Significant Subjective Effects Research Articles

Lack of Acute Agomelatine Effect in a Model of Social Anxiety in Healthy Volunteers: A Double-Blind, Placebo-Controlled Trial.

Agomelatine is an antidepressant drug that acts as an agonist of melatoninergic MT1/2 receptors and an antagonist of serotonergic 5-HT2C receptors. Studies suggest that agomelatine has anxiolytic properties in social anxiety, but there are no studies that assessed the effects of this compound in human experimental anxiety induced by a public speaking test. The objective of our investigation was to assess the effects of agomelatine on human experimental anxiety using the Simulation Public Speaking Test (SPST). Agomelatine (25 mg, n = 14), citalopram (20 mg, n = 14), venlafaxine (75 mg, n = 14), or placebo (n = 14) were administered in single doses to healthy volunteers in a double-blind study. Subjective anxiety was assessed with the Visual Analogue Mood Scale. Arterial blood pressure, heart rate, and blood levels of prolactin and cortisol were also recorded, as well as plasma levels of the 3 drugs. The SPST induced significant subjective, physiological, and hormonal effects in all groups. The SPST also increased the anxiety and decreased mental sedation Visual Analogue Mood Scale factors during the anticipatory and performance phases of the test. Citalopram increased anxiety during the test in females, whereas agomelatine and venlafaxine were not different from placebo. Confirming previous results, a serotonin selective reuptake inhibitor, citalopram, caused an anxiogenic effect in the SPST only in females. Acute administration of a low dose of agomelatine failed to modify the behavioral and physiological changes caused by this test. Future studies using higher doses and repeated administration should investigate if agomelatine behavioral and physiological effects could be detected in human experimental anxiety models.

Re‐evaluating the choice of gamma stimulation frequency for potential treatment of Alzheimer’s disease: Novel invisible spectral flicker evokes gamma responses at various frequencies

AbstractBackgroundWith recent advances in the potential usage of visual gamma stimulation at 40 Hz for treatment of Alzheimer’s disease, there is reason to evaluate the use of other low gamma frequencies. The choice of 40 Hz is based on studies that describe “40 Hz” oscillations with considerable frequency variability. Results are also ambiguous on the acute effects of varying the frequency when stimulating with stroboscopic flicker in the low gamma range (30‐50 Hz). As stroboscopic visual stimulation may also affect adherence in clinical trials due to its inherent flickering, invisible spectral flicker (ISF) was proposed as a more comfortable alternative for entraining 40 Hz. This study investigates the ability of ISF to entrain gamma responses at several frequencies in the range of 36‐44 Hz.MethodTwenty healthy young volunteers were included in an electroencephalography (EEG) experiment (DTU Compute IRB Approval: COMP‐IRB‐2021‐01) with an initial eyes‐open baseline recording followed by a stimulation paradigm using ISF at nine different frequencies (36‐44 Hz, 1 Hz interval) in a randomized complete block design with five blocks. The responses were evaluated as the signal‐to‐noise ratio (SNR) averaged over the O1 and O2 electrodes at the stimulation frequency and analysed using mixed‐effect models with frequency as a fixed factor and subject and block as random factors. All two‐way interactions were included as random factors. Evoked responses were compared to baseline and between frequencies post hoc, correcting for multiple comparisons with Tukey’s method.ResultThe EEG power (Figure 1) showed that stimulus SNR values were significantly higher than baseline for all frequencies (P<.05, see Figure 2), but no stimuli resulted in significantly different SNR. There was significant subject effect (P<<.05), and one subject responded 1‐2 orders of magnitude higher than the others. This suggests higher variability between subjects than frequencies alone.ConclusionOur results indicate that ISF can induce steady‐state visually evoked potentials at several frequencies in the low gamma range of 36‐44 Hz. Across the population of participants, we found no preference or trend for any specific gamma stimulation frequency in the tested range.

Differences in Behavior between Normal and Atopic Keratinocytes in Culture: Pilot Studies.

Skin barrier dysfunction is important in atopic dermatitis and can be secondary to inflammation. Observation of keratinocytes in culture may show intrinsic differences. TransEpithelial Electrical Resistance (TEER) measures epithelial permeability. We cultured normal and atopic keratinocytes and found that TEER of atopic keratinocytes was significantly lower (p < 0.0001) than that of normals. Atopic keratinocytes grew upwards, first creating isolated dome-like structures and later horizontally into a monolayer. At time of confluence (D0), atopic keratinocytes were more differentiated, with higher filaggrin gene expression than normals. No differences existed between groups for TJ proteins (claudin, occludin, and Zonula Occludens-1) on D0 and D6. On D6, claudin and occludin were higher than D0, in normal (p = 0.0296 and p = 0.0011) and atopic keratinocytes (p = 0.0348 and 0.0491). Immunofluorescent staining showed nuclear location of filaggrin on D0 and cytoplasmic on D6. ANOVA showed increased cell size from D0 to D6 in both groups (effect of time, p = 0.0076) but no differences between groups. Significant subject effect (p = 0.0022) was found, indicating that cell size was subject-dependent but not disease-dependent. No difference for continuity for TJ protein existed between groups. These observations suggest that decreased TEER in atopics is not linked to TJ differences but is possibly linked to different growth behavior.

Undergraduate student financial education interventions: Medium term evidence of retention, decay, and confidence in financial literacy

University is a significant transition period for young adults as they seek and gain independence, including financial independence. This would appear an ideal teachable moment for delivering financial education, though evidence of financial education intervention outcomes is mixed. We report medium-term empirical evidence, three years after the completion of an undergraduate personal finance semester-length unit, evidence notably absent in the literature. We find students retain significant objective and subjective financial literacy effects, with modest decay, three years after completing a unit of personal finance education. Effects on behavior and behavior intentions are less robust over time as boosts reported immediately after completion dissipate three years hence, though in absolute terms positive behaviors remain high. We found little evidence to link completion of a unit of study with overconfidence, as has previously been suggested, and students overall appear more discerning in their search for financial information sources after the unit.

Umicore, Apeiron end metathesis suit.

University is a significant transition period for young adults as they seek and gain independence, including financial independence. This would appear an ideal teachable moment for delivering financial education, though evidence of financial education intervention outcomes is mixed. We report medium-term empirical evidence, three years after the completion of an undergraduate personal finance semester-length unit, evidence notably absent in the literature. We find students retain significant objective and subjective financial literacy effects, with modest decay, three years after completing a unit of personal finance education. Effects on behavior and behavior intentions are less robust over time as boosts reported immediately after completion dissipate three years hence, though in absolute terms positive behaviors remain high. We found little evidence to link completion of a unit of study with overconfidence, as has previously been suggested, and students overall appear more discerning in their search for financial information sources after the unit.

Memory Buttons in Combination with Mobile Application-Induced Objective and Subjective Effects in Patients with Atopic Dermatitis.

Background Atopic dermatitis (AD) is a chronic skin condition where nonadherence often results in lack of disease control. Objective We wanted to determine whether the combination of an electronic memory button and a supportive application (app) would affect the Quality of Life and subjective and objective severity measures among AD patients over one month following the patient's normal schedules of treatment. Methods A randomized, investigator-blinded, prospective observational feasibility study for one month where patients diagnosed with AD were randomized based on POEM severity score and divided into 3 groups. The 3 groups were (1) the control group with two consultations, (2) in addition to group 1, patients also received electronic memory buttons to click every time they used their topical products, and (3) in addition to group 2, patients also received an app to track their treatment schedules. At both consultations, patients were evaluated using SCORAD, EASI, POEM, and DLQI. Results 96 patients were enrolled and randomized, of which 83 patients completed the study. EASI and SCORAD scores were lower in all groups at 2nd consultation (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 (Conclusion A reduction in severity following objective assessments of the AD was observed for all groups and was highly significant for patients offered a memory button and the corresponding app. Furthermore, patients reported a significant subjective beneficial effect if they used the memory button and app. This indicates that digital solutions may have a benefit in clinical practice and may reduce nonadherence and increase the wellbeing of the patients.

Intranasal Oxytocin Does Not Modulate Responses to Alcohol in Social Drinkers.

Preclinical and clinical evidence suggest that the neuropeptide oxytocin may be of value in treating alcohol use disorder, by either reducing the rewarding effects of alcohol or reducing negative affect induced by alcohol withdrawal. However, the effect of a single dose of oxytocin on subjective and psychomotor responses to alcohol in social drinkers is not known. This study examined the effect of intranasal oxytocin on subjective, behavioral, and physiological responses to a moderate dose of alcohol (0.8g/kg) in young adult social drinkers. Participants (N=35) completed 2 study sessions at which they consumed beverages containing alcohol (ALC; N=20) or placebo (NoALC; N=15) in combination with intranasal oxytocin (40IU with a 20IU booster) or placebo. They received oxytocin at one session and placebo at the other session (order counterbalanced) 20minutes before consuming beverages. Subjective mood and drug effects ratings, heart rate and blood pressure, and 4 behavioral tasks (flanker task, digit span, go/no-go, and pursuit rotor) were the primary outcome measures. ALC produced its expected subjective and behavioral effects; including feeling intoxicated and impaired performance on the digit span and go/no-go tasks. Oxytocin alone had no significant subjective or physiological effects, and it did not affect responses to alcohol on any measure. We can conclude that, under these conditions, a single dose of intranasal oxytocin does not alter the effects of acute alcohol in healthy young adult social drinkers. Further research is needed to determine whether oxytocin alters responses to alcohol under different conditions, and to determine its potential as an aid in treatment for substance use disorders.

Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

Rationale3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally and investigated as an adjunct to psychotherapy. Methylphenidate and modafinil are psychostimulants that are used to treat attention-deficit/hyperactivity disorder and narcolepsy, respectively, but they are also misused as cognitive enhancers. Little is known about differences in the acute effects of equally cardiostimulant doses of these stimulant-type substances compared directly within the same subjects.MethodsWe investigated the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg), and placebo in a double-blind, cross-over study in 24 healthy participants. Acute drug effects were tested using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI).ResultsAll active drugs produced comparable hemodynamic and adverse effects. MDMA produced greater increases in pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness than methylphenidate or modafinil. Only MDMA reduced subjective anxiety and impaired fear recognition and led to misclassifications of emotions as happy on the FERT. On the SADI, only MDMA produced sexual arousal-like effects. Only MDMA produced marked increases in cortisol, prolactin, and oxytocin. In contrast to MDMA, methylphenidate increased subjective anxiety, and methylphenidate and modafinil increased misclassifications of emotions as angry on the FERT. Modafinil had no significant subjective drug effects but significant sympathomimetic and adverse effects.ConclusionsMDMA induced subjective, emotional, sexual, and endocrine effects that were clearly distinct from those of methylphenidate and modafinil at the doses used.

Clinical efficiency and dermoprotection of 2-ethyl-6-methyl-3-hydroxypyridine succinate drug in case of psoriasis: from the antioxidation point of view

Objective. To study the clinical significance of oxidative processes modulation within frames of 2-ethyl-6-methyl-3-hydroxypyridine succinate dermatropic efficiency assessment in patients with psoriasis affected by arterial hypertension. Materials and methods. The results of this study are based on data of comprehensive examination and supervision of 30 patients suffering from psoriasis with different clinical forms such as normal levels of blood pressure (the control group) or in combination with hypertension (the study group). Results. The comparative description of the antioxidative therapy efficiency was performed by the end of treatment. The findings showed significantly positive antioxidant-dependent mechanisms of 2-ethyl-6-methyl-3-hydroxypyridine succinate clinical efficiency in patients with psoriasis affected by arterial hypertension. In case of patients with combined psoriasis and essential hypertension course 2-ethyl-6-methyl-3-hydroxypyridine succinate therapy caused reliable decrease of free-radical oxidation intensification in particular nitrosative (reliable decrease of nitrotyrosine) and oxidative (negative dynamics of endothelin-1 and positive dynamics as to glutathione metabolism) stresses. That, in its turn, decreased the evidence of apoptotic and inflammatory processes (caspase-8 and TNF-α regress) both directly and indirectly by means of mediating anti-inflammatory effect on endothelium cells and macrophages of anticoagulant proteinase through endothelial protein C receptor (EPCR) with production of components and structures of extracellular matrix and disturbance of microcirculation. Thus, it determines the key pathogenetic aspects of psoriasis. The decrease of VEGF expression indicators level (vascular endothelial growth factor) and serotonin, associated with this combined therapy, had stipulated statistically significant positive clinical and subjective effect in form of regress of dermatological changes (PASI index), decrease of itch (optimization of serotonin biosynthesis and reduction of methionine conversion (with homocysteine formation)) and improvement of life quality. Conclusions. Taking into account potential influence of 2-ethyl-6-methyl-3-hydroxypyridine succinate on these pathophysiological predictors and pathogenesis, which are to some extent involved in formation and progression of psoriatic disease, use of 2-ethyl-6-methyl-3-hydroxypyridine succinate is sufficiently effective in conditions of psoriasis therapy optimization.

Marijuana’s dose-dependent effects in daily marijuana smokers.

Active marijuana produces significant subjective, psychomotor, and physiological effects relative to inactive marijuana, yet demonstrating that these effects are dose-dependent has proven difficult. This within-subject, double-blind study was designed to develop a smoking procedure to obtain a marijuana dose-response function. In four outpatient laboratory sessions, daily marijuana smokers (N = 17 males, 1 female) smoked six 5-s puffs from 3 marijuana cigarettes (2 puffs/cigarette). The number of puffs from active (≥5.5% Δ⁹-tetrahydrocannabinol/THC) and inactive (0.0% THC) marijuana varied according to condition (0, 2, 4, or 6 active puffs); active puffs were always smoked before inactive puffs. Subjective, physiological, and performance effects were assessed prior to and at set time points after marijuana administration. Active marijuana dose-dependently increased heart rate and decreased marijuana craving, despite evidence (carbon monoxide expiration, weight of marijuana cigarettes post-smoking) that participants inhaled less of each active marijuana cigarette than inactive cigarettes. Subjective ratings of marijuana "strength," "high," "liking," "good effect," and "take again" were increased by active marijuana compared with inactive marijuana, but these effects were not dose-dependent. Active marijuana also produced modest, non-dose-dependent deficits in attention, psychomotor function, and recall relative to the inactive condition. In summary, although changes in inhalation patterns as a function of marijuana strength likely minimized the difference between dose conditions, dose-dependent differences in marijuana's cardiovascular effects and ratings of craving were observed, whereas subjective ratings of marijuana effects did not significantly vary as a function of dose.

Caffeine increases psychomotor performance on the effort expenditure for rewards task

Preclinical studies suggest that cost/benefit decision-making involves interactions between adenosine and dopamine (DA). In rats, DA depletion decreases willingness to incur effort costs, while adenosine antagonism reverses these effects, likely by increasing DA transmission. Caffeine is a non-selective adenosine antagonist commonly used to facilitate effortful tasks, and thus may affect decisions involving effort costs in humans. The current study examined acute effects of 200mg of caffeine on willingness to exert effort for monetary rewards at varying levels of reward value and reward probability, in young adult light caffeine users. Based on previous findings with amphetamine, we predicted that caffeine would increase willingness to exert effort. At separate sessions, 23 healthy normal adults received placebo or 200mg caffeine under counterbalanced double-blind conditions, then completed the effort expenditure for rewards task (EEfRT). Measures of subjective and cardiovascular effects were obtained at regular intervals. Caffeine produced small but significant subjective and cardiovascular effects, and sped psychomotor performance on the EEfRT. Caffeine did not alter willingness to exert effort, except in high cardiovascular responders to caffeine, in whom it decreased willingness to exert effort. These results were contrary to our predictions, but consistent with rodent studies suggesting that moderate doses of caffeine alone do not affect effort, but rather only influence effort in the context of DA antagonism. Our results demonstrate that psychomotor speeding and decisional effects on the EEfRT are dissociable, providing additional evidence for the EEfRT as a specific measure of effort-based decision-making. This study provides a starting point for exploring contributions of the adenosine system to motivation in humans.

Bioeqivalence Assessment of Two Domperidone Tablet Formulations

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two domperidone (CAS 57808-66-9) tablet formulations, Domperidone (test) and a commercially available original preparation (reference) under fasting conditions. A 10 mg dose of each formulation was administered to 36 healthy male volunteers with a one-week washout period, 17 blood samples were collected over 48 h, plasma concentrations of domperidone were analyzed by a locally validated LC-MS-MS assay, and the pharmacokinetic parameters were determined by the standard non-compartmental method. Mean +/- SD maximum concentration (C(max)), time to reach maximum concentration (T(max)), areas under the curve (AUC(0 --> t and AUC(0 --> infininty)), and elimination constant (K(el)) were 17.13 +/- 9.62 and 17.67 +/- 7.97 ng/ml, 0.87 +/- 0.58, and 0.89 +/- 0.33 h, 73.12 +/- 43.37 and 71.45 +/- 35.41 ng x h/ml, 90.32 +/- 48.55 and 87.08 +/- 40.29 ng x h/ml, and 0.069 +/- 0.046 and 0.068 +/- 0.048 h(-1) for the test and reference formulation, respectively. The parametric 90% confidence intervals on the mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range for AUC(0 --> t) (87.84% to 109.60%), AUC(0 --> infinity) (89.05% to 111.67%) and C(max) (83.28% to 107.50%). ANOVA revealed significant subject's effect for AU4C(0 --> t), AUC((0 -->infinity), C(max), and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 2.10, 1.55, 1.10, and 1.02, respectively. The results indicate that the two formulations are equivalent in relation to the extent and rate of absorption and confirm the previously reported marked intra-individual variations in the pharmacokinetics of domperidone.

Bioequivalence Assessment of Two Capsule Formulations of Omeprazole in Healthy Volunteers

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two omeprazole (CAS 73590-58-6) capsule formulations, Emilok (test) and a commercially available original preparation (reference), under fasting conditions. A 20 mg dose of each formulation was administered to 36 healthy male volunteers with one-week washout period, 17 blood samples were collected over 12 h, plasma omeprazole concentrations were determined by a locally validated high performance liquid chromatography (HPLC) assay, and omeprazole pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD of Cmax, Tmax, AUC(0 --> t), AUC(0 --> infinity), and t1/2 were 0.41 +/- 0.21 and 0.48 +/- 0.27 microg/ml, 1.98 +/- 1.02 and 1.63 +/- 0.78 h, 0.95 +/- 0.78 and 1.00 +/- 0.90 microg x h/ml, 0.99 +/- 0.81 and 1.04 +/- 0.95 microg x h/ml, and 1.30 +/- 0.64 and 1.14 +/- 0.61 h for the test and reference formulations, respectively. The parametric 90% confidence intervals on mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range of 80% to 125% for AUC(0 --> t) and AUC(0 --> infinity) (88.63% to 104.98%, and 91.71% to 106.86%, respectively) but not for Cmax (76.27% to 103.63%). ANOVA revealed significant subject's effect for AUC(0 --> t), AUC(0 --> infinity), Cmax, and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 3.66, 3.92, 1.25, and 1.46, respectively. The results confirm the presence of marked individual variations in the pharmacokinetics of omeprazole and indicate that the two formulations are equivalent in relation to the extent but not the rate of absorption.

A high intake of industrial or ruminant trans fatty acids does not affect the plasma proteome in healthy men

Consumption of industrial trans fat raises the risk of cardiovascular disease, but it is unclear whether cis9,trans11-conjugated linoleic acid (CLA)--a trans fatty acid in dairy products--modulates disease development. We investigated the effects of complete diets providing 7% of energy as industrial trans fat or cis9, trans11 CLA, compared with oleic acid, on regulation of plasma proteins in 12 healthy men. Diets were provided for 3 wk each, in random order. Plasma was collected at the end of each 3 wk intervention period, depleted of its 12 most abundant proteins and analyzed by 2-DE. Principal component analysis of protein spot intensity values revealed that the nature of the dietary intervention did not significantly affect the plasma proteome. The intervention provided in the 1st period produced a significant treatment effect compared with the interventions provided in the other two periods, and there was a significant subject effect. In conclusion, the nature of an extreme dietary intervention, i.e. 7% of energy provided by industrial trans fat or cis9,trans11 CLA, did not markedly affect the plasma proteome. Thus plasma proteomics using 2-DE appears, by and large, an unsuitable approach to detect regulation of plasma proteins due to changes in the diet.

A role for glutamate in subjective response to smoking and its action on inhibitory control.

RationaleOur previous study using memantine in smokers suggests that there may be a differential role for N-methyl-d-aspartate (NMDA) receptors in the subjective and cognitive effects of smoking.ObjectivesThis study was designed to investigate if d-cycloserine (DCS) would modulate the subjective and cognitive effects of limited smoking.MethodsForty-eight habitual smokers abstinent for a minimum of 2 h were randomly allocated to receive either placebo or 50 mg DCS (double-blind) and were subsequently required either to smoke half of one cigarette or to remain abstinent. Subjective and physiological effects of DCS were measured at baseline, 90 min postcapsule, and again after the partial-smoking manipulation, while the effects on sustained attention (rapid visual information processing test—RVIP) and cognitive flexibility (intra–extra dimensional set-shift test—IED) were evaluated only after the partial-smoking manipulation.ResultsDCS alone did not produce significant subjective effects other than an increase in ratings of “Stimulated”. In combination with partial smoking, however, DCS blocked the smoking-induced increase in “Stimulated” and the decrease in “Relaxed” ratings. Furthermore, in combination with smoking, DCS reduced the number of false alarms during the RVIP test (an index of inhibitory control) and produced a small increase in diastolic blood pressure. DCS failed to modulate IED performance.ConclusionsThese findings provide further evidence of a role for glutamate release in the subjective effects of smoking but not the effects on attention and cognitive flexibility. Furthermore, our results indicate that glutamate release may also be involved in the effect of smoking on inhibitory control.

Subjective Relaxing Effect of a Hospital's Rooftop Forest on Elderly Patients Requiring Care -Using a Simplified Emotional Score-

To clarify the relaxing effects of a 5-min stay in a hospital's rooftop forest on elderly patients requiring care. This was a within-subject, cross-sectional study. The participants were 30 elderly female patients requiring help in walking, aged 81.2±6.4 (mean±SD). A simplified emotional 7-point rating scale from -3 to 3 for 5 pairs of emotions, which was derived from the two-question Whooley Depression Screen, was used as a subjective indicator. The experimental areas were the rooftop forest that covered an area of 122 m(2) on the rooftop of a four-story health service facility and an outdoor car park area (as the control area). The participants were instructed to sit still in a wheelchair and view the scenery for 5 min in each experimental area and were then assessed. Data from the participants during exposure to the rooftop forest were compared with those during exposure to the control area. First, 15 participants moved to the rooftop forest from the preroom, and the other 15 moved to the outdoor car park area, and then they moved to the other site to eliminate any order effect. In the rooftop forest, the mean scores of the simplified emotional rating were 1.70 (1.17 for control) for "hopeful", 1.70 (1.17) for "interest in doing things", 1.53 (1.10) for "enjoyment", 1.67 (1.17) for "calm", and 2.03 (1.30) for "secure". The scores were all significantly higher than those in the control (p<0.01). It was demonstrated that a visit to the rooftop forest induced a significant subjective relaxing effect in elderly female patients requiring care.

Pharmacokinetics and bioequivalence evaluation of two losartan potassium 50-mg tablets: A single-dose, randomized-sequence, open-label, two-way crossover study in healthy Chinese male volunteers

Background: Losartan is a nonpeptide angiotensin II receptor antagonist used as an antihypertensive agent. The relative bioavailability of a newly developed tablet compared with an established branded formulation has not been reported in a Chinese population. Objective: To meet the requirements for marketing a new generic product, the study was designed to compare the pharmacokinetic parameters and relative bioavailability of a new generic losartan potassium 50-mg tablet (test formulation) with a branded 50-mg tablet (reference formulation) in healthy Chinese male volunteers. Methods: A single-dose, randomized-sequence, openlabel, 2-way crossover study was conducted in healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive a single 50-mg tablet of the test or reference formulation, followed by a 1-week washout period and then administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 36 hours. Tolerability was evaluated by recording adverse events (AEs) and monitoring vital signs, ECGs, and laboratory tests at baseline and at completion of the study. Plasma concentrations of losartan and its active metabolite (EXP3174) were analyzed by LC-MS/MS. Pharmacokinetic parameters, including C max, AUC 0–36, and AUC 0−∞, were calculated. If the 90% CIs for the log-transformed values of AUC were within 80% to 125%, and that of C max was within 70% to 143%, the 2 products would be considered bioequivalent according to the guidelines of the US Food and Drug Administration and the State Food and Drug Administration of China. Results: Twenty–seven healthy Chinese male volunteers participated in this study (mean [SD] age, 24.5 [2.3] years [range, 20–29 years]; weight, 64.6 [4.0] kg [range, 60.0-75.0 kg]; height, 172.2 [4.8] cm [range, 165.0183.0 cm]; and body mass index, 21.8 [1.2] kg/m 2 [range, 20.0–25.0 kg/m 2]). One volunteer (3.7%) experienced an AE (microscopic hematuria) after administration of the test formulation. This resolved spontaneously after 10 days and was considered by the investigator as mild; the relationship with the study drug was uncertain. No serious AEs were reported. Both formulations were associated with significant reductions in systolic and diastolic blood pressure and significant increases in heart rate compared with baseline values (all, P < 0.05). No period, formulation, or sequence effects were observed for any pharmacokinetic parameter, except for a significant subject effect. For parent losartan, the 90% CIs for the ratios (test/reference) of C max, AUC 0–36, and AUCAUC 0−∞ were 83.65% to 113.36%, 89.79% to 98.25%, and 90.95% to 99.55%, respectively. For the metabolite EXP3174, the 90% CIs for the ratios of C max, AUC 0–36, and AUCAUC 0−∞ were 93.49% to 103.61%, 96.79% to 104.09%, and 97.06% to 105.83%. Both C max and AUC met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation to the reference formulation was 93.92% for losartan and 100.40% for EXP3174. Conclusions: In this small study in healthy Chinese male volunteers, a single 50-mg oral dose of a losartan potassium tablet (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated.

Influence of footwear and soil density on loading within the shoe and soil surface during running

Using pressure transducers in soil surfaces prepared in controlled conditions, the vertical stress was recorded at 100 mm, 200 mm, and 350 mm depth within two soil surfaces of 1460 kg/m3 and 1590 kg/m3 for five subjects of 747–843 N body weight running at 4 m/s (5 per cent). Simultaneous in-shoe pressure data were collected to investigate the influence of soil density on loading experienced by the player and to provide information on the load applied to the surface. For each soil density, the subjects wore three different footwear types: soccer boots with traditional studs, boots with moulded studs, and boots designed for synthetic turf. For the mean of all subjects, there was no significant difference in the maximum vertical soil stress or loading rate between surfaces at any depth but within each surface there was a significant reduction of 32 kPa between –100 mm and the other depths. The peak loading rate was two orders of magnitude greater at –100 mm than at –200 mm or –350 mm. The variation in maximum vertical stress at –100 mm for different subjects was significant ( p&lt;0.001) and increased with increasing subject weight ( R2 = 0.87); at –200 mm and –350 mm there was no significant subject or density effect; a similar pattern was observed with the peak loading rate, with a linear relationship between the loading rate and the subject weight. In-shoe pressure data revealed no significant differences in the peak force or loading rate between surfaces, but a significantly lower heel pressure for the soft (1460 kg/m3) surface compared with the hard (1590 kg/m3) surface ( p&lt;0.05). Wearing of different footwear had no influence on the peak force or pressure but revealed a lower rate of loading of force for the moulded boot than for the studded boot when performing on the hard surface. There was a low and non-significant relationship between the peak input force and the peak force experienced within the surface ( R2 = 0.01; p &gt; 0.05), however, peak resultant pressure data were used successfully to model the vertical stress distribution during running using a linear elastic model of soil behaviour. This novel approach to understanding the behaviour of the soil surface and the player has revealed a complex relationship between the input load and the load experienced by the surface. Future models will seek to understand this relationship further.

The Analgesic Effects of Opioids and Immersive Virtual Reality Distraction: Evidence from Subjective and Functional Brain Imaging Assessments

Immersive virtual reality (VR) is a novel form of distraction analgesia, yet its effects on pain-related brain activity when used adjunctively with opioid analgesics are unknown. We used subjective pain ratings and functional magnetic resonance imaging to measure pain and pain-related brain activity in subjects receiving opioid and/or VR distraction. Healthy subjects (n = 9) received thermal pain stimulation and were exposed to four intervention conditions in a within-subjects design: (a) control (no analgesia), (b) opioid administration [hydromorphone (4 ng/mL target plasma level)], (c) immersive VR distraction, and (d) combined opioid + VR. Outcomes included subjective pain reports (0-10 labeled graphic rating scales) and blood oxygen level-dependent assessments of brain activity in five specific, pain-related regions of interest. Opioid alone significantly reduced subjective pain unpleasantness ratings (P < 0.05) and significantly reduced pain-related brain activity in the insula (P < 0.05) and thalamus (P < 0.05). VR alone significantly reduced both worst pain (P < 0.01) and pain unpleasantness (P < 0.01) and significantly reduced pain-related brain activity in the insula (P < 0.05), thalamus (P < 0.05), and SS2 (P < 0.05). Combined opioid + VR reduced pain reports more effectively than did opioid alone on all subjective pain measures (P < 0.01). Patterns of pain-related blood oxygen level-dependent activity were consistent with subjective analgesic reports. These subjective pain reports and objective functional magnetic resonance imaging results demonstrate converging evidence for the analgesic efficacy of opioid administration alone and VR distraction alone. Furthermore, patterns of pain-related brain activity support the significant subjective analgesic effects of VR distraction when used as an adjunct to opioid analgesia. These results provide preliminary data to support the clinical use of multimodal (e.g., combined pharmacologic and nonpharmacologic) analgesic techniques.

Comparison of speech production in upright and supine position

Speech is usually produced in an upright sitting or standing posture. Measurements and judgments of speech may be made in conditions requiring a supine position, however. These conditions include MRI recordings, and oral procedures, such as, adjustments to dental appliances, medical and surgical procedures. It is of interest, therefore, to see whether gravity has strong or systematic effects on tongue behavior. In the present study, 13 subjects repeated several words, which contained extreme consonant and vowel tongue positions, during upright and supine condition. Ultrasound imaging provided midsagittal tongue contours, in each condition, for comparison. A neck brace was used to stabilize transducer placement and the palate was used as a physiological reference to register the data sets. Results showed a significant subject effect. In supine position the tongue was more posterior than upright for seven subjects, more anterior for two subjects and varied by phoneme for four subjects. However, there was no significant phoneme effect. The direction of change and the amount of change were not directly related. Most subjects had small upright-supine differences. The largest differences, less than 3 mm on average, were in the posterior tongue.