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Purpose: Plasma concentrations of tafluprost acid and timolol were compared after single (Day 1) and repeated (Day 8) instillations of once-daily tafluprost 0.0015%-timolol 0.5% preservative-free (PF) fixed-dose combination (FDC), once-daily PF tafluprost 0.0015%, and twice-daily PF timolol 0.5%.Patients and Methods: Fifteen healthy volunteers were randomized to this double-masked, single-center, three-period cross-over study. A wash-out interval of at least 4 weeks separated each three 8-day dosing period. Blood samples were drawn on the first and last day of each dosing period, prior to the morning dose, as well as 5, 10, 15, 30, and 45 min, and 1, 1.5, 2, 4, 8, and 12 h post-dosing. Sample plasma concentrations of tafluprost acid and/or timolol were determined and maximum concentration (C max), area under the concentration-over-time curve from time zero to the last time point with a quantifiable measurement (AUC0-last), and time to maximum concentration were calculated. Intraocular pressure (IOP), adverse events, and ocular/systemic safety variables were also evaluated.Results: Plasma concentrations of tafluprost acid were low, with similar levels measured subsequent to either single or repeated dosing of PF FDC and PF tafluprost. On both sampling days, concentrations peaked at 10 min after the dose, and were cleared from the blood circulation by 30 min; average C max ranged from 17 to 24 pg/mL, and AUC0-last from 3 to 5 pg*h/mL. Plasma concentrations of timolol were comparable after the first dose of PF FDC or PF timolol. Concentrations peaked at 15 min post-dose and diminished in a similar manner after 2 h; average C max was 800 pg/mL and AUC0-last 3900 pg*h/mL. As expected, PF timolol produced a higher Day 8 pre-dose timolol concentration than PF FDC (235 vs. 37 pg/mL; p < 0.001, respectively). The Day 8 post-dose changes in timolol concentrations were relative to this pre-dose difference. All study treatments were well tolerated and safe. PF FDC seemed to provide the best IOP reduction.Conclusions: PF FDC demonstrated good IOP-lowering efficacy and displayed similar pharmacokinetic characteristics to the monotherapy agents. Exposure to timolol was reduced via the halved dosing. [ABSTRACT FROM AUTHOR]

Background and Objectives: Canagliflozin is an orally active, reversible, selective sodium-glucose co-transporter-2 inhibitor. A population pharmacokinetic (popPK) model of canagliflozin, including relevant covariates as sources of inter-individual variability, was developed to describe phase I, II, and III data in healthy volunteers and in patients with type 2 diabetes mellitus (T2DM).Methods: The final analysis included 9061 pharmacokinetic (PK) samples from 1616 volunteers enrolled in nine phase I, two phase II, and three phase III studies and was performed using NONMEM(®) 7.1. Inter-individual variability was evaluated using an exponential model and the residual error model was additive in the log domain. The first-order conditional estimation method with interaction was applied and the model was parameterized in terms of rate constants. Covariate effects were explored graphically on empirical Bayes estimates of PK parameters, as shrinkage was low. Clinical relevance of statistically significant covariates was evaluated. The predictive properties of the model were illustrated by prediction-corrected visual predictive checks.Results: A two-compartment PK model with lag-time and sequential zero- and first-order absorption and first-order elimination best described the observed data. Sex, age, and weight on apparent volume of distribution of the central compartment, body mass index on first-order absorption rate constant, and body mass index and over-encapsulation on lag-time, and estimated glomerular filtration rate (eGFR, by MDRD equation), dose, and genetic polymorphism (carriers of UGT1A9*3 allele) on elimination rate constant were identified as statistically significant covariates. The prediction-corrected visual predictive checks revealed acceptable predictive performance of the model.Conclusion: The popPK model adequately described canagliflozin PK in healthy volunteers and in patients with T2DM. Because of the small magnitude of statistically significant covariates, they were not considered clinically relevant. However, dosage adjustments are recommended for T2DM patients with renal impairment (eGFR ≥60 mL/min/1.73 m(2): 100 or 300 mg/day; eGFR of 45 to <60 mL/min/1.73 m(2): 100 mg/day). [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the effects of different therapeutic 1-MHz ultrasound waveforms on endothelial function before and after cyclooxygenase (COX) inhibition. Forty-two healthy volunteers aged 27.2 ± 3.8 y underwent interventions and an evaluation for endothelial function (n = 15; with COX inhibition, n = 15; duration of the vasodilator effect, n = 12) by technique flow-mediated dilation. Continuous ultrasound therapy (0.4 W/cm(2 SATA)), pulsed ultrasound therapy (20% duty cycle, 0.08 W/cm(2 SATA)) or placebo (equipment power off) was randomly applied over the brachial artery for 5 min. COX inhibition (aspirin) was carried out 30 min before treatments. In relation to the placebo, flow-mediated dilation increased by 4.8% using continuous ultrasound and by 3.4% using pulsed ultrasound. After COX, flow-mediated dilation was enhanced by 2.1% by continuous ultrasound and 2.6% by pulsed ultrasound. This vasodilation persisted for 20 min. Continuous and pulsed therapeutic 1-MHz ultrasound waveforms improved endothelial function in humans, which provided them with anti-inflammatory vascular effects. [ABSTRACT FROM AUTHOR]

Background: Improving gastric accommodation and gastric emptying is an attractive physiological treatment target in patients with functional dyspepsia (FD). We evaluated the effect of DA-9701, a new drug for FD, on gastric motor function after a meal in healthy volunteers using magnetic resonance imaging (MRI). Methods: Forty healthy volunteers were randomly allocated to receive either DA-9701 or placebo. After 5 days of treatment, subjects underwent gastric MRI (60 min before and 15, 30, 45, 60, 90, and 120 min after a liquid test meal). Gastric volume was measured through 3-dimensional reconstruction from MRI data. We analyzed 4 outcome variables including changes in total gastric volume (TGV), proximal TGV, and proximal to distal TGV ratio after a meal and gastric emptying rates after adjusting values at the pre-test meal. Results: Changes in TGV and proximal TGV after a meal did not differ between the DA-9701 and placebo groups (difference between groups -25.9 mL, 95% confidence interval [CI] -54.0 to 2.3 mL, P = 0.070 and -2.9 mL, 95% CI -30.3 to 24.5 mL, P = 0.832, respectively). However, pre-treatment with DA-9701 increased postprandial proximal to distal TGV ratio more than placebo (difference between groups 0.93, 95% CI 0.08 to 1.79, P = 0.034). In addition, pre-treatment with DA-9701 significantly increased gastric emptying as compared with placebo (mean difference between groups 3.41%, 95% CI 0.54% to 6.29%, P = 0.021, by mixed model for repeated measures). Conclusion: Our results suggested that DA-9701 enhances gastric emptying and does not significantly affect gastric accommodation in healthy volunteers. Further studies to confirm whether DA-9701 enhances these gastric motor functions in patients with FD are warranted. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Rationale: Benzodiazepines, such as diazepam, are anxiolytic-sedative drugs, used for the treatment of several different disorders. The pharmacological mechanism of action of benzodiazepines is well understood; however, it remains unclear which neural networks and systems are involved in translating these neurochemical actions into their therapeutic effects. Objectives: The objective of this study was to investigate the effects of 7-day diazepam administration compared to placebo on resting-state functional connectivity in healthy adults independent of any task. Methods: Thirty-four healthy participants were randomly assigned to receive either diazepam ( N = 17) or placebo (15 mg daily for 7 days) and underwent resting-state functional magnetic resonance acquisition. Model-free data analysis was performed using independent component analysis and dual regression. Results: Consistent with previous research, 11 resting-state networks were identified. Increased connectivity in response to diazepam administration was found in the medial visual network and middle/inferior temporal network. Diazepam did not cause any decreases in functional connectivity. Conclusions: Diazepam administration increases functional connectivity in areas of emotional processing independent of any task. Diazepam also enhanced functional connectivity in the medial visual system, which is a brain region rich in GABA receptors, and shows high binding of GABAergic drugs. These increases in functional connectivity are characteristic of CNS depressants. [ABSTRACT FROM AUTHOR]

Background/Objectives:The superiority of cholecalciferol (D3) over ergocalciferol (D2) in sustaining serum 25-hydroxy vitamin D (25OHD) levels is controversial. To compare D2 with D3 we performed a single-blind, placebo-controlled randomized trial spanning 11 weeks.Subjects/Methods:Healthy volunteers (n=33, aged 33.4±6 years) were divided into three groups (n=11, each): D2, D3 and placebo. Treatment started with a loading dose (100 000 IU) followed by 4800 IU/day (d) between d7 and d20 and follow-up until d77. Serum samples were obtained at baseline and at days 3, 7, 14, 21, 35, 49, 63 and 77.Results:Baseline 25OHD values in the D2 group were lower than those in the D3 and placebo groups (P<0.01). Placebo 25OHD levels never changed. As after the loading dose both D2 and D3 groups had reached similar 25OHD levels, we tested equivalence of the area under the concentration × time curve (AUC) between d7 and d77. The AUC was 28.6% higher for D3 compared with D2, and both were higher with respect to placebo. At d77, D2 25OHD levels were higher than those at baseline, but similar to placebo; both were lower than D3 (P<0.04). According to raw data, the elimination half-life of 25OHD was 84 and 111 days under D2 and D3 supplementation, respectively; after subtracting the placebo values, the corresponding figures were 33 and 82 days.Conclusions:D2 and D3 were equally effective in elevating 25OHD levels after a loading dose. In the long term, D3 seems more appropriate for sustaining 25OHD, which could be relevant for classic and non-classic effects of vitamin D. [ABSTRACT FROM AUTHOR]

Aim:To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers.Methods:This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin.Results:The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects.Conclusion:Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to evaluate the effectiveness of unstable shoes in reducing low back pain in health professionals. Methods Of a volunteer sample of 144 participants, 40 with nonspecific chronic low back pain were eligible and enrolled in this study. Participants were randomized to an intervention group, who wore unstable shoes (model MBT Fora), or a control group, who wore conventional sports shoes (model Adidas Bigroar). The participants had to wear the study shoes during their work hours, and at least 6 hours per workday, over a period of 6 weeks. The primary outcome was low back pain assessed on a Visual Analog Scale. The secondary outcomes were patient satisfaction, disability evaluated using Roland-Morris questionnaire and quality of life evaluated using EQ-VAS. Results The intervention group showed a significant decrease in pain scores compared to the control group. The rate of satisfaction was higher in the intervention group (79%) compared to the control group (25%). There was no significant difference for the Roland-Morris disability questionnaire score and the EQ-VAS scale. Conclusions The results of this clinical trial suggest that wearing unstable shoes for 6 weeks significantly decreases low back pain in patients suffering from chronic low back pain but had no significant effect on quality of life and disability scores. [ABSTRACT FROM AUTHOR]

Background: LBR-101 is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide.Objective: The objective of this article is to characterize the safety and tolerability of LBR-101 when administered intravenously to healthy volunteers, by presenting the pooled results of the Phase 1 program.Methods: LBR-101 was administered to 94 subjects, while 45 received placebo. Doses ranged from 0.2 mg to 2000 mg given once (Day 1), as a single IV infusion, or up to 300 mg given twice (Day 1 and Day 14).Results: Subjects receiving placebo reported an average of 1.3 treatment-emerging adverse events vs 1.4 per subject among those receiving any dose of LBR-101, and 1.6 in those receiving 1000 mg or higher. Treatment-related adverse events occurred in 21.2% of subjects receiving LBR-101, compared to 17.7% in those receiving placebo. LBR-101 was not associated with any clinically relevant patterns of change in vital signs, ECG parameters, or laboratory findings. The only serious adverse event consisted of "thoracic aortic aneurysm" in a participant later found to have an unreported history of Ehlers-Danlos syndrome.Conclusion: Single IV doses of LBR-101 ranging from 0.2 mg up to 2000 mg and multiple IV doses up to 300 mg were well tolerated. Overt safety concerns have not emerged. A maximally tolerated dose has not been identified. [ABSTRACT FROM AUTHOR]

Abstract: The study of healthy human volunteers ascending to high altitude provides a robust model of the complex physiological interplay that emulates human adaptation to hypoxaemia in clinical conditions. Nitric oxide (NO) metabolism may play an important role in both adaptation to high altitude and response to hypoxaemia during critical illness at sea level. Circulating nitrate and nitrite concentrations can be augmented by dietary supplementation and this is associated with improved exercise performance and mitochondrial efficiency. We hypothesised that the administration of a dietary substance (beetroot juice) rich in nitrate would improve oxygen efficiency during exercise at high altitude by enhancing tissue microcirculatory blood flow and oxygenation. Furthermore, nitrate supplementation would lead to measurable increases in NO bioactivity throughout the body. This methodological manuscript describes the design and conduct of the ‘Xtreme Alps’ expedition, a double-blind randomised controlled trial investigating the effects of dietary nitrate supplementation on acclimatisation to hypobaric hypoxia at high altitude in healthy human volunteers. The primary outcome measure was the change in oxygen efficiency during exercise at high altitude between participants allocated to receive nitrate supplementation and those receiving a placebo. A number of secondary measures were recorded, including exercise capacity, peripheral and microcirculatory blood flow and tissue oxygenation. Results from this study will further elucidate the role of NO in adaption to hypoxaemia and guide clinical trials in critically ill patients. Improved understanding of hypoxaemia in critical illness may provide new therapeutic avenues for interventions that will improve survival in critically ill patients. [Copyright &y& Elsevier]

Background: Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation. Objective: The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects. Methods: Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis. Results: Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R2 = 0.492 for HPT, R2 = 0.538 for PPT, R2 = 0.558 for HPTo and R2 = 0.584 for PPTo). Conclusions: The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. : Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). : IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre. [ABSTRACT FROM AUTHOR]

Objective. Enterotoxigenic Escherichia coli (ETEC) is the leading cause of travelers' diarrhea. The aim of this study was to investigate the ability of a powdered extract of hyperimmune bovine colostrum to protect against diarrhea in volunteers challenged with ETEC. Materials and methods. Tablets were manufactured from a colostrum extract from cattle immunized with 14 ETEC strains, including serogroup O78. Two separate randomized, double-blind, placebo-controlled trials involving 90 healthy adult volunteers were performed to investigate the ability of different tablet formulations to protect against diarrhea following an oral challenge with an O78 ETEC strain. Results. The first study with 30 participants evaluated the efficacy of tablets, containing 400 mg of colostrum protein, taken thrice daily with bicarbonate buffer. This regimen conferred 90.9% protection against diarrhea in the group receiving the active preparation compared with the placebo group ( p == 0.0005). The second study examined the efficacy of tablets containing 400 mg colostrum protein given with buffer (83.3% protection; p == 0.0004) or without buffer (76.7% protection; p == 0.007), and tablets containing 200 mg colostrum protein given without buffer (58.3% protection; p == 0.02), compared with placebo. The difference between buffered and unbuffered treatments was not significant ( p > 0.1). Conclusions. Active tablet formulations were significantly more effective than placebo in protecting volunteers against the development of diarrhea caused by ETEC. These results suggest that administration of a tablet formulation of hyperimmune bovine colostrum containing antibodies against ETEC strains may reduce the risk of travelers' diarrhea. [ABSTRACT FROM AUTHOR]

Abstract: The basilic vein offers an alternative site for peripheral intravenous access for emergency access. The use of a two-operator ultrasound-guided basilic vein cannulation technique has been shown to be a safe and effective technique for use on Emergency Department patients. However, the one-operator technique is more customary by other services. We sought to compare the more customary one-person technique to the two-person technique in basilic vein cannulation in novice operators. This was a prospective, randomized controlled trial of two techniques of ultrasound-guided basilic vein cannulation (one-operator vs. two-operators) in healthy adult volunteers. Each volunteer underwent each technique, one technique on each arm. We selected the initial arm and technique using computer-generated block randomization. In the one-operator technique, a single operator held the transducer in transverse short-axis plane while attempting cannulation using a 20-gauge, 1.88-inch catheter. In the two-operator technique, a second operator held the transducer in place while the first operator attempted cannulation. The primary outcome variable was first-attempt cannulation success. Secondary outcome variables were overall success, number of attempts, time-to-cannulation, complications, and ease-of-technique rated by the operators. There were 32 subjects enrolled. One-operator first-attempt success was 18/32 (56%); two-operator was 21/32 (65%), with a mean difference in proportion of −9% (95% confidence interval [CI] −33–14%). Overall success for one operator was 23/32 (72%) and two-operator was 24/32 (75%), with mean difference in proportion of −3% (95% CI −24–18). The median number of attempts for one-operator was 1.6 (interquartile range [IQR] 1–5) and two-operator was 1.4 (IQR 1–5) (p = 0.8). Time to cannulation for one-operator was 57 s (± 62) and two-operator was 44 s (± 37) (p = 0.33). The median score for ease-of-technique for one-operator was 4.3 (IQR 1–6) and for two-operator was 3.6 (IQR 1–6) (p = 0.26). There were no complications with either technique (95% CI 0–10%). Novice operators can reliably perform a basilic vein cannulation using ultrasound guidance. However, we were unable to demonstrate any advantage for any particular technique in cannulating the basilic vein. [Copyright &y& Elsevier]