Once‐daily,prolonged‐release tacrolimus vs twice‐daily,immediate‐release tacrolimus in de novo living‐donor liver transplantation: A Phase 4, randomized,open‐label,comparative, single‐center study

Randomized, open‐label, comparative, single‐center, Phase 4, 24‐week study comparing pharmacokinetics (PK), safety, and efficacy of once‐daily, prolonged‐release tacrolimus (PR‐T) with twice‐daily, immediate‐release tacrolimus (IR‐T) in adult de novo living‐donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR‐T or IR‐T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration‐time curve over 24 hour (AUC_0‐24). Predefined similarity interval for confidence intervals of ratios: 80%‐125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C₂₄), patient/graft survival, biopsy‐confirmed acute rejection (BCAR), treatment‐emergent adverse events (TEAEs). One‐hundred patients were included (PR‐T, n = 50; IR‐T, n = 50). Compared with IR‐T, 40% and 66% higher mean PR‐T daily doses resulted in similar AUC_0‐24 between formulations on Day 6 (PR‐T:IR‐T ratio of means 96.8%), and numerically higher AUC_0‐24 with PR‐T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC_0‐24 and C₂₄, and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR‐T vs IR‐T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR‐T was efficacious; no new safety signals were detected.     

Single‐Dose,Randomized, Double‐Blind,Placebo‐Controlled Study of ACE‐011 (ActRIIA‐IgG1) in Postmenopausal Women

The effects of ACE‐011 on safety, pharmacokinetics, and bone biomarkers were evaluated in healthy, postmenopausal women. Our data indicate that ACE‐011 results in a sustained increase in biomarkers of bone formation and reduction in markers of bone resorption. The activin type IIA receptor (ActRIIA) is the high‐affinity receptor for activin. ACE‐011 is a dimeric fusion protein consisting of the extracellular domain of the human ActRIIA linked to the Fc portion of human IgG1. ACE‐011 binds to activin, preventing activin from binding endogenous receptors. A randomized, double‐blind, placebo‐controlled study was conducted to evaluate the safety and tolerability of ACE‐011. Forty‐eight healthy, postmenopausal women were randomized to receive either a single dose of ACE‐011 or placebo and were followed for 4 mo. Dose levels ranged from 0.01 to 3.0 mg/kg intravenously and from 0.03 to 0.1 mg/kg subcutaneously. Safety and pharmacokinetic (PK) analyses and the biological activity of ACE‐011, as assessed by markers of bone turnover, and follicle stimulating hormone (FSH) levels were measured. No serious adverse events (AEs) were reported. AEs were generally mild and transient. The PK of ACE‐011 was linear over the dose range studied, with a mean half‐life of 24–32 days. The absorption after subcutaneous dosing was essentially complete. ACE‐011 caused a rapid and sustained dose‐dependent increase in serum levels of bone‐specific alkaline phosphatase (BSALP) and a dose‐dependent decrease in C‐terminal type 1 collagen telopeptide (CTX) and TRACP‐5b levels. There was also a dose‐dependent decrease in serum FSH levels consistent with inhibition of activin. ACE‐011 is a novel agent with biological evidence of both an increase in bone formation and a decrease in bone resorption. ACE‐011 may be an effective therapy in a variety of diseases involving bone loss.     

Exploring performance of,and attitudes to,Stop‐ and Mock‐Before‐You‐Block in preventing wrong‐side blocks

We conducted an online survey to assess the career experiences of wrong side blocks, the practice of Stop‐Before‐You‐Block, the recently described method of Mock‐Before‐You‐Block and attitudes to these. Respondents were 208 anaesthetists across nine hospitals (173 consultants or Staff and Associate Specialist doctors'), representing 3623 years of collective anaesthetic practice. There had been a total of 62 wrong side blocks (by 51 anaesthetists and one current trainee). Predisposing factors for this were commonly ascribed to distractions (35 (69%), for example due to rushing or teaching), patient positioning (9 (18%)) or miscommunication (6 (12%)). Two (4%) respondents felt they had performed Stop‐Before‐You‐Block too early; 62 (41%) of all respondents stated they performed Stop‐Before‐You‐Block as early as preparing the skin or on arrival of the patient in the anaesthetic room, and not any later. Twenty (10%) respondents admitted to not performing Stop‐Before‐You‐Block at all or only occasionally (including 5 (2%) who had performed a wrong side block). Mock‐Before‐You‐Block was easily understood (by 169 out of 197 (86%)) and 14 out of 61 (23%) respondents felt it would have prevented the wrong side error in their case. However, free‐text comments indicated that many anaesthetists were reluctant to use a method that interrupted their performance of the block. We conclude that considerable work is needed to achieve full compliance with Stop‐Before‐You‐Block at the correct time.     

HLA‐A, ‐B, ‐C, ‐DR,and ‐DQ Matching in Pancreas Transplantation: Effect on Graft Rejection and Survival

To enhance selection of appropriate deceased donors for pancreas transplants, we sought to determine whether HLA matching improved posttransplantation outcomes. In this single‐center study of 1219 pancreas transplants, we correlated posttransplantation outcomes with HLA‐A, ‐B, ‐C, ‐DR, and ‐DQ matches and mismatches. Rejection was linearly correlated with the number of mismatches. The individual number of HLA mismatches reached significance at four or more with a 2.3‐ to 2.9‐fold increase in rejection. The effect was most predominant with HLA‐B (1.8‐fold with one mismatch and 2.0‐fold with two mismatches) and ‐DR (1.9‐fold with two mismatches) loci, whereas HLA‐A, ‐C, and ‐DQ matches or mismatches did not independently predict acute rejection. The affect was strongest in solitary pancreas transplants, with little impact for simultaneous pancreas and kidney (SPK). In contrast, HLA matching did not affect graft or patient survival rates but was associated with a reduced risk of opportunistic infection. Avoidance of acute rejection saved an estimated $32 000 for solitary pancreas recipients and $52 000 for SPK recipients in hospital costs. Our data do not support the use of HLA matching for predicting pancreas graft survival but do support its significance for the reduction of acute rejection, particularly for solitary pancreas recipients.     

A Steady‐State Head‐to‐Head Pharmacokinetic Comparison of All FK‐506 (Tacrolimus) Formulations (ASTCOFF): An Open‐Label,Prospective, Randomized,Two‐Arm,Three‐Period Crossover Study

This two‐sequence, three‐period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice‐daily immediate‐release tacrolimus capsules [IR‐Tac]; once‐daily extended‐release tacrolimus capsules [ER‐Tac]; novel once‐daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR‐Tac:ER‐Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0–8.0) mg for IR‐Tac and ER‐Tac and 4.8 (3.3–6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (T_max) to peak concentration (C_max) were found for LCPT versus IR‐Tac or ER‐Tac. ER‐Tac showed no differences versus IR‐Tac in exposure, C_max, T_max or fluctuation. The observed exposure of IR‐Tac was used to normalize exposure for LCPT and ER‐Tac, resulting in the following recommended total daily dose conversion rates: IR‐Tac:ER‐Tac, +8%; IR‐Tac:LCPT, ?30%; ER‐Tac:LCPT, ?36%. After exposure normalization, C_max was ~17% lower for LCPT than for IR‐Tac or ER‐Tac; C_min was ~6% lower for LCPT compared with IR‐Tac and 3% higher compared with ER‐Tac.     

Once‐Weekly Risedronate in Men With Osteoporosis: Results of a 2‐Year,Placebo‐Controlled,Double‐Blind,Multicenter Study

Male osteoporosis is increasingly recognized as a major public health issue. This multinational, 2‐yr, randomized, double‐blind, placebo‐controlled study was conducted to determine the efficacy and safety of 35 mg once‐a‐week risedronate in men with osteoporosis. Patients had to be men ≥30 yr old, with lumbar spine T‐score ≤ ?2.5 and femoral neck T‐score ≤ ?1 SD or lumbar spine T‐score ≤ ?1 and femoral neck T‐score ≤ ?2 SD (based on young normal men). Patients were randomized 2:1 to risedronate 35 mg once a week or placebo for 2 yr; all patients took 1000 mg elemental calcium and 400–500 IU vitamin D daily. Lumbar spine BMD at month 24 using last observation carried forward was the primary endpoint. Other endpoints included lumbar spine BMD at time points other than month 24, proximal femur BMD, bone turnover markers (BTMs), new vertebral fractures, clinical fractures, and adverse event (AE) assessment. There were 284 men enrolled in the study. Treatment with risedronate resulted in a significant increase from baseline to endpoint in lumbar spine BMD compared with placebo (4.5%; 95% CI: 3.5%, 5.6%; p < 0.001). Few new vertebral and nonvertebral fractures were reported, with no differences in fracture rates between the two groups. There was a significant (p < 0.01) reduction from baseline in BTMs for the risedronate group compared with placebo at all time points. No apparent differences in the pattern or distribution of AEs including serious and upper gastrointestinal AEs were observed. Risedronate therapy was well tolerated during this 2‐yr study and was rapidly effective as indicated by significant BTM decreases at month 3 and BMD increases at month 6 (the earliest time points tested). The effects of risedronate treatment on BMD and BTMs in this study were similar to those previously shown to be associated with fracture risk reductions in women with postmenopausal osteoporosis.     

Optimism,self‐efficacy and information processing of threat‐ and well‐being‐related stimuli

The purpose of this study was to examine whether information bias associated with dispositional optimism and generalized self‐efficacy can account for the link between general expectations and well‐being. A modified Stroop task was used in this study. Our hypothesis was that individuals with high self‐efficacy expectations or dispositional optimism would show greater bias towards well‐being‐related stimuli, whereas individuals with low self‐efficacy or optimism would exhibit bias towards threat‐related stimuli. A secondary hypothesis was that both self‐efficacy and optimism would act as mediators of the latency, perceived distress relationship. One hundred and two undergraduate students participated in the study. After controlling for daily mood, the results showed that individuals high in optimism and self‐efficacy showed greater informational bias towards well‐being‐related stimuli. The low self‐efficacy group exhibited greater bias towards threat‐related stimuli. Also, consistent with our hypothesis, optimism and self‐efficacy mediated the relationship between the Stroop colour‐naming latencies and perceived distress. These findings suggest that associations, which refer to automatic processes, may form an additional way through which expectations are related to functioning. Copyright © 2007 John Wiley & Sons, Ltd.     

Dihydroartemisinin,an Anti‐Malaria Drug,Suppresses Estrogen Deficiency‐Induced Osteoporosis,Osteoclast Formation,and RANKL‐Induced Signaling Pathways

Osteoporosis is an osteolytic disease that features enhanced osteoclast formation and bone resorption. Identification of agents that can inhibit osteoclast formation and function is important for the treatment of osteoporosis. Dihydroartemisinin is a natural compound used to treat malaria but its role in osteoporosis is not known. Here, we found that dihydroartemisinin can suppress RANKL‐induced osteoclastogenesis and bone resorption in a dose‐dependent manner. Dihydroartemisinin inhibited the expression of osteoclast marker genes such as cathepsin K, calcitonin receptor, and tartrate‐resistant acid phosphatase (TRAcP). Furthermore, dihydroartemisinin inhibited RANKL‐induced NF‐κB and NFAT activity. In addition, using an in vivo ovariectomized mouse model, we show that dihydroartemisinin is able to reverse the bone loss caused by ovariectomy. Together, this study shows that dihydroartemisinin attenuates bone loss in ovariectomized mice through inhibiting RANKL‐induced osteoclast formation and function. This indicates that dihydroartemisinin, the first physiology or medicine nobel prize discovery of China, is a potential treatment option against osteolytic bone disease. © 2015 American Society for Bone and Mineral Research.     

A Double‐Blind,Double‐Dummy,Flexible‐Design Randomized Multicenter Trial: Early Safety of Single‐ Versus Divided‐Dose Rabbit Anti‐Thymocyte Globulin Induction in Renal Transplantation

A previous nonblinded, randomized, single‐center renal transplantation trial of single‐dose rabbit anti‐thymocyte globulin induction (SD‐rATG) showed improved efficacy compared with conventional divided‐dose (DD‐rATG) administration. The present multicenter, double‐blind/double‐dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD‐rATG versus DD‐rATG induction for noninferiority in early (7‐day) safety and tolerability. Ninety‐five patients (randomized 1:1) received 6 mg/kg SD‐rATG or 1.5 mg/kg/dose DD‐rATG, with tacrolimus‐mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12‐month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD‐rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD‐rATG induction to be noninferior to DD‐rATG induction in early tolerability and equivalent in 12‐month safety. (Clinical Trials.gov #NCT00906204.)     

Whole‐body vibration for functional constipation: a single‐centre,single‐blinded,randomized controlled trial

Aim The aim of this trial was to determine whether whole‐body vibration (WBV) induced via a noninvasive oscillation platform could improve symptoms and health‐related quality of life (HRQOL) in patients with chronic functional constipation. Method A single‐blinded, randomized controlled trial was performed in a single hospital in Taiwan. Patients diagnosed with chronic functional constipation, as per the Rome III diagnostic criteria, were included and randomized to either the WBV treatment or no treatment (control) group. The treatment group received six 15‐min sessions of WBV therapy over a 2‐week period. Patients received vibrations of 2 mm in amplitude at a frequency of 12 Hz. The primary outcome was whether constipation symptoms improved, assessed by the constipation severity instrument (CSI) and the secondary outcome measure was whether there was an improvement in HRQOL. Results Whole‐body vibration therapy over a 2‐week period in patients with chronic functional constipation (n = 14) significantly reduced the total CSI and obstructive defaecation subscale scores compared with control (n = 13). However, WBV did not improve the pain and chronic inertia subscale scores of the CSI or HRQOL. Conclusion These findings suggest that low‐intensity WBV induced via a noninvasive oscillation platform may be an effective therapy for reducing symptom severity in patients with chronic functional constipation.