Three-way Crossover Study Research Articles

Multiple Oral Insulin (ORMD-0801) Doses Elicit a Cumulative Effect on Glucose Control in T2DM Patients

Efforts to overcome the narrow therapeutic index of subcutaneously delivered insulin, have propelled the development of orally delivered alternatives. The enteric-coated ORMD-0801 oral insulin capsule has been shown to provide effective glucose control in both type 1 and type 2 diabetes patients. In this single-center, randomized, double-blind, placebo-controlled, three-way crossover study, 31 adult T2DM patients were treated with a placebo capsule during the first three days of three 1-week treatment periods, followed by five days of treatment with an oral placebo (n=31) or a 460 IU insulin capsule, delivered one (qd; n=20), two (bid; n=21) or three (tid; n=20) time per day. Run-in (Days 1-3) vs. treatment (Days 4-8) period continuous glucose monitoring (CGM) data were compared, as were pre- vs. post-treatment insulin and c-peptide levels. Patients were of a mean age of 57.5±7.8, and most were male (61.3%) and Caucasian (80.6%). Mean placebo-adjusted change from baseline in 24-hour glucose (all run-in days vs. all treatment days) ranged from -7.65 mg/dL for qd to -9.91 mg/dL for tid, with a more dramatic change observed in subjects with higher glucose (>190 mg/dL; n=17) at baseline (-12.44 mg/dL (qd) and -18.43 (tid)). Pre- vs. posttreatment and placebo vs. active treatment c-peptide and insulin ratios were similar across all regimens. ORMD-0801 was well tolerated and did not elicit any serious adverse effects. The vast majority of hyperglycemic events were recorded during placebo treatment (n=27), while hypoglycemic events were evenly distributed across treatment groups (≤5/group). Thus, multiple-dose ORMD-0801 regimens safely provide for improved glucose control, which is expected to be enhanced with more extended treatment. Its impact may be of particular benefit to patients uncontrolled by current drug regimens. Disclosure R. Eldor: Consultant; Self; Oramed Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Medtronic. J. Neutel: None. K.E. Homer: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc..

Dose-response of an extrafine dry powder inhaler formulation of glycopyrronium bromide: randomized, double-blind, placebo-controlled, dose-ranging study (GlycoNEXT).

IntroductionAn extrafine formulation of the long-acting muscarinic antagonist, glycopyrronium bromide (GB), has been developed for delivery via the NEXThaler dry powder inhaler (DPI). This study assessed the bronchodilator efficacy and safety of different doses of this formulation in patients with COPD to identify the optimal dose for further development.Patients and methodsThis was a multicenter, randomized, double-blind, placebo-controlled, incomplete block, three-way crossover study, including three 28-day treatment periods, each separated by a 21-day washout period. Eligible patients had a diagnosis of COPD and post-bronchodilator forced expiratory volume in 1 s (FEV1) 40%–70% predicted. Treatments administered were GB 6.25, 12.5, 25 and 50 μg or matched placebo; all were given twice daily (BID) via DPI, with spirometry assessed on Days 1 and 28 of each treatment period. The primary end point was FEV1 area under the curve from 0 to 12 h (AUC0–12 h) on Day 28.ResultsA total of 202 patients were randomized (61% male, mean age 62.6 years), with 178 (88%) completing all the three treatment periods. For the primary end point, all the four GB doses were superior to placebo (p<0.001) with mean differences (95% CI) of 114 (74, 154), 125 (85, 166), 143 (104, 183) and 187 (147, 228) mL for GB 6.25, 12.5, 25 and 50 μg BID, respectively. All four GB doses were also statistically superior to placebo for all secondary efficacy end points, showing clear dose–response relationships for most of the endpoints. Accordingly, GB 25 μg BID met the criteria for the minimally acceptable dose. Adverse events were reported by 15.5, 16.2, 10.9 and 14.3% of patients receiving GB 6.25, 12.5, 25 and 50 μg BID, respectively, and 14.8% receiving placebo.ConclusionThis study supports the selection of GB 25 μg BID as the minimal effective dose for patients with COPD when delivered with this extrafine DPI formulation.

Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.

SETTING:Rifampicin (RMP) drives treatment response in drug-susceptible tuberculosis. Low RMP concentrations increase the risk of poor outcomes, and drug quality needs to be excluded as a contributor to low RMP exposure.OBJECTIVES AND DESIGN:We performed an open-label, three-way cross-over study of three licensed RMP-containing formulations widely used in South Africa to evaluate the bioavailability of RMP in a two-drug fixed-dose combination tablet (2FDC) and a four-drug FDC (4FDC) against a single-drug reference. RMP dosed at 600 mg was administered 2 weeks apart in random sequence. Plasma RMP concentrations were measured pre-dose and 1, 2, 3, 4, 6, 8 and 12 h post-dose. The area under the concentration-time curve (AUC0–12) of the FDCs was compared to the single drug reference. Simulations were used to predict the impact of our findings.RESULTS:Twenty healthy volunteers (median age 22.8 years, body mass index 24.2 kg/m2) completed the study. The AUC0–12 of the 4FDC/reference (geometric mean ratio [GMR] 78%, 90%CI 69–89) indicated an average 20% reduction in RMP bioavailability in the 4FDC. The 2FDC/reference (GMR 104%, 90%CI 97–111) was bioequivalent. Simulations suggested dose adjustments to compensate for the poor bioavailability of RMP with the 4FDC, and revised weight-band doses to prevent systematic underdosing of low-weight patients.CONCLUSION:Post-marketing surveillance of in vivo bioavailability of RMP and improved weight band-based dosing are recommended.

S43. A PROOF-OF-MECHANISM STUDY OF THE PDE10 INHIBITOR RG7203 IN PATIENTS WITH PROBING REWARD FUNCTIONS WITH IMAGING AND BEHAVIORAL APPROACHES

BackgroundThe enzyme phosphodiesterase 10A (PDE10A) is highly expressed in the striatum where it modulates both dopamine D2 and D1 dependent signaling. Its inhibition leads to a suppression of D2 mediated signaling –similar to effects of D2 antagonists - and an enhancement of D1 dependent signaling. D1-dependent signaling has been implicated in reward based learning. Its deficient activation may be a key factor underlying deficient reward functions including reward anticipation and reward based learning that have been implicated as major drivers of negative symptoms of schizophrenia. Therefore, inhibition of PDE10 could be a way to ameliorate such deficits and consequently negative symptoms. In healthy volunteers the PDE10 inhibitor RG7203 indeed enhanced performance in tasks that probed reward functioning suggestive of its potential utility to treat negative symptoms in schizophrenia. We therefore tested the hypothesis that it should enhance imaging and behavioral markers of reward functions in patients with moderate negative symptoms in order to establish mechanistic proof of its utility as treatment of negative symptoms.MethodsIn a three-way cross-over study we investigated the effects of two doses of RG7203 (5 mg and 15 mg) and placebo given as adjunctive treatment to stable background antipsychotic treatment on reward functioning and reward-based effortful behavior using the monetary incentive delay (MID) task during fMRI and the effort choice task in patients with chronic schizophrenia and moderate levels of negative symptoms (PANSS negative symptom factor score ≥ 18 points). Each treatment period lasted three weeks followed by a 2 week washout period. fMRI and behavioral tasks were administered at the end of each treatment period. Key outcome measures were the differential BOLD during reward anticipation and overall BOLD activity during the MID task and the percentage of high-effort high-reward choices when the probability of reward was 100% during the effort choice task.ResultsThirty-three patients with schizophrenia (30 male; 21 B, 9 W, 3 A; mean age 36.6 ± 7 y; PANSS NSFS = 22.8 (±1.4) at screening) were recruited at three study centers in the US. Twenty-four subjects finished the entire study. RG7203 at 5 mg significantly increased differential BOLD activity during reward anticipation in the MID task. However, this enhancement occurred in the context of a significant decrease of BOLD activity across all conditions during the MID task under treatment with RG7203. RG7203 significantly worsened reward-based effortful behavior in the effort choice task (the high-effort high-reward choice: 67% for both doses of RG7203 versus 73% for placebo). Multiple regression revealed that the decrease in effortful behavior was significantly related to the decrease in overall BOLD activity during the MID task and not related to the difference of BOLD activity during reward anticipation versus the control condition.DiscussionIn contrast to our expectation and previous results in healthy volunteers, RG7203 worsened indices of reward functions which we hypothesize may be due to a further enhancement of D2 antagonistic activity. The results do not support the utility of a PDE10 inhibitor as adjunctive treatment for negative symptoms in patients with schizophrenia. Given the previous observation that RG7203 enhanced reward functions in healthy volunteers who were not treated with D2 antagonist, the results of our study point to potentially deleterious effects of D2 blockade on reward functions and by extension on negative symptoms of schizophrenia. They raise the question if the presence of D2 antagonistic treatment curtails the potential effects of any adjunctive treatment for negative symptoms.

Acetazolamide Reduces Blood Pressure and Sleep-Disordered Breathing in Patients With Hypertension and Obstructive Sleep Apnea: A Randomized Controlled Trial.

The carbonic anhydrase inhibitor acetazolamide (AZT) modulates blood pressure at high altitude and reduces sleep-disordered breathing in patients with obstructive sleep apnea (OSA). We aimed to investigate the treatment effect of AZT and in combination with continuous positive airway pressure (CPAP) on blood pressure in patients with hypertension and OSA. In a prospective, randomized, three-way crossover study, 13 male patients with hypertension and moderate to severe OSA (age 64 ± 7 years, body mass index 29 ± 4 kg/m2, and mean apnea-hypopnea index 37 ± 23 events/h) received AZT, CPAP, or AZT plus CPAP for 2-week periods. Antihypertensive medication was washed out. Office and 24-hour blood pressure, arterial stiffness, polygraphic sleep study data, and blood chemistry were compared. AZT alone and AZT plus CPAP, but not CPAP alone, reduced office mean arterial pressure compared to baseline (-7 [95% CI -11 to -4], -7 [95% CI -11 to -4] and -1 [95% CI -5 to 4] mmHg, respectively; repeated- measures analysis of variance (RM-ANOVA; P = .015). Aortic systolic pressure and augmentation index, assessed by radial artery oscillatory tonometry, were unaffected by CPAP but decreased after AZT and AZT plus CPAP (RM-ANOVA P = .030 and .031, respectively). The apnea-hypopnea index was significantly reduced in all three treatment arms, most prominently by AZT plus CPAP (RM-ANOVA P = .003). The reduction of venous bicarbonate concentration following AZT was correlated with the change of apnea-hypopnea index (r = 0.66, P = .013). AZT reduced blood pressure, vascular stiffness, and sleep-disordered breathing in patients with OSA and comorbid hypertension. Carbonic anhydrase inhibition may constitute a potential target for drug therapy in patients with sleep apnea and comorbid hypertension. Registry: ClinicalTrials.gov; Identifier: NCT02220803; Title: A Short Term Open, Randomized Cross-over Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension and Vascular Dysfunction; URL: https://clinicaltrials.gov/ct2/show/NCT02220803 and Registry: EU Clinical Trials Register; EudraCT Number: 2013-004866-33; Title: A short term open, randomized cross over trial exploring the effect of carbonic anhydrase inhibition by acetazolamide on sleep apnea associated hypertension; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004866-33.

Effects of levocetirizine and diphenhydramine on regional glucose metabolic changes and hemodynamic responses in the human prefrontal cortex during cognitive tasks.

ObjectiveAntihistamines often have sedative side effects. This was the first study to measure regional cerebral glucose (energy) consumption and hemodynamic responses in young adults during cognitive tests after antihistamine administration.MethodsIn this double‐blind, placebo‐controlled, three‐way crossover study, 18 healthy young Japanese men received single doses of levocetirizine 5 mg and diphenhydramine 50 mg at intervals of at least six days. Subjective feeling, task performances, and brain activity were evaluated during three cognitive tests (word fluency, two‐back, and Stroop). Regional cerebral glucose consumption changes were measured using positron emission tomography with [18F]fluorodeoxyglucose. Regional hemodynamic responses were measured using near‐infrared spectroscopy.ResultsEnergy consumption in prefrontal regions was significantly increased after antihistamine administration, especially diphenhydramine, whereas prefrontal hemodynamic responses, evaluated with oxygenated hemoglobin levels, were significantly lower with diphenhydramine treatment. Stroop test accuracy was significantly impaired by diphenhydramine, but not by levocetirizine. There was no significant difference in subjective sleepiness.ConclusionsPhysiological “coupling” between metabolism and perfusion in the healthy human brain may not be maintained under pharmacological influence due to antihistamines. This uncoupling may be caused by a combination of increased energy demands in the prefrontal regions and suppression of vascular permeability in brain capillaries after antihistamine treatment. Further research is needed to validate this hypothesis.

Effects of Milk or Apple Juice Ingestion on the Pharmacokinetics of Elvitegravir and Cobicistat in Healthy Japanese Male Volunteers: A Randomized, Single-Dose, Three-Way Crossover Study.

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) is specified in its package insert to be taken with food to obtain sufficient exposure of EVG. It has been reported that a nutritional protein-rich drink shows comparable pharmacokinetics (PK) of EVG to those with a standard breakfast. In this study, the PK profiles of EVG and COBI were evaluated by administration of a single dose of EVG/COBI/FTC/TAF, after ingestion of either a nutritional protein-rich drink, milk, or apple juice. The geometric means for Cmax and AUCinf of EVG following milk ingestion slightly decreased by 21% and 14%, respectively, and those following apple juice ingestion decreased by 67% and 61%, respectively, compared with a nutritional protein-rich drink. There were no differences in any PK parameters of COBI. Therefore, taking EVG/COBI/FTC/TAF after milk or apple juice ingestion appeared to be not appropriate. However, for plasma trough concentrations (Ctau ), it is known that Ctau is best correlated with the efficacy of EVG. The mean C24 of EVG after milk ingestion was 620.6 ng/mL, which was more than 10-fold the protein binding-adjusted 95% inhibitory concentration. With all the above considerations, it was concluded that taking EVG/COBI/FTC/TAF with milk could be an option to maintain sufficient plasma concentrations of EVG.

Comparison of the early effects of vonoprazan, lansoprazole and famotidine on intragastric pH: a three-way crossover study.

To promote symptom relief from acid-related diseases, a medicine with a rapid-onset effect is ideal. The aim of this study was to investigate the early inhibitory effect on gastric acid secretion after a single oral administration of vonoprazan, which represents a new class of proton pump inhibitors, and to compare this effect with those of lansoprazole and famotidine. Ten Helicobacter pylori (HP)-negative male subjects participated in this randomized, three-way crossover study. A single oral administration of vonoprazan (20 mg), lansoprazole (30 mg) or famotidine (20 mg) was performed, and the intragastric pH was continuously monitored for 6 h. Each drug was administered at least seven days apart. The average intragastric pH during the 6-h period after the administration of famotidine was higher than that after the administration of lansoprazole (median: 4.45 vs 2.65; p = 0.0284). A similar result was observed for vonoprazan and lansoprazole (median: 4.30 vs 2.65; p = 0.0322). In conclusions, oral administration of vonoprazan and famotidine in HP-negative healthy male subjects caused the intragastric pH to rise more quickly than did lansoprazole. (Trial Registration: UMIN000020989)

Measurement Equivalence of Patient-Reported Outcome Measure Response Scale Types Collected Using Bring Your Own Device Compared to Paper and a Provisioned Device: Results of a Randomized Equivalence Trial

ObjectivesThe aim of this study was to assess the measurement equivalence of individual response scale types by using a patient reported outcome measure (PROM) collected on paper and migrated into electronic format for use on the subject’s own mobile device (BYOD) and on a provisioned device (site device). MethodsSubjects suffering from chronic health conditions causing daily pain or discomfort were invited to participate in this single-site, single visit, three-way crossover study. Association between individual item and instrument subscale scores was assessed by using the intraclass correlation coefficient (ICC) and its CI. Participant attitudes toward the use of BYOD in a clinical trial were assessed through use of a questionnaire. ResultsIn this study, 155 subjects (females 83 [54%]; males 72 [46%]) ages 19 to 69 years (mean ± SD: 48.6 ± 13.1) were recruited. High association between the modes of administration (paper, BYOD, site device) was shown with analysis of ICCs (0.79–0.98) for each response scale type, including visual analogue scale, numeric rating scale, verbal response scale, and Likert scale. Of the subjects, 94% (146 of 155) stated that they would definitely or probably be willing to download an app onto their own mobile device for a forthcoming clinical trial. Forty-five percent of subjects felt BYOD would be more convenient compared with 15% preferring a provisioned device (40% had no preference). ConclusionsThis study provides strong evidence supporting the use of BYOD for PROM collection in terms of the conservation of instrument measurement equivalence across the most widely used response scale types, and high patient acceptance of the approach.

Inhibitory effect of Phlai capsules on skin test responses among allergic rhinitis patients: a randomized, three-way crossover study

BackgroundZingiber cassumunar Roxb., commonly known as Phlai in Thai, has been used as a traditional medicine in Thailand for the treatment of various diseases, including inflammation and chronic airway disease. ObjectiveThe purpose of this study was to assess the antihistaminic effect of Phlai on skin testing. Design, Setting, Participants and InterventionThis was a randomized, open-label, three-way crossover study. Twenty allergic rhinitis (AR) patients were enrolled. In randomized sequence, patients received a single dose of Phlai capsules (100 or 200 mg) or loratadine (10 mg) with a washout period of 1 week between each treatment. Main Outcome MeasuresSkin prick testing for histamine and common aeroallergen (house dust mite) were performed before treatment and after 1, 2, 3, 4, 6, 8, 12 and 24 hours of treatment. The main treatment outcomes were the mean wheal and flare responses to the skin prick test after treatment. ResultsBoth 100 mg and 200 mg Phlai doses suppressed wheal and flare responses to house dust mite allergen, but only 200 mg of Phlai capsules significantly suppressed wheal and flare responses to histamine. Repeated measures analysis of variance showed that loratadine caused more wheal and flare suppression than Phlai capsules in responses to the histamine skin prick test. However, there were no significant differences among the effects of 100 mg Phlai capsules, 200 mg Phlai capsules and loratadine in suppression of wheal and flare induced by the mite skin prick test. Both doses of Phlai were well-tolerated with no adverse events. ConclusionBoth 100 mg (compound D 4 mg) and 200 mg (compound D 8 mg) Phlai capsules, when taken as a single therapeutic dose, inhibited skin reactivity to histamine and mite skin prick tests in AR patients. Trial RegistrationThai clinical trial registry (TCTR20160510001).

Sea buckthorn decreases and delays insulin response and improves glycaemic profile following a sucrose-containing berry meal: a randomised, controlled, crossover study of Danish sea buckthorn and strawberries in overweight and obese male subjects

Berries and mixed berry products exert acute effects on postprandial glycaemia and insulinemia, but very few berries have been studied, and primarily in normal weight subjects. Sea buckthorn and strawberry are compositionally widely different berries and may likely produce different responses. The effects of strawberry and sea buckthorn on postprandial glycaemia and insulinemia were examined in overweight or obese male subjects. Subjective appetite sensations and ad libitum intake were also examined. The study was conducted as a randomised, controlled, single-blinded, three-way crossover study. Eighteen subjects were studied in three 2-h meal tests followed by a subsequent ad libitum meal. Test meals contained added sucrose and either sea buckthorn, strawberry or no berries with added fructose (control). Blood samples were collected at t = 0, 30, 45, 60, 90 and 120min. Subjective appetite sensations were recorded at t = 0, 15, 30, 45, 60, 90, 120, and 140min and subsequent ad libitum intake was recorded. Statistical differences in all continuous measures were evaluated based on the existence of a meal or a time-meal interaction by repeated measures linear model analyses or by differences in AUC by linear mixed models. None of the berries affected postprandial glucose. However, sea buckthorn improved glycaemic profile (44.7%, p < 0.01) compared to control. Sea buckthorn also resulted in a decrease in plasma insulin concentration at 30min (39.6%, p < 0.01) and at 45min (16.5%, p < 0.05) compared to control and the maximal increase in plasma insulin was lower following sea buckthorn compared with control (23.6%, p < 0.01). Strawberry did not affect postprandial insulin concentrations compared to control. No differences between control and each of the two berries were observed for any of the appetite parameters, except for desire for something sweet, which was increased following the sea buckthorn meal compared to control. There was no effect on postprandial glucose response to a sugar challenge given together with purees of strawberry or sea buckthorn. Sea buckthorn decreased and delayed the insulin response and improved glycaemic profile compared with control. Strawberry had no such effects. No important differences were seen for the appetite measures. Sea buckthorn might be useful as a culinary tool for lowering meal insulin response.

The effect of glycopyrronium and indacaterol, as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics: a randomized three-way crossover study

BackgroundMethacholine dose-response curves illustrate pharmacologic bronchoprotection against methacholine-induced airway hyperresponsiveness and can be used to quantitate changes in airway sensitivity (position), reactivity (slope), and maximal responsiveness following drug administration. Our objective was to determine the influence of single-dose glycopyrronium (long-acting muscarinic antagonist) and indacaterol (ultra-long acting β2 agonist), as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics and to compare these findings with a non-asthmatic control curve.MethodsThis was a randomized, double blind, double dummy, three-way crossover study. For asthmatic participants (n = 14), each treatment arm included a baseline methacholine challenge, drug administration, and repeat methacholine challenges at 1, 24, and 48 h. Non-asthmatic control participants (n = 15) underwent a single methacholine challenge and did not receive any study treatment. Methacholine dose-response curves were graphed as the percent fall in forced expiratory volume in 1 s (FEV1) for each methacholine concentration administered. Best-fit curves were then generated. Differences in airway reactivity were calculated through linear regression. Changes in airway sensitivity were assessed as the shift in the provocative concentration of methacholine causing a 20% fall in FEV1.ResultsCompared to baseline, all treatments significantly reduced airway sensitivity to methacholine at 1 h post-dose (indacaterol ~1.5 doubling concentrations; glycopyrronium ~5 doubling concentrations; combination ~5 doubling concentrations). Bronchoprotection at 24 and 48 h remained significant with glycopyrronium and combination therapy only. Airway reactivity was not influenced by indacaterol whereas glycopyrronium significantly reduced airway reactivity at all time-points (p = 0.003-0.027). The combination significantly decreased slope at 1 (p = 0.021) and 24 (p = 0.039) hours only. The non-asthmatic control and 1-h glycopyrronium curves are nearly identical. Only the non-asthmatic control and 1-h post-combination therapy curves appeared to generate a true response plateau (three data points within 5%), which occurred at a 14% fall in FEV1.ConclusionsMethacholine dose-response curves differentiate the bronchoprotective mechanisms triggered by different classes of asthma medications. Assessment of bronchoprotection using methacholine dose-response curves may be useful during clinical development of respiratory medications when performing superiority, equivalence, or non-inferiority trials.Trial registrationclinicaltrials.gov (NCT02953041). Retrospectively registered on October 24th 2016.

Influence of Ethanol on Oxycodone-induced Respiratory Depression: A Dose-escalating Study in Young and Elderly Individuals.

Respiratory depression is a potentially fatal complication of opioid use, which may be exacerbated by simultaneous ethanol intake. In this three-way sequential crossover dose-escalating study, the influence of coadministration of oral oxycodone and intravenous ethanol was assessed on resting ventilation, apneic events and the hypercapnic ventilatory response in healthy young and older volunteers. Twelve young (21 to 28 yr) and 12 elderly (66 to 77 yr) opioid-naive participants ingested one 20 mg oxycodone tablet combined with an intravenous infusion of 0, 0.5, or 1 g/l ethanol. Resting respiratory variables and the primary outcome, minute ventilation at isohypercapnia (end-tidal partial pressure of carbon dioxide of 55 mmHg or VE55), were obtained at regular intervals during treatment. Oxycodone reduced baseline minute ventilation by 28% (P < 0.001 vs. control). Ethanol caused a further decrease of oxycodone-induced respiratory depression by another 19% at 1 g/l ethanol plus oxycodone (P < 0.01 vs. oxycodone). Ethanol combined with oxycodone caused a significant increase in the number of apneic events measured in a 6-min window with a median (range) increase from 1 (0 to 3) at 0 g/l ethanol to 1 (0 to 11) at 1 g/l ethanol (P < 0.01). Mean (95% CI) VE55 decreased from 33.4 (27.9 to 39.0) l/min (control) to 18.6 (15.6 to 21.6) l/min (oxycodone, P < 0.01 vs. control) and to 15.7 (12.7 to 18.6) l/min (oxycodone combined with ethanol, 1 g/l; P < 0.01 vs. oxycodone). Ethanol together with oxycodone causes greater ventilatory depression than either alone, the magnitude of which is clinically relevant. Elderly participants were more affected than younger volunteers.

Early effect on intragastric pH of oral administration of rabeprazole with mosapride compared with rabeprazole alone.

BackgroundAn ideal medication for acid-related diseases would offer prompt stopping of blood flow as well as efficient symptom resolution. The aim of this study was to investigate the gastric acid suppression potency of a single oral dose of rabeprazole alone, compared with administration of rabeprazole plus mosapride.MethodsTwelve male volunteers, Helicobacter pylori (H. pylori)-negative, participated in this randomized, three-way crossover study. After a single oral administration of rabeprazole, rabeprazole with mosapride, or rabeprazole administered 1 h after mosapride, we monitored their intragastric pH constantly for 6 h. A 7-day washout period was allowed between each administration.ResultsThe median 6-h intragastric pH after the administration of rabeprazole 1 h after mosapride was 4.41±1.22 (mean±s.d.), significantly higher than after rabeprazole alone 3.45±1.33, P=0.0376). There was no significant difference between the median 6-h pH after the administration of rabeprazole plus mosapride and that after rabeprazole alone (3.81±0.98 vs. 3.45±1.33, respectively; P=0.0927).ConclusionAn oral dose of rabeprazole administered 1 h after mosapride increased the intragastric pH more rapidly than rabeprazole alone, in healthy, male, H. pylori-negative volunteers.

Tolerability and safety of the intake of bovine milk oligosaccharides extracted from cheese whey in healthy human adults.

Mechanistic research suggests a unique evolutionary relationship between complex milk oligosaccharides and cognate bifidobacteria enriched in breast-fed infants. Bovine milk oligosaccharides (BMO) were recently identified as structurally and functionally similar to human milk oligosaccharides. The present single-blind three-way crossover study is the first to determine the safety and tolerability of BMO consumption by healthy human participants (n 12) and its effects on faecal microbiota and microbial metabolism. Participants consumed each supplement (placebo-control; low- and high-BMO doses) for eleven consecutive days, followed by a 2-week washout period prior to initiating the next supplement arm. Low and high BMO doses were consumed as 25 and 35% of each individual's daily fibre intake, respectively. Safety and tolerability were measured using standardised questionnaires on gut and stomach discomfort and stool consistency. Faecal extracts were profiled for bacterial populations by next-generation sequencing (NGS) and bifidobacteria presence was confirmed using quantitative PCR. Urine was analysed for changes in microbial metabolism using nuclear magnetic resonance spectroscopy (1H-NMR). Consumption of both the low and high BMO doses was well tolerated and did not change stool consistency from baseline. Multivariate analysis of the NGS results demonstrated no change in faecal microbiota phyla among the placebo-control and BMO supplement groups. In conclusion, BMO supplementation was well tolerated in healthy adults and has the potential to shift faecal microbiota toward beneficial strains as part of a synbiotic treatment with probiotic cultures that selectively metabolise oligosaccharides.

Effects of the Red Bull energy drink on cognitive function and mood in healthy young volunteers.

The present study compared the cognitive and mood effects of two commercially available products, Red Bull energy drink 250 mL and Red Bull Sugarfree energy drink 250 mL, together with a matching placebo 250 mL. Twenty-four healthy young volunteers took part in a randomised, placebo controlled, double-blind, three-way cross-over study. Cognitive function was assessed using an integrated set of nine computerised tests of attention, working and episodic memory. On each study day the volunteers received a standardised breakfast prior to completing a baseline performance on cognitive tests and mood scales, followed by the consumption of the study drink. The cognitive tests and scales were then re-administered at 30, 60 and 90 min post-dose. Red Bull was found to produce significant improvements over both the Sugarfree version and the placebo drink on two composite scores from the six working and episodic memory tests; one combining the 12 accuracy measures from the six tasks and the other the average speed of correct responses from the working memory and episodic recognition memory tasks. These improvements were in the range of a medium effect size, which reflects a substantial enhancement to memory in young volunteers.

Solithromycin, a novel macrolide, does not prolong cardiac repolarization: a randomized, three-way crossover study in healthy subjects.

Macrolide antibiotics may cause QT prolongation. To study the QT effect of a novel macrolide, solithromycin. This was a thorough QT study with a three-way crossover design performed in healthy male and female subjects to evaluate the ECG effects of a novel macrolide, solithromycin. Forty-eight subjects were randomized to receive 800 mg of intravenous (iv) solithromycin, 400 mg of oral moxifloxacin and placebo in three separate treatment periods. Continuous 12 lead ECGs were recorded at a pre-dose baseline and serially after drug administration for 24 h. After the 40 min infusion of 800 mg of solithromycin, the geometric mean solithromycin peak plasma concentration (Cmax) reached 5.9 (SD: 1.30) μg/mL. Solithromycin infusion caused a heart rate increase with a peak effect of 15 bpm immediately after the end of the infusion. The change-from-baseline QTcF (ΔQTcF) was similar after dosing with solithromycin and placebo and the resulting placebo-corrected ΔQTcF (ΔΔQTcF) for solithromycin was therefore small at all timepoints with a peak effect at 4 h of only 2.8 ms (upper bound of the 90% CI: 4.9 ms). Using a linear exposure-response model, a statistically significant, slightly negative slope of -0.86 ms per ng/mL (90% CI: -1.19 to -0.53; P = 0.0001) was observed with solithromycin. The study's ability to detect small QT changes was confirmed by the moxifloxacin response. Solithromycin did not have a clinically meaningful effect on the PR or QRS interval. The study demonstrated that solithromycin, unlike other macrolide antibiotics, does not cause QT prolongation.

Psychophysical Vision Simulation of Diffractive Bifocal and Trifocal Intraocular Lenses.

PurposeThe visual performance of monofocal, bifocal, and trifocal intraocular lenses was evaluated by human individuals using a vision simulator device. This allowed investigation of the visual impression after cataract surgery, without the need actually to implant the lenses.MethodsThe randomized, double-masked, three-way cross-over study was conducted on 60 healthy male and female subjects aged between 18 and 35 years. Visual acuity (Early Treatment Diabetic Retinopathy Study; ETDRS) and contrast sensitivity tests (Pelli-Robson) under different lighting conditions (luminosities from 0.14–55 cd/m2, mesopic to photopic) were performed at different distances.ResultsVisual acuity tests showed no difference for corrected distance visual acuity data of bi- and trifocal lens prototypes (P = 0.851), but better results for the trifocal than for the bifocal lenses at distance corrected intermediate (P = 0.021) and distance corrected near visual acuity (P = 0.044). Contrast sensitivity showed no differences between bifocal and trifocal lenses at the distant (P = 0.984) and at the near position (P = 0.925), but better results for the trifocal lens at the intermediate position (P = 0.043). Visual acuity and contrast sensitivity showed a strong dependence on luminosity (P < 0.001).ConclusionsAt all investigated distances and all lighting conditions, the trifocal lens prototype often performed better, but never worse than the bifocal lens prototype.Translational RelevanceThe vision simulator can fill the gap between preclinical lens development and implantation studies by providing information of the perceived vision quality after cataract surgery without implantation. This can reduce implantation risks and promotes the development of new lens concepts due to the cost effective test procedure.

Pharmacological interactions between brivaracetam and ethanol in healthy males.

This double-blind, randomized, three-way crossover study explored the potential pharmacokinetic and pharmacodynamic interactions between ethanol and brivaracetam in 18 healthy males, as required for the development of CNS-active drugs. Subjects received (A) ethanol+brivaracetam, (B) ethanol placebo+brivaracetam and (C) ethanol+brivaracetam placebo. Ethanol was infused as a 5.5-hour intravenous clamp with the first 0.5-hour as loading phase to a target level of 0.6 g/L, and brivaracetam was orally administered as a single 200 mg dose. No relevant pharmacokinetic interactions were observed. Co-administration of brivaracetam and ethanol resulted in decreased saccadic peak velocity, smooth pursuit, adaptive tracking and VAS alertness, and increased body sway, saccadic reaction time and VAS score for ethanol effect compared with brivaracetam alone or ethanol alone. Additionally, the immediate word recall scores were generally lower when brivaracetam was co-administered with ethanol, whereas the delayed word test did not show clear additional effects. A post-hoc exploratory analysis for supra-additivity suggested that most pharmacodynamic effects were likely to be additive in nature, except for adaptive tracking, which appeared to be slightly supra-additive. In conclusion, brivaracetam increased ethanol effects on psychomotor function, attention and memory in healthy males. Intake of brivaracetam with alcohol is not recommended.

Failure of sucrose replacement with the non-nutritive sweetener erythritol to alter GLP-1 or PYY release or test meal size in lean or obese people

There is considerable interest in the effect of foods containing high intensity sweeteners on satiation. However, less is known about low-calorie bulk sweeteners such as erythritol. In this randomized three-way crossover study, we studied 10 lean and 10 obese volunteers who consumed three test meals on separate occasions: (a) control sucrose meal; (b) isovolumic meal with partial replacement of sucrose by erythritol; (c) isocaloric meal which contained more erythritol but equivalent calories to the control meal. We measured gut hormone levels, hunger and satiety scores, ad libitum food intake, sucrose preference and intake after the manipulations. There was a greater post-prandial excursion in glucose and insulin levels after sucrose than after the erythritol meals. There was no difference in GLP-1/PYY levels or subsequent energy intake and sucrose preference between sucrose control and isovolumic erythritol meals. In lean (but not obese) participants, hunger decreased to a greater extent after the isocaloric erythritol meal compared to the control meal (p = 0.003) reflecting the larger volume of this meal. Replacing sucrose with erythritol leads to comparable hunger and satiety scores, GLP-1 and PYY levels, and subsequent sucrose preference and intake.