled trials, are still required. ClinicalTrials.gov identifier: NCT02254655. 相似文献13.
Background
Pragmatic dissemination and implementation (D&I) research approaches can benefit patient care because they emphasize real-world settings and populations. Nurse scientists have an opportunity to reduce the gap between science and practice by using pragmatic D&I research and sustainability strategies.Purpose
This article discusses pragmatic models, methods, and measures used in D&I research and their relevance for nursing research and enhancing population health.Methods
Summary of pragmatic D&I models and related methods for designing a pragmatic studies. We discuss the RE-AIM framework and the PRECIS-2 planning aid and figure in detail. A case study is provided and application to nursing research is discussed.Discussion
Successful translation of pragmatic D&I research demands an approach that addresses external validity, and customization at multiple levels including the patient, clinician, and setting. Context is critically important, and it is never too early to design for dissemination.Conclusions
Pragmatic D&I approaches are needed to speed research translation, reduce avoidable waste of funding, improve clinical care, and enhance population health. Pragmatic D&I research is an area of tremendous opportunity for the nursing science community. 相似文献14.
Annie Penfield-Cyr Carmen Monthe-Dreze Marcela C. Smid Sarbattama Sen 《Clinical therapeutics》2018,40(10):1659-1667.e1
Purpose
Maternal body mass index (BMI) and systemic fatty acid (FA) concentrations affect inflammatory balance in pregnancy and play a key role in fetal growth and well-being. Little is known about how maternal BMI may affect the association between key FA concentrations and neonatal outcomes. The objective of this study was to examine the associations between the maternal omega (n)6:n3 FA ratio and neonatal outcomes according to maternal pre-pregnancy BMI category.Methods
This study is a secondary analysis of the Maternal-Fetal Medicine Units Network randomized controlled trial of omega-3 FA supplementation to prevent recurrent preterm birth. At consent (16–22 weeks of pregnancy), women were randomized to either the intervention arm (2g of n3 FAs) or the control arm (placebo). For the present analysis, the primary exposure was the ratio of proinflammatory to anti-inflammatory (n6:n3) FAs at 25 to 28 weeks of pregnancy. The primary outcome was fetal growth as measured by using birth-weight-for-gestational-age z score, birth-length-for-gestational-age z score, and head-circumference-for-gestational-age z score. BMI categories were defined as lean (18.5–24.9 kg/m²) and overweight/obese (OWOB) (≥25.0 kg/m²). Final analysis was stratified according to BMI and adjusted for education, race, parity, smoking status, total fish intake at the time of the blood draw, and number of days in the study at the time of delivery.Findings
A total of 440 participants were included in this analysis; 49% were lean, and 51% were OWOB. After adjustment for covariates, a higher maternal n6:n3 FA ratio was associated with impaired fetal growth (birth-weight-for-gestational-age z score, β?=?–0.04 per unit increase in n6:n3; 95% CI, –0.07 to –0.01), 1day shorter length of gestation (β?=?–0.14 week; 95% CI, –0.27 to –0.01), higher incidence of neonatal respiratory distress syndrome (odds ratio, 1.37; 95% CI, 1.04 to 1.80), and increased length of neonatal hospital stay (β?=?0.29 day; 95% CI, 0.003 to 0.58) in OWOB, but not lean, participants.Implications
Higher maternal inflammation during pregnancy, as measured by using the n6:n3 FA ratio, may be a marker of adverse perinatal and neonatal outcomes, particularly among OWOB women. 相似文献15.
Yun Liu Brian Tomlinson Jiyuan Guo Mahnaz Asgharnejad Lars Bauer Erwin Surmann Xiaojuan Guo Jan-Peer Elshoff 《Clinical therapeutics》2018,40(7):1108-1121.e8
Purpose
The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature–stable (PR2.2.1) formulations of rotigotine in healthy Chinese men.Methods
In treatment period 1 of SP0913, subjects received a single application of rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2–6); treatment period 2 (days 6–14) involved multiple doses of rotigotine 2 mg/24 hours (days 7–9) followed by multiple doses of rotigotine 4 mg/24 hours (days 10–12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring.Results
Twenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total rotigotine increased to a plateau beginning at ～8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic Tmax was observed for unconjugated and total rotigotine. The respective geometric mean Cmax, Cmax,ss, AUC from zero up to the last analytically quantifiable concentration, and AUC0–24,ss values for unconjugated and total rotigotine were similar when rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean Cmax,ss and AUC0–24,ss of both unconjugated and total rotigotine were ～2-fold higher for rotigotine 4 mg/24 hours than for rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature–stable formulation of rotigotine were highly comparable to the cold-chain formulation.Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures.Implications
PK profiles and derived PK parameters of unconjugated and total rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the rotigotine transdermal patch. Single and repeated daily doses of the rotigotine transdermal patch were well tolerated. Room temperature–stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796. 相似文献16.
Michael S. Broder Mallik Greene Eunice Chang Ann Hartry Maëlys Touya Jennifer Munday Tingjian Yan 《Clinical therapeutics》2018,40(10):1670-1682
Purpose
Schizophrenia (SCZ) and bipolar disorder (BD) are typically viewed as nonconcurrent psychiatric disorders, yet patients may experience mood and SCZ symptoms simultaneously. Several studies have shown overlap between SCZ and BD symptoms and susceptibility genes. This study explored the following: (1) patterns of administrative claims; (2) demographic characteristics and comorbidities; (3) health care resource use; and (4) health care costs in patients with diagnoses of SCZ, type I BD (BD-I), and both in a real-world setting.Methods
This study was a retrospective cohort trial using 4.5years (January 1, 2012–June 30, 2016) of Truven MarketScan commercial, Medicaid, and Medicare supplemental databases. We considered a patient to have a new episode of SCZ if he or she had 1 inpatient claim or 2 outpatient claims for SCZ within the identification period (January 1, 2013–June 30, 2015). BD-I was defined in an analogous way. Three study cohorts were defined: (1) SCZ alone (cohort I), met the claims-based diagnostic criteria for SCZ; (2) BD-I alone (cohort II), met the claims-based diagnostic criteria for BD-I; and (3) BD-I and SCZ (cohort III), met the claims-based diagnostic criteria for both SCZ and BD-I.Findings
Of the 63,725 patients in the final sample, 11.5% (n?=?7336) had a new episode of SCZ alone (cohort I), 80.8% (n?=?51,480) had a new episode of BD-I alone (cohort II), and 7.7% (n?=?4909) had new episodes of both SCZ and BD-I (cohort III). Considering cohort III, 18.8% (n?=?927) received both diagnoses on the same day. In the year after diagnosis, the cohort having a diagnosis of both SCZ and BD-I (cohort III) had the highest all-cause hospitalization rates (67.4% vs 39.5% in SCZ alone and 33.7% in BD-I alone) and the highest mean (SD) number of emergency department visits (3.44 [7.1] vs 1.39 [3.5] in SCZ alone and 1.29 [3.2] in BD-I alone). All-cause total health care costs were highest in the cohort having a diagnosis of both SCZ and BD-I (mean [SD]), $51,085 [$62,759]), followed by the SCZ alone cohort ($34,204 [$52,995]), and the BD-I alone cohort ($26,396 [$48,294]).Implications
Our analyses indicate that a substantial number of patients received diagnoses of both SCZ and BD-I, based on claims, in a 2.5-year period. Patients with a diagnosis of both SCZ and BD-I had higher health care utilization and costs than patients with either diagnosis alone. We identified differential patient characteristics, utilization of medications and health care services, and health care costs among the cohorts. 相似文献17.
Hamed Aminiahidashti Sajad Shafiee Seyed Mohammad Hosseininejad Abulfazl Firouzian Ayyub Barzegarnejad Alieh Zamani Kiasari Behzad Feizzadeh Kerigh Farzad Bozorgi Misagh Shafizad Ahmad Geraeeli 《The American journal of emergency medicine》2018,36(10):1766-1770
Objective
Many procedures performed in emergency department are stressful and painful, and creating proper and timely analgesia and early and effective assessment are the challenges in this department. This study has been conducted in order to compare the efficacy of propofol and fentanyl combination with propofol and ketamine combination for procedural sedation and analgesia (PSA) in trauma patients in the emergency department.Method
This is a randomized prospective double-blind clinical trial conducted in the emergency department of Imam Khomeini Hospital, a tertiary academic trauma center in northern Iran. Patients with trauma presenting to the emergency department who needed PSA were included in study. Patients were divided into two groups of propofol fentanyl (PF) and propofol ketamine (PK). Pain score and sedation depth were set as primary outcome measures and were recorded.Results
Out of about 379 patients with trauma, who needed PSA, 253 met the criteria to be included in the study, 117 of which were excluded. The remaining 136 patients were randomly allocated to either PF group (n?=?70) or PK group (n?=?66). Pain management after drug administration was significantly different between the groups and the analgesia caused by fentanyl was significantly higher than ketamine. The sedation score after 15?min of PSA in the group PF was significantly higher than the group PK.Conclusion
It seems that regarding PSA in the emergency department, PF caused better analgesia and deeper sedation and it is recommended to use PF for PSA in the emergency departments. 相似文献18.
Bai-Li Song Meng Wan Dan Tang Chao Sun Yu-Bing Zhu Nyame Linda Hong-Wei Fan Jian-Jun Zou 《Clinical therapeutics》2018,40(7):1170-1178
Purpose
Some studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme (CYP2C19) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population.Methods
Twenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n?=?8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n?=?10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n?=?2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate–induced platelet aggregation was measured by light-transmittance aggregometry.Findings
There were no significant differences in Cmax and AUC0–t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM Cmax value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [P?=?0.003] and 19.55 [2.19] ng/mL [P?=?0.004], respectively). The mean CAM AUC0–t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng · h/mL [P?=?0.007] and 27.08 [2.72] ng · h/mL [P?=?0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group (P?=?0.001). The correlations between the pharmacokinetic properties (Cmax, AUC0–t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P < 0.01).Implication
In these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382. 相似文献19.
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