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Sample records for age-matched healthy volunteers

  1. Cardiovascular function is better in veteran football players than age-matched untrained elderly healthy men.

    PubMed

    Schmidt, J F; Andersen, T R; Andersen, L J; Randers, M B; Hornstrup, T; Hansen, P R; Bangsbo, J; Krustrup, P

    2015-02-01

    The aim of the study was to determine whether lifelong football training may improve cardiovascular function, physical fitness, and body composition. Our subjects were 17 male veteran football players (VPG; 68.1 ± 2.1 years) and 26 healthy age-matched untrained men who served as a control group (CG; 68.2 ± 3.2 years). Examinations included measurements of cardiac function, microvascular endothelial function [reactive hyperemic index (RHI)], maximum oxygen uptake (VO2max), and body composition. In VPG, left ventricular (LV) end-diastolic volume was 20% larger (P < 0.01) and LV ejection fraction was higher (P < 0.001). Tissue Doppler imaging revealed an augmented LV longitudinal displacement, i.e., LV shortening of 21% (P < 0.001) and longitudinal 2D strain was 12% higher (P < 0.05), in VPG. In VPG, resting heart rate was lower (6 bpm, P < 0.05), and VO2max was higher (18%, P < 0.05). In addition, RHI was 21% higher (P < 0.05) in VPG. VPG also had lower body mass index (P < 0.05), body fat percentage, total body fat mass, android fat percentage, and gynoid fat percentage (all P < 0.01). Lifelong participation in football training is associated with better LV systolic function, physical fitness, microvascular function, and a healthier body composition. Overall, VPG have better cardiovascular function compared with CG, which may reduce their cardiovascular morbidity and mortality.

  2. Healthy Volunteer 2020: Comparing Peace Corps Volunteers' health metrics with Healthy People 2020 national objectives.

    PubMed

    Henderson, Susan J; Newman, Jeannette; Ferguson, Rennie W; Jung, Paul

    2016-12-01

    Healthy People 2020 (HP2020) provides a set of quantifiable objectives for improving the health and well-being of Americans. This study examines Peace Corps Volunteers' health metrics in comparison with the Leading Health Indicators (LHIs) in order to set baseline measures for Volunteers' health care and align our measurements with Healthy People 2020 standards. Health data from multiple internal Peace Corps datasets were compared with relevant LHIs and analyzed using descriptive statistics. Seventeen (65%) of the 26 LHIs were relevant to Peace Corps Volunteers. Of these, Volunteers' health measures met or were more favorable than the goals of 13 (76%) of the LHIs. There were no data available for 4 (24%) of the LHIs. The entire Volunteer population has full access to primary care, oral health, and reproductive health services. No suicides or homicides were reported among Volunteers during the analyzed time period. Utilizing the LHIs, we have identified high-priority public health issues relevant for the Peace Corps Volunteer population. We discuss the need for quality data to measure and monitor Volunteers' health progress and outcomes over time, and also to standardize our measurements with Healthy People 2020 benchmarks. This framework may foster greater collaboration to engage in health promotion and disease prevention activities driven by evidence-based information, which may, in turn, encourage healthy behavior among Volunteers.

  3. Impact of Limiting Visual Input on Gait: Individuals with Parkinson Disease, Age-matched Controls and Healthy Young Participants

    PubMed Central

    Pilgram, Laura M.; Earhart, Gammon M.; Pickett, Kristen A.

    2016-01-01

    Normal and limited vision gait was investigated in individuals with Parkinson disease (PD), healthy older and healthy young individuals. Participants walked a GAITRite mat with normal vision or vision of lower limbs occluded. Results indicate individuals with PD walked more slowly, with shorter and wider steps and spent more time in double support with limited vision as compared to full vision. Healthy young and old individuals took shorter steps but were otherwise unchanged between conditions. PMID:26987577

  4. The Long-Term Effect of Radical Prostatectomy on Erectile Function, Urinary Continence, and Lower Urinary Tract Symptoms: A Comparison to Age-Matched Healthy Controls

    PubMed Central

    Ponholzer, Anton; Augustin, Herbert; Madersbacher, Stephan; Pummer, Karl

    2017-01-01

    Introduction. To analyze the impact of radical prostatectomy (RPE) on erectile function and lower urinary tract function in comparison to age-matched healthy men. Materials and Methods. Patients who underwent radical retropubic prostatectomy completed questionnaires containing the IIEF-5, the Bristol female LUTS questionnaire, and the International Prostate Symptom Score (IPSS). Results. Patients after RPE were included (n = 363). Age-matched healthy men (n = 363) were included. The mean IIEF-5 of patients aged 61–70 yrs after RPE was 10.4 ± 6.6 versus 18.8 ± 5.3 in the control cohort; the respective values for men aged 71–80 yrs after RPE were 7.2 ± 6.5 versus 13.6 ± 7.7 in the control cohort. Urinary incontinence after RPE was reported in 41.9% (61–70 years) and 37.7% (71–80) versus 7.5% and 15.1% in the control cohort. The mean IPSS of patients after RPE aged 61–70 yrs was 5.0 ± 4.4 versus 5.5 ± 4.9 in the control cohort; the respective values for men aged 71–80 yrs were 6.0 ± 4.9 versus 7.5 ± 5.7 in the healthy cohort. Conclusions. The negative effect of radical prostatectomy on erectile and urinary incontinence remains substantial. The physiologically declining erectile and lower urinary tract function with ageing reduces the difference between healthy men and those after surgery. Healthy men have a higher IPSS presumably due to the presence of bladder outlet obstruction. PMID:28261619

  5. Hypoconnectivity of Resting-State Networks in Persons with Aphasia Compared with Healthy Age-Matched Adults

    PubMed Central

    Sandberg, Chaleece W.

    2017-01-01

    Aphasia is a language disorder affecting more than one million people in the US. While language function has traditionally been the focus of neuroimaging research, other cognitive functions are affected in this population, which has implications not only for those specific processes but also for the interaction of language and other cognitive functions. Resting state fMRI (rs-fMRI) is a practical and informative way to explore and characterize general cognitive engagement and/or health in this population, but it is currently underutilized. The aim of this study was to explore the functional connectivity in resting state networks (RSNs) and in the semantic network in seven persons with aphasia (PWA) who were at least 6 months post onset compared with 11 neurologically healthy adults (NHA) in order to gain a more comprehensive understanding of general cognitive engagement in aphasia. These preliminary results show that PWA exhibit hypoconnectivity in the semantic network and all RSNs except the visual network. Compared with NHA, PWA appear to have fewer cross- and left-hemispheric connections. However, PWA exhibit some stronger connections than NHA within the semantic network, which could indicate compensatory mechanisms. Importantly, connectivity for RSNs appear to increase with decreasing aphasia severity and decrease with increasing lesion size. This knowledge has the potential to improve aphasia therapy by furthering the understanding of lesion effects on the cognitive system as a whole, which can guide treatment target selection and promotion of favorable neural reorganization for optimal recovery of function. PMID:28293185

  6. Pharmacogenetics of healthy volunteers in Puerto Rico

    PubMed Central

    Claudio-Campos, Karla; Orengo-Mercado, Carmelo; Renta, Jessicca Y.; Peguero, Muriel; García, Ricardo; Hernández, Gabriel; Corey, Susan; Cadilla, Carmen L.; Duconge, Jorge

    2016-01-01

    Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer’s disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island. PMID:26501165

  7. Prediction of Psilocybin Response in Healthy Volunteers

    PubMed Central

    Studerus, Erich; Gamma, Alex; Kometer, Michael; Vollenweider, Franz X.

    2012-01-01

    Responses to hallucinogenic drugs, such as psilocybin, are believed to be critically dependent on the user's personality, current mood state, drug pre-experiences, expectancies, and social and environmental variables. However, little is known about the order of importance of these variables and their effect sizes in comparison to drug dose. Hence, this study investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin. The analysis was based on the pooled data of 23 controlled experimental studies involving 409 psilocybin administrations to 261 healthy volunteers. Multiple linear mixed effects models were fitted for each of 15 response variables. Although drug dose was clearly the most important predictor for all measured response variables, several non-pharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of Absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychological problems in past weeks were most strongly associated with pleasant and mystical-type experiences, whereas high Emotional Excitability, low age, and an experimental setting involving positron emission tomography most strongly predicted unpleasant and/or anxious reactions to psilocybin. The results confirm that non-pharmacological variables play an important role in the effects of psilocybin. PMID:22363492

  8. Prediction of psilocybin response in healthy volunteers.

    PubMed

    Studerus, Erich; Gamma, Alex; Kometer, Michael; Vollenweider, Franz X

    2012-01-01

    Responses to hallucinogenic drugs, such as psilocybin, are believed to be critically dependent on the user's personality, current mood state, drug pre-experiences, expectancies, and social and environmental variables. However, little is known about the order of importance of these variables and their effect sizes in comparison to drug dose. Hence, this study investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin. The analysis was based on the pooled data of 23 controlled experimental studies involving 409 psilocybin administrations to 261 healthy volunteers. Multiple linear mixed effects models were fitted for each of 15 response variables. Although drug dose was clearly the most important predictor for all measured response variables, several non-pharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of Absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychological problems in past weeks were most strongly associated with pleasant and mystical-type experiences, whereas high Emotional Excitability, low age, and an experimental setting involving positron emission tomography most strongly predicted unpleasant and/or anxious reactions to psilocybin. The results confirm that non-pharmacological variables play an important role in the effects of psilocybin.

  9. Antithrombin III: biodistribution in healthy volunteers.

    PubMed

    Knot, E A; de Jong, E; ten Cate, J W; Gie, L K; van Royen, E A

    1987-12-18

    Five healthy volunteers were injected intravenously with 73-90 uCi purified human 131I-Antithrombin III (AT III), specific biological activity 5.6 U/mg. The tracer data were analysed using a three compartment model. The plasma radioactivity half life was 66.2 +/- 1.2 (sem) h, the fractional catabolic rate constant of the plasma pool was 0.025 +/- 0.002 (sem) h-1. These data were comparable with those described in the literature. Because of the difficulty in translating the mathematical analysis of various compartments into the biological model, biodistribution was monitored by a gamma camera linked to a DEC PDP 11/34 computer system. Dynamic and static images were obtained at fixed time intervals following the injection of 131I-AT III. Whole body scanning at intervals between the time of injection (t = 0) and t = 24.5 h showed 131I-AT III distribution over the heart, lungs, liver, spleen and great vessels. Dynamic scanning was performed over the heart, spleen and liver. Overlayed frames in the first ten minutes after the 131I-AT III injection showed the following radioactivity expressed as percentage of the injected dose; 5.9% +/- 0.3 (sem) over the heart, 10.6% +/- 0.9 (sem) over the liver and 1.1% +/- 0.1 (sem) over the spleen. A slower decline of the radioactivity between t = 0 and t = 24 h; (19%) was measured over the liver compared with the radioactivity disappearance over the heart region. This shows, in combination with the fact that the radioactivity disappearance over the heart was identical with the radioactivity decline measured in the plasma samples that retention of 131I-AT III occurred in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients.

    PubMed

    Cutler, N R

    2001-01-01

    In clinical trials of dopamine-blocking antipsychotics, significant adverse events may occur in healthy volunteers at dose levels that are well tolerated by schizophrenic patients. Because of these differences in tolerability, bioequivalence and pharmacokinetic studies of antipsychotics should be performed in schizophrenic patients rather than in healthy volunteers. When clozapine is the drug being investigated, pharmacokinetic and bioequivalence studies should be carried out in real-life dosage conditions because the half-life of clozapine increases with multiple doses. Under real-life conditions, the evaluation of multiple doses of clozapine in a population of schizophrenic patients can provide direct therapeutic relevance to bioavailability findings. This article discusses patient recruitment and informed consent in pharmacokinetic trials of schizophrenia, issues in studying antipsychotic agents in healthy volunteers versus schizophrenic patients, and a bioequivalency study of Clozaril (Novartis Pharmaceuticals) and generic clozapine (Creighton [Sandoz]) in schizophrenic patients.

  11. Measurement of eosinophil kinetics in healthy volunteers.

    PubMed

    Farahi, Neda; Loutsios, Chrystalla; Simmonds, Rosalind P; Porter, Linsey; Gillett, Daniel; Heard, Sarah; Peters, A Michael; Condliffe, Alison M; Chilvers, Edwin R

    2014-01-01

    Radiolabelled leukocyte scans are widely used in nuclear medicine to locate sites of infection and inflammation. Radiolabelling of leukocyte subpopulations can also yield valuable information on cell trafficking and kinetics in vivo, but care must be taken to minimize inadvertent cell activation ex vivo. Here, we describe the use of autologous indium(111)-labelled eosinophils to measure eosinophil intravascular life-span and monitor their distribution and fate using gamma camera imaging in healthy non-atopic individuals.

  12. Limits on risks for healthy volunteers in biomedical research.

    PubMed

    Resnik, David B

    2012-04-01

    Healthy volunteers in biomedical research often face significant risks in studies that offer them no medical benefits. The U.S. federal research regulations and laws adopted by other countries place no limits on the risks that these participants face. In this essay, I argue that there should be some limits on the risks for biomedical research involving healthy volunteers. Limits on risk are necessary to protect human participants, institutions, and the scientific community from harm. With the exception of self-experimentation, limits on research risks faced by healthy volunteers constitute a type of soft, impure paternalism because participants usually do not fully understand the risks they are taking. I consider some approaches to limiting research risks and propose that healthy volunteers in biomedical research should not be exposed to greater than a 1% chance of serious harm, such as death, permanent disability, or severe illness or injury. While this guideline would restrict research risks, the limits would not be so low that they would prevent investigators from conducting valuable research. They would, however, set a clear upper boundary for investigators and signal to the scientific community and the public that there are limits on the risks that healthy participants may face in research. This standard provides guidance for decisions made by oversight bodies, but it is not an absolute rule. Investigators can enroll healthy volunteers in studies involving a greater than 1% chance of serious harm if they show that the research addresses a compelling public health or social problem and that the risk of serious harm is only slightly more than 1%. The committee reviewing the research should use outside experts to assess these risks.

  13. Self-selection for personality variables among healthy volunteers.

    PubMed

    Pieters, M S; Jennekens-Schinkel, A; Schoemaker, H C; Cohen, A F

    1992-01-01

    1. Healthy student volunteers (n = 103) participating in ongoing clinical pharmacological research completed the Dutch Personality Inventory (DPI), the Dutch version of the Spielberger State-Trait Anxiety Inventory (STAI-DY) and the Dutch version of the Sensation Seeking Scale (SSS). 2. The volunteers were more extrovert (P less than 0.001), more flexible (P less than 0.001), more tolerant or less impulsive (P less than 0.001), had more self-confidence and initiative (P less than 0.001), and were more satisfied and optimistic (P less than 0.01) when compared with the general norm. When compared with a student norm, volunteers had lower levels of state (P less than 0.001) and trait (P less than 0.05) anxiety. The general sensation seeking tendency of volunteers was higher than in the student norm group (P less than 0.001). The volunteers had a greater tendency to thrill-and-adventure-seeking (P less than 0.001) and to disinhibition (P less than 0.01). 3. Hence, volunteers were a selected sample of the total population of students. This may influence the interpretation of pharmacokinetic and pharmacodynamic parameters. 4. Personality screening should be added to the screening procedures for volunteers.

  14. Psychopharmacology of theobromine in healthy volunteers

    PubMed Central

    Baggott, Matthew J.; Childs, Emma; Hart, Amy B.; de Bruin, Eveline; Palmer, Abraham A.; Wilkinson, Joy E.; de Wit, Harriet

    2013-01-01

    Background Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, currently evidence for this is limited. Objectives We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants. Results Caffeine had the expected effects on mood including feelings of alertness, and cardiovascular parameters. Theobromine responses differed according to dose: it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses we also examined individual differences in the drugs' effects in relation to genes related to their target receptors, but few associations were detected. Conclusions This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes effects become negative. PMID:23420115

  15. Platelet proteome in healthy volunteers who smoke.

    PubMed

    Della Corte, Anna; Tamburrelli, Chiara; Crescente, Marilena; Giordano, Lucia; D'Imperio, Marco; Di Michele, Michela; Donati, Maria Benedetta; De Gaetano, Giovanni; Rotilio, Domenico; Cerletti, Chiara

    2012-01-01

    Smoking accelerates atherosclerosis and is a well-known risk factor for acute cardiovascular complications; however, the mechanisms of these effects have not been completely clarified. Recently developed proteomic approaches may offer new clues when combined with well-established functional tests. Platelet proteome of healthy smokers and non-smokers was resolved by two-dimensional difference gel electrophoresis, compared by Decyder software and identified by mass spectrometry analysis (nano-LC-MS/MS). In smokers, three proteins (Factor XIII-A subunit, platelet glycoprotein IIb and beta-actin) were significantly up-regulated, whereas WDR1 protein and chaperonine HSP60 were down-regulated. Furthermore, the highest scored network derived by Ingenuity Pathway Analysis using the modulated proteins as input showed the involvement of several proteins to be related to inflammation and apoptosis. Platelet function tests and the levels of markers of platelet and leukocyte activation were not different in smokers vs. non-smoker subjects. The platelet proteomic approach confirms that cigarette smoking triggers several inflammatory reactions and may help clarify some of the molecular mechanisms of smoke effect on cellular systems relevant for vascular integrity and human health.

  16. Pharmacokinetic Interaction Study of Ranitidine and Daijokito in Healthy Volunteers

    PubMed Central

    Endo, Yusuke; Ishihara, Yoshitaka; Tsuno, Satoshi; Matsuda, Akiko; Qian, Weibin; Miura, Norimasa; Hasegawa, Junichi

    2016-01-01

    Background Ranitidine is a histamine 2 receptor antagonist, and daijokito is a Kampo (Chinese herbal medicine as practiced in Japan) formula, which is traditionally used for treating constipation and digestive trouble. Previous study demonstrated that daijokito significantly affected the pharmacokinetics of ranitidine in rats; however, the doses of ranitidine and daijokito in that study were higher than in clinical practice. Therefore, we examined the pharmacokinetic interaction between ranitidine and daijokito in clinical practice doses in healthy volunteers. Methods This was a randomized, open label, two-period crossover study in healthy volunteers (n = 7). Volunteers received administrations of either a single dose of ranitidine 300 mg, or ranitidine 300 mg in combination with daijokito extract granules 2.5 g. Plasma concentrations of ranitidine were measured over 12 h by LC/MS/MS method. Results Plasma concentrations of ranitidine were lower with co-administration of daijokito compared with ranitidine alone. Co-administration of daijokito significantly decreased ranitidine area under the plasma concentration-time curve from 0 to 12 h (AUC0–12) and maximum plasma concentration (Cmax) with geometric mean (GM) ratio [90% confidence interval (CI)] for AUC0–12 of 0.609 (0.449, 0.826) and Cmax of 0.515 (0.345, 0.771). Conclusion Co-administration of ranitidine with daijokito resulted in a significant decrease in plasma level of ranitidine in healthy volunteers. PMID:27493481

  17. Cryptosporidium muris: Infectivity and Illness in Healthy Adult Volunteers

    PubMed Central

    Chappell, Cynthia L.; Okhuysen, Pablo C.; Langer-Curry, Rebecca C.; Lupo, Philip J.; Widmer, Giovanni; Tzipori, Saul

    2015-01-01

    Although Cryptosporidium parvum and C. hominis cause the majority of human cryptosporidiosis cases, other Cryptosporidium species are also capable of infecting humans, particularly when individuals are immunocompromised. Ten C. muris cases have been reported, primarily in human immunodeficiency virus (HIV) -positive patients with diarrhea. However, asymptomatic cases were reported in two HIV-negative children, and in another case, age and immune status were not described. This study examines the infectivity of C. muris in six healthy adults. Volunteers were challenged with 105 C. muris oocysts and monitored for 6 weeks for infection and/or illness. All six patients became infected. Two patients experienced a self-limited diarrheal illness. Total oocysts shed during the study ranged from 6.7 × 106 to 4.1 × 108, and the number was slightly higher in volunteers with diarrhea (2.8 × 108) than asymptomatic shedders (4.4 × 107). C. muris-infected subjects shed oocysts longer than occurred with other species studied in healthy volunteers. Three volunteers shed oocysts for 7 months. Physical examinations were normal, with no reported recurrence of diarrhea or other gastrointestinal complaints. Two persistent shedders were treated with nitazoxanide, and the infection was resolved. Thus, healthy adults are susceptible to C. muris, which can cause mild diarrhea and result in persistent, asymptomatic infection. PMID:25311695

  18. Normal range values for thromboelastography in healthy adult volunteers.

    PubMed

    Scarpelini, S; Rhind, S G; Nascimento, B; Tien, H; Shek, P N; Peng, H T; Huang, H; Pinto, R; Speers, V; Reis, M; Rizoli, S B

    2009-12-01

    Thromboelastography (TEG) provides a functional evaluation of coagulation. It has characteristics of an ideal coagulation test for trauma, but is not frequently used, partially due to lack of both standardized techniques and normal values. We determined normal values for our population, compared them to those of the manufacturer and evaluated the effect of gender, age, blood type, and ethnicity. The technique was standardized using citrated blood, kaolin and was performed on a Haemoscope 5000 device. Volunteers were interviewed and excluded if pregnant, on anticoagulants or having a bleeding disorder. The TEG parameters analyzed were R, K, alpha, MA, LY30, and coagulation index. All volunteers outside the manufacturer's normal range underwent extensive coagulation investigations. Reference ranges for 95% for 118 healthy volunteers were R: 3.8-9.8 min, K: 0.7-3.4 min, alpha: 47.8-77.7 degrees, MA: 49.7-72.7 mm, LY30: -2.3-5.77%, coagulation index: -5.1-3.6. Most values were significantly different from those of the manufacturer, which would have diagnosed coagulopathy in 10 volunteers, for whom additional investigation revealed no disease (81% specificity). Healthy women were significantly more hypercoagulable than men. Aging was not associated with hypercoagulability and East Asian ethnicity was not with hypocoagulability. In our population, the manufacturer's normal values for citrated blood-kaolin had a specificity of 81% and would incorrectly identify 8.5% of the healthy volunteers as coagulopathic. This study supports the manufacturer's recommendation that each institution should determine its own normal values before adopting TEG, a procedure which may be impractical. Consideration should be given to a multi-institutional study to establish wide standard values for TEG.

  19. Sodium Thiosulfate Pharmacokinetics in Hemodialysis Patients and Healthy Volunteers

    PubMed Central

    Stauffer, Emilie; Kalicki, Robert; Hildebrandt, Tatjana; Frey, Brigitte M.; Frey, Felix J.; Uehlinger, Dominik E.; Pasch, Andreas

    2011-01-01

    Summary Background and objectives Vascular calcification is a major cause of morbidity and mortality in dialysis patients. Human and animal studies indicate that sodium thiosulfate (STS) may prevent the progression of vascular calcifications. The pharmacokinetics of STS in hemodialysis patients has not been investigated yet. Design, setting, participants, & measurements STS was given intravenously to 10 hemodialysis patients on- and off-hemodialysis. Additionally, STS was applied to 9 healthy volunteers once intravenously and once orally. Thiosulfate concentrations were measured by using a specific and sensitive HPLC method. Results In volunteers and patients, mean endogenous thiosulfate baseline concentrations were 5.5 ± 1.82 versus 7.1 ± 2.7 μmol/L. Renal clearance was high in volunteers (1.86 ± 0.45 ml/min per kg) and reflected GFR. Nonrenal clearance was slightly, but not significantly, higher in volunteers (2.25 ± 0.32 ml/min per kg) than in anuric patients (2.04 ± 0.72 ml/min per kg). Hemodialysis clearance of STS was 2.62 ± 1.01 ml/min per kg. On the basis of the nonrenal clearance and the thiosulfate steady-state serum concentrations, a mean endogenous thiosulfate generation rate of 14.6 nmol/min per kg was calculated in patients. After oral application, only 4% of STS was recovered in urine of volunteers, reflecting a low bioavailability of 7.6% (0.8% to 26%). Conclusions Given the low and variable bioavailability of oral STS, only intravenous STS should be prescribed today. The biologic relevance of the high hemodialysis clearance for the optimal time point of STS dosing awaits clarification of the mechanisms of action of STS. PMID:21566113

  20. Diurnal variation in the quantitative EEG in healthy adult volunteers

    PubMed Central

    Cummings, L; Dane, A; Rhodes, J; Lynch, P; Hughes, A M

    2000-01-01

    Aims To define the change in power in standard waveband frequencies of quantitative cortical electroencephalogram (EEG) data over a 24 h period, in a drug free representative healthy volunteer population. Methods This was an open, non randomised study in which 18 volunteers (9 male and 9 female) were studied on 1 study day, over a 24 h period. Volunteers had a cortical EEG recording taken at 0, 2, 4, 6, 8, 10, 12, 16 and 24 h. Each recording lasted for 6 min (3 min eyes open, 3 min eyes closed). All EEG recordings were taken in a quietened ward environment with the curtains drawn round the bed and the volunteer supine. During the 3 min eyes open, volunteers were asked to look at a red circle on a screen at the foot of the bed, and refrain from talking. Results Plots produced of geometric mean power by time of the standard wave band frequencies gave some indication of a circadian rhythm over the 24 h period for θ (4.75–6.75 Hz), α1 (7.0–9.5 Hz) and β1 (12.75–18.50 Hz) wavebands. Mixed models were fitted to both the eyes open and eyes closed data which confirmed a change in mean waveband power with time with statistical significance at the conventional 5% level (P < 0.05). Conclusions These data indicate the presence of a diurnal variation in the cortical quantitative EEG. They support the use of a placebo control group when designing clinical trials which utilize quantitative EEG to screen for central nervous system (CNS) activity of pharmaceutical agents, to control for the confounding variable of time of day at which the EEG recordings were made. PMID:10886113

  1. Population pharmacokinetic analysis of axitinib in healthy volunteers

    PubMed Central

    Garrett, May; Poland, Bill; Brennan, Meghan; Hee, Brian; Pithavala, Yazdi K; Amantea, Michael A

    2014-01-01

    AIMS Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers. METHODS Plasma concentration–time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (nonmem) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19). RESULTS A two compartment structural model with first order absorption and lag time best described axitinib pharmacokinetics. Population estimates for systemic clearance (CL), central volume of distribution (Vc), absorption rate constant (ka) and absolute bioavailability (F) were 17.0 l h−1, 45.3 l, 0.523 h−1 and 46.5%, respectively. With axitinib Form IV, ka and F increased in the fasted state by 207% and 33.8%, respectively. For Form XLI (marketed formulation), F was 15% lower compared with Form IV. CL was not significantly influenced by any of the covariates studied. Body weight significantly affected Vc, but the effect was within the estimated interindividual variability for Vc. CONCLUSIONS The analysis established a model that adequately characterizes axitinib pharmacokinetics in healthy volunteers. Vc was found to increase with body weight. However, no change in plasma exposures is expected with change in body weight; hence no dose adjustment is warranted. PMID:23834452

  2. Bioequivalence Study of Atorvastatin Tablets in Healthy Pakistani Volunteers.

    PubMed

    Mohammad, Sohail; Arshad, Usman; Abbass, Nasir; Parvez, Irfan; Abbas, Ghulam; Mahmood, Wajahat

    2015-01-01

    A two way, randomized cross-over bioequivalence study was conducted to analyse the rate and extent of absorption of atorvastatin after a single dose of 80 mg atorvastatin as atorvastatin calcium tablets. The study was carried out using healthy male volunteers (N = 24). A high performance liquid chromatography method was employed to determine the level of drug in human plasma. It was concluded that the test and the reference drug exhibited comparable values of pharmacokinetic parameters. It was also concluded that since there was no significant difference between the rate and extent of absorption of the drug from the test and the reference formulations: these two formulations could thus be declared bioequivalent.

  3. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers.

    PubMed

    Modaghegh, Mohammad-Hadi; Shahabian, Masoud; Esmaeili, Habib-Allah; Rajbai, Omid; Hosseinzadeh, Hossein

    2008-12-01

    Saffron (Crocus sativus) stigma tablets were evaluated for short-term safety and tolerability in healthy adult volunteers. The study was a double-blind, placebo-controlled design consisting of a 1 week treatment of saffron tablets. Volunteers were divided into 3 groups of 10 each (5 males and 5 females). Group I received placebo; groups 2 and 3 received 200 and 400mg saffron tablets, respectively, for 7 days. General measures of health were recorded during the study such as hematological, biochemical and electrocardiographic parameters done in pre- and post-treatment periods. Clinical examination showed no gross changes in all volunteers after intervention. Saffron with higher dose (400mg) decreased standing systolic blood pressure and mean arterial pressures significantly. Saffron decreased slightly some hematological parameters such as red blood cells, hemoglobin, hematocrit and platelets. Saffron increased sodium, blood urea nitrogen and creatinine. This study showed that saffron tablets may change some hematological and biochemical parameters. However, these alterations were in normal ranges and they were not important clinically.

  4. Bioavailability of ranitidine in healthy Mexican volunteers: effect of food.

    PubMed

    Juárez-Olguín, H; Flores, J; Pérez, G; Hernández, G; Flores, C; Guillé, A; Camacho, A; Toledo, A; Carrasco, M; Lares, I

    2002-01-01

    Is well known that food can affect the bioavailability of several drugs, its impact is major for those drugs that have to act near of drug absorption. Documentation about alterations of ranitidine bioavailability by effect of food is poor. The purpose of this work was to evaluate the effect of food over the bioavailability of ranitidine. Twenty healthy Mexican volunteers were included for the study. The study was made in two stages, in the first one the volunteers had 12 hour fast and took a 300 mg of oral dose of ranitidine (without food, WOF) and blood samples were drawn. Two weeks later, the volunteers took a normal diet just before ranitidine intake (with food, WF). The area under the curve (AUC) was 30% greater in WOF, Cmax was 921.5 ng/ml (WF) vs. 1685.2 (WOF), and t1/2 was 2.70 +/- 1.38 (WF) h vs 3.66 +/- 1.34 (WOF). The AUC, Cmax and t1/2 were statistically different. It is evident that there are differences in the drug disposition due to the presence of food, then, it is possible that the efficacy of ranitidine as inhibitor of gastric secretion being limited by food.

  5. Single dose pharmacokinetics and tolerance of pancopride in healthy volunteers.

    PubMed

    Dewland, P; Pérez Campos, A; Martinez-Tobed, A

    1995-02-01

    Pancopride (LAS 30451, CAS 121650-80-4) is a new selective 5-hydroxytryptamine3 receptor antagonist which has demonstrated antiemetic properties in animal models. The tolerance and pharmacokinetics of pancopride and its effect on the 5-hydroxytryptamine flare test were examined in healthy male volunteers, in three single-dose studies. The studies consisted of two rising dose tolerance and kinetic studies with placebo control, each involving 14 volunteers, and an absolute bioavailability study involving 12 volunteers. The doses used in the rising dose studies were 0.5-20 mg intravenous pancopride in the first study, and 5-40 mg pancopride as oral solution in the second study. For the absolute bioavailability study, 20 mg doses as intravenous infusion, oral tablet and oral solution were compared. Pancopride was well tolerated at these doses in these studies. There were no significant effects on pulse rate, blood pressure, or electrocardiograms, or on haematology or serum biochemistry. Few adverse events were recorded, the most significant being gastrointestinal effects (including diarrhoea and soft stools) seen particularly with the 40 mg oral dose. Pharmacokinetic parameters for the 24 h after dosing were derived from plasma and urine pancopride levels, determined using a capillary gas chromatography-mass spectrometry method. Linear kinetics appeared to apply over the intravenous dose range 5-20 mg. Urinary recovery of unchanged pancopride was in the order of 10-17% over the 24 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Pharmacokinetics of ambroxol and clenbuterol tablets in healthy Chinese volunteers

    PubMed Central

    Yang, Yong-Ge; Song, Li-Xue; Jiang, Nan; Xu, Xue-Ting; Di, Xiao-Hui; Zhang, Mei

    2015-01-01

    Objective: To investigate the pharmacokinetics of Ambroxol and Clenbuterol Tablets in Chinese healthy volunteers after a single or multiple dosages oral administration. Methods: A total of 9 healthy adult subjects were given Ambroxol and Clenbuterol Tablets in a single dosage or multiple dosages respectively. LC/MS/MS were used for the determination of Ambroxol and Clenbuterol of in plasma. The important pharmacokinetic parameters were calculated by DAS 2.0 software (compartment model). Results: Single and multiple dosage groups of Ambroxol and Clenbuterol were all fitted two-compartment model. The pharmacokinetics fitted first order kinetics process. No difference in pharmacokinetics of Ambroxol in single and multiple dosage groups volunteers was observed, Which showed no marked changes, suggesting that multiple dosing did not influence the velocity of drug metabolism. Moreover, parameters of Clenbuterol had significant difference between the single and multiple dosage groups (P<0.05), showing there was accumulation in the body. 9 subjects had completed single or multiple dosages oral administration test, with no adverse drug reactions appeared during the test. Conclusion: There was no obvious accumulation of Ambroxol after repeated dosing. But obvious accumulation of Clenbuterol was noted in multiple-dose administration. The established method is sensitive, accurate, reliable and specific, and it can meet the requirement of clinical pharmacokinetic trial. PMID:26770490

  7. Tympanic displacement analysis in healthy volunteers after indomethacin administration.

    PubMed

    Walsted, Alice; Wagner, Niels; Andersen, Kim Møller

    2002-12-01

    The aim of this study was to investigate whether a tympanic displacement analyser could detect decreases in cerebral blood flow and intracranial pressure after administration of indomethacin in healthy volunteers. In a double-blind crossover study involving 14 healthy volunteers all subjects first underwent a test-retest evaluation to investigate reproducibility followed by tests performed in sitting and supine positions to confirm intracranial-cochlear pressure transfer. In two further sessions tests were performed before and 90 min after subjects were blindly administered a suppository containing either 100 mg of indomethacin or placebo. It was found that tympanic membrane analysis performed 90 min after administration of such a suppository did not mirror the induced reduction in cerebral blood flow after administration of active drug. After administration of indomethacin eight of the subjects experienced discomfort and dizziness; after placebo none experienced subjective symptoms. After administration of indomethacin a statistically significant decrease in heart rate was demonstrated. The exponential form of the intracranial pressure-volume curve may explain why a decrease in intracranial pressure was not detected using the tympanic membrane displacement method, because the measurements were made in subjects with normal intracranial pressure. More significant findings may be found in patients with elevated intracranial pressure.

  8. Neurobehavioral and Cognitive Changes Induced by Hypoxia in Healthy Volunteers.

    PubMed

    Lanteaume, Laura; Cassé-Perrot, Catherine; Lefebvre, Marie-Noëlle; Audebert, Christine; Deguil, Julie; Auffret, Alexandra; Otten, Lisa; Bartrés-Faz, David; Blin, Olivier; Bordet, Régis; Micallef, Joëlle

    2016-01-01

    The early assessment of new symptomatic drugs against Alzheimer's disease remains difficult because of the lack of a predictive end-point. The use of a battery including different parameters could improve this early development. In order to test the reverse effect of symptomatic drugs in healthy volunteers, scientists have developed new experimental paradigms to artificially induce transient cognitive impairments in healthy volunteers akin to those observed in Alzheimer's disease, i.e. Cognitive Challenge Models. In this context, transient hypoxia could be a relevant Cognitive Challenge Model. The deleterious effects of hypoxia on cognition, as described in the literature, should be considered carefully since they are usually assessed with different populations that do not have the same hypoxic sensitivity. Hypoxia can be obtained by the means of two different methods: normobaric and hypobaric hypoxia. In both designs, cognitive changes can be directly modulated by the severity of hypoxic levels. The purpose of this review is to gather existing support on the application of hypoxia within different cognitive domains and to highlight the scientific interests of such a model to predict and select promising drug candidates. We aimed at reviewing in detail the methods, designs and cognitive paradigms used in non-pharmacological hypoxia studies. Probing the four main cognitive functions will allow identifying the extent to which different hypoxia designs selectively compromise cognitive functioning. For each cognitive process, the convergent and divergent results are discussed in terms of paradigm differences whereas we will focus on defining the optimal methodology for obtaining the desired effects.

  9. Comparative bioequivalence study of leflunomide tablets in Indian healthy volunteers.

    PubMed

    Agarwal, S; Das, A; Ghosh, D; Sarkar, A K; Chattaraj, T K; Pal, T K

    2012-03-01

    The pharmacokinetics of teriflunomide [CAS No. 163451-81-8], the metabolite of leflunomide [CAS No. 75706-12-6] has been evaluated in adult human volunteers after oral administration of tablet formulation. However, no published data is available regarding the bioavailability of this in the Indian population. In light of the above, a study was designed to carry out a bioequivalence study of 2 preparations of leflunomide 20 mg in healthy Indian male volunteers.24 healthy male volunteers (age, 25±4.1 years; weight, 57.58±7.01 kg) were enrolled in this study. Each subject received a test and reference formulation in a single dose, fasting 2 period, 2 way crossover study with a wash out period of 4 weeks. Analysis of teriflunomide from plasma samples was done by a simple and sensitive HPLC method using UV detection developed in our laboratory. An analysis of variance was performed on the pharmacokinetic parameters Cmax, AUC0-t, AUC0-∞ using GLM procedures in which sources of variation were subject, formulation, and period.The results indicated that there are no statistically significant differences between the 2 products in either the mean concentration-time profiles or in the obtained pharmacokinetic parameters. 90% confidence limits for the log transformed data of Cmax, AUC0-t, AUC0-∞. were within the acceptable range of 0.80-1.25.The results indicate that the 2 products are bioequivalent in terms of rate and extent of drug absorption. Both the preparations were well tolerated with no adverse reactions throughout the study.

  10. MDMA Impairs Response to Water Intake in Healthy Volunteers.

    PubMed

    Baggott, Matthew J; Garrison, Kathleen J; Coyle, Jeremy R; Galloway, Gantt P; Barnes, Allan J; Huestis, Marilyn A; Mendelson, John E

    2016-01-01

    Hyponatremia is a serious complication of 3,4-methylenedioxymethamphetamine (MDMA) use. We investigated potential mechanisms in two double-blind, placebo-controlled studies. In Study 1, healthy drug-experienced volunteers received MDMA or placebo alone and in combination with the alpha-1 adrenergic inverse agonist prazosin, used as a positive control to release antidiuretic hormone (ADH). In Study 2, volunteers received MDMA or placebo followed by standardized water intake. MDMA lowered serum sodium but did not increase ADH or copeptin, although the control prazosin did increase ADH. Water loading reduced serum sodium more after MDMA than after placebo. There was a trend for women to have lower baseline serum sodium than men, but there were no significant interactions with drug condition. Combining studies, MDMA potentiated the ability of water to lower serum sodium. Thus, hyponatremia appears to be a significant risk when hypotonic fluids are consumed during MDMA use. Clinical trials and events where MDMA use is common should anticipate and mitigate this risk.

  11. Comparative bioavailability of two different diclofenac formulations in healthy volunteers.

    PubMed

    Silva, L C; Simões, I G; Lerner, F E; Belém, G R; de Moraes, M E; De Nucci, G

    1999-11-01

    The aim of the study was to assess the bioequivalence of two different diclofenac (CAS 15307-86-5) formulations (diclofenac free acid suspension as test formulation and diclofenac resinate suspension, Cataflam, as reference formulation) in 24 healthy volunteers. After an overnight fast, the volunteers received a single oral dose (50 mg) of each formulation, following an open, randomized, two-period crossover design, with a fourteen-day washout interval between doses. Serum samples were obtained over a 24-h interval post-dosing, and were analysed for their diclofenac content by HPLC-UV. No adverse effect was reported for any of the formulations administered. Geometric mean test/reference individual ratios were: 92.8% for AUC(0-24 h), 93.2% for AUC(0-infinity), 117.2% for Cmax, 131.0% for Ke and 76.2% for T1/2. The variability of Cmax parameter expressed as CV was greater than 25%. Since the 90% CI for AUC(0-24 h) mean ratio were within the 80-125% interval proposed by the Food and Drug Administration, it can be concluded that diclofenac free acid formulation is bioequivalent to diclofenac resinate formulation for the extent of absorption. Since the European Community Agency accepts a 90% CI for Cmax of 70-143%, it can be concluded that diclofenac free acid formulation is bioequivalent to diclofenac resinate formulation for both the rate and the extent of absorption after single dose administration.

  12. MDMA Impairs Response to Water Intake in Healthy Volunteers

    PubMed Central

    Garrison, Kathleen J.; Coyle, Jeremy R.; Galloway, Gantt P.; Huestis, Marilyn A.; Mendelson, John E.

    2016-01-01

    Hyponatremia is a serious complication of 3,4-methylenedioxymethamphetamine (MDMA) use. We investigated potential mechanisms in two double-blind, placebo-controlled studies. In Study 1, healthy drug-experienced volunteers received MDMA or placebo alone and in combination with the alpha-1 adrenergic inverse agonist prazosin, used as a positive control to release antidiuretic hormone (ADH). In Study 2, volunteers received MDMA or placebo followed by standardized water intake. MDMA lowered serum sodium but did not increase ADH or copeptin, although the control prazosin did increase ADH. Water loading reduced serum sodium more after MDMA than after placebo. There was a trend for women to have lower baseline serum sodium than men, but there were no significant interactions with drug condition. Combining studies, MDMA potentiated the ability of water to lower serum sodium. Thus, hyponatremia appears to be a significant risk when hypotonic fluids are consumed during MDMA use. Clinical trials and events where MDMA use is common should anticipate and mitigate this risk. PMID:27403159

  13. Multiple-dose pharmacokinetics of ceftibuten in healthy volunteers.

    PubMed Central

    Lin, C; Radwanski, E; Affrime, M; Cayen, M N

    1995-01-01

    The pharmacokinetics of ceftibuten, a new cephalosporin antibiotic, and its conversion product, ceftibutentrans, were studied in healthy male volunteers following daily oral administration of a 400-mg capsule for 7 days. Mean concentrations of ceftibuten in plasma obtained on day 5 were similar to those obtained on day 7. Analysis of variance indicated that the concentrations in plasma on days 5 and 7 were at steady state. The mean accumulation factor was 1.14 for day 5 and 1.13 for day 7. The half-life (2.4 h) was independent of the duration of drug administration, and the mean maximum concentration of drug in plasma was 18 to 19 micrograms/ml. Urinary excretion was the major elimination route for ceftibuten, by which 57 to 59% of the drug was excreted unchanged over a 24-h period. The amounts of ceftibuten-trans in plasma and urine were low. PMID:7726497

  14. Comparison of aspirin and indobufen in healthy volunteers.

    PubMed

    Lee, Jong-Young; Sung, Ki-Chul; Choi, Hyo-In

    2016-01-01

    The aim of this study is to quantify the extent and recovery of platelet inhibition after administration of indobufen and aspirin in healthy volunteers. Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme, thereby suppressing thromboxane synthesis. Twenty healthy volunteers completed the study and received aspirin (200 mg/day for 2 weeks) followed by a 4-week washout period and then indobufen (200 mg twice a day for 2 weeks). The percent (%) inhibition of platelet aggregation (IPA) was assessed using arachidonic acid (0.5 mg/ml) and adenosine diphosphate (5 µM) at 4, 12, 24 and 48 hours after last dose of each drug. IPA assessed using arachidonic acid as the agonist was similar at 4 hours after the last dose of indobufen (81.07 ± 9.36%) and aspirin (96.99 ± 0.29%, p = 0.10), but significantly lower at 12 hours (74.04 ± 9.55% vs. 97.94 ± 0.28%, p = 0.02), 24 hours (33.39 ± 11.13% vs. 97.48 ± 0.32%, p < 0.001) and 48 hours (14.12 ± 9.74% vs. 98.22 ± 0.31%, p < 0.001) after indobufen, compared to the relative values for aspirin. IPA assessed using adenosine diphosphate as the agonist was similar in the two groups at 4, 12 and 24 hours after the last dose, but significantly lower 48 hours after the last dose of indobufen, compared to the relative value for aspirin (1.98 ± 3.57% vs. 12.61 ± 2.71%, p = 0.002). Indobufen (200 mg twice a day) caused equivalent initial inhibition of platelet aggregation to aspirin (200 mg daily), and the anti-aggregation effect diminished faster than after aspirin.

  15. Healthy Volunteers Can Be Phenotyped Using Cutaneous Sensitization Pain Models

    PubMed Central

    Rowbotham, Michael C.; Dahl, Jørgen B.

    2013-01-01

    Background Human experimental pain models leading to development of secondary hyperalgesia are used to estimate efficacy of analgesics and antihyperalgesics. The ability to develop an area of secondary hyperalgesia varies substantially between subjects, but little is known about the agreement following repeated measurements. The aim of this study was to determine if the areas of secondary hyperalgesia were consistently robust to be useful for phenotyping subjects, based on their pattern of sensitization by the heat pain models. Methods We performed post-hoc analyses of 10 completed healthy volunteer studies (n = 342 [409 repeated measurements]). Three different models were used to induce secondary hyperalgesia to monofilament stimulation: the heat/capsaicin sensitization (H/C), the brief thermal sensitization (BTS), and the burn injury (BI) models. Three studies included both the H/C and BTS models. Results Within-subject compared to between-subject variability was low, and there was substantial strength of agreement between repeated induction-sessions in most studies. The intraclass correlation coefficient (ICC) improved little with repeated testing beyond two sessions. There was good agreement in categorizing subjects into ‘small area’ (1st quartile [<25%]) and ‘large area’ (4th quartile [>75%]) responders: 56–76% of subjects consistently fell into same ‘small-area’ or ‘large-area’ category on two consecutive study days. There was moderate to substantial agreement between the areas of secondary hyperalgesia induced on the same day using the H/C (forearm) and BTS (thigh) models. Conclusion Secondary hyperalgesia induced by experimental heat pain models seem a consistent measure of sensitization in pharmacodynamic and physiological research. The analysis indicates that healthy volunteers can be phenotyped based on their pattern of sensitization by the heat [and heat plus capsaicin] pain models. PMID:23671631

  16. Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics

    PubMed Central

    Li, Junfeng; Zhang, Zhaoyun; Liu, Xiaoxia; Wang, Yi; Mao, Fei; Mao, Junjun; Lu, Xiaolan; Jiang, Dongdong; Wan, Yun; Lv, Jia-Ying; Cao, Guoying; Zhang, Jing; Zhao, Naiqing; Atkinson, Mark; Greiner, Dale L.; Prud'homme, Gerald J.; Jiao, Zheng; Li, Yiming; Wang, Qinghua

    2015-01-01

    Preclinical studies show that GABA exerts anti-diabetic effects in rodent models of type 1 diabetes. Because little is known about its absorption and effects in humans, we investigated the pharmacokinetics and pharmacodynamics of GABA in healthy volunteers. Twelve subjects were subjected to an open-labeled, three-period trial involving sequential oral administration of placebo, 2 g GABA once, and 2 g GABA three times/day for 7 days, with a 7-day washout between each period. GABA was rapidly absorbed (Tmax: 0.5 ~ 1 h) with the half-life (t1/2) of 5 h. No accumulation was observed after repeated oral GABA administration for 7 days. Remarkably, GABA significantly increased circulating insulin levels in the subjects under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01). GABA also increased glucagon levels only under fasting conditions (1.3-fold, single dose, p < 0.05; 1.5-fold, repeated dose, p < 0.01). However, there were no significant differences in the insulin-to-glucagon ratio and no significant change in glucose levels in these healthy subjects during the study period. Importantly, GABA significantly decreased glycated albumin levels in the repeated dosing period. Subjects with repeated dosing showed an elevated incidence of minor adverse events in comparison to placebo or the single dosing period, most notably transient discomforts such as dizziness and sore throat. However, there were no serious adverse events observed throughout the study. Our data show that GABA is rapidly absorbed and tolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal secretion, suggest potential therapeutic benefits for diabetes. PMID:26617516

  17. Tryptophan supplementation and the response to unfairness in healthy volunteers

    PubMed Central

    Cerit, Hilâl; Schuur, Rachel J.; de Bruijn, Ellen R. A.; Van der Does, Willem

    2015-01-01

    Experimental manipulation of serotonin (5-HT) availability has been shown to modulate social behavior. For instance, serotonin depletion increased the rejection rates of unfair offers in the ultimatum game (UG), whereas a single dose of the serotonin reuptake inhibitor (citalopram) decreased rejection rates. These effects were observed immediately after the manipulation. The aim of this study was to investigate the effect of prolonged tryptophan (TRP) supplementation on UG performance in healthy individuals. A randomized double-blind placebo (PLC)-controlled design was used. Healthy volunteers (N = 47) completed the UG before and after a 6-day intervention of TRP (2.8 g/day) or PLC. Impulsivity was measured with a Go-Stop task. The overall analyses showed that TRP supplementation had no significant effect on UG scores, but the direction of the effect was opposite from expectations. Because repeated performance of the UG may lead to unwanted learning effects or strategical changes, additional analyses were conducted in which participants (N = 7) who accepted all offers on the second measurement were excluded. These analyses revealed that the TRP-group rejected very unfair offers more often than the PLC group. The groups did not differ on impulsivity. Increasing serotonin through TRP supplements increased the rejection of very unfair offers. The direction of our findings is inconsistent with earlier studies that showed that increasing 5-HT availability results in less rejection of unfair offers. The current findings thus importantly suggest that effects of acute vs. prolonged enhancement of 5-HT availability may differ. Also, the outcomes show that the UG is a complex task and participants’ decisions may depend on context, e.g., prior experience with the task. PMID:26236273

  18. Interaction between the LMWH reviparin and aspirin in healthy volunteers

    PubMed Central

    Klinkhardt, Ute; Breddin, Hans Klaus; Esslinger, Heinz Ulrich; Haas, Silvia; Kalatzis, Andreas; Harder, Sebastian

    2000-01-01

    Aims To investigate potential interactions between reviparin and acetylsalicylic acid (ASA 300 mg o.d. from day 1–5). Methods In an open, randomized, three-way-cross over study nine healthy volunteers received reviparin (s.c. injection of 6300 anti-Xa units) or placebo from days 3 to 5 and acetylsalicylic acid (ASA 300 mg) or placebo from days 1 to 5. Assessments included bleeding time (BT), collagen (1 µg ml−1) induced platelet aggregation (CAG), heptest, plasma antifactor Xa-activity and activated partial thromboplastin time (aPTT). Results Median bleeding time at day 5 was 5.5 min after reverparin alone and after ASA alone and was 9.6 min after the combination of reviparin and ASA. ASA treatment reduced CAG from 84% to 40 to 50% of Amax; values after combined treatment of reviparin with ASA were not different from those after ASA alone. aPTT was prolonged to 32 s after reviparin; this effect was not modified if subjects received ASA. Combined treatment with ASA and reviparin had no effect on plasma anti-Xa-activity and heptest compared with reviparin alone. Conclusions We could not entirely exclude a small interaction between reviparin and ASA on bleeding time, but the effect is probably without clinical significance. PMID:10759689

  19. Antitussive effects of nasal thymol challenges in healthy volunteers.

    PubMed

    Gavliakova, S; Biringerova, Z; Buday, T; Brozmanova, M; Calkovsky, V; Poliacek, I; Plevkova, J

    2013-06-01

    Eighteen healthy volunteers with normal lung function were tested for cough. Before and after nasal administration of thymol (0.025 ml, 10(-3) M) into both nostrils, urge-to-cough, cough threshold, cumulative and total count of coughs per provocation were estimated during standardized and validated capsaicin cough challenge. Nasal thymol challenges induced pleasant olfactory sensation and in 6 out of the 18 subjects also mild cooling sensation. Cough threshold was not influenced when compared with intranasal saline and vehicle challenges (12.5 vs. 13.2 vs. 10.2 μM of capsaicin to induce two or more coughs (C2), respectively), but the total count of coughs after nasal thymol challenge was significantly lower than that obtained after saline or vehicle (19 vs. 20 vs. 14 coughs/provocation, respectively; p<0.05). Importantly, subjects did not report the urge to cough, which appeared to correspond to C2. We conclude that the modulation of cough by thymol is mostly of olfactory origin.

  20. Cardiovascular responses to metipranolol and timolol eyedrops in healthy volunteers.

    PubMed Central

    Bacon, P J; Brazier, D J; Smith, R; Smith, S E

    1989-01-01

    1. Intraocular pressure and cardiovascular responses to metipranolol 0.1% and 0.3% and timolol 0.25% eyedrops were measured in a balanced single dose placebo-controlled crossover study in eight healthy volunteers aged 34-58 years. 2. Timolol 0.25% and metipranolol 0.3% reduced intraocular pressure throughout the 6 h period of observation to a similar extent. Metipranolol 0.1% was marginally less effective, significantly reducing pressure up to 4 h only. 3. No drug treatment significantly altered resting heart rate or blood pressure. Timolol 0.25% significantly reduced exercise tachycardia (P less than 0.05), an effect which was not shown by metipranolol 0.1 or 0.3%. Exertional pain in the legs occurred more frequently after timolol 0.25% and metipranolol 0.3% than after metipranolol 0.1% or placebo eyedrops. 4. Octan-1-ol/pH 7.4 buffer distribution coefficients at 37 degrees C were found to be: metipranolol 5.19, timolol 0.84, indicating that metipranolol has an approximately 6-fold greater lipid solubility. 5. It is concluded that, by comparison with timolol, metipranolol in eyedrop concentrations up to 0.3%, despite its greater lipid solubility, reaches concentrations in the systemic circulation which are less likely to affect the heart. PMID:2565117

  1. Interaction between erythromycin and nitrazepam in healthy volunteers.

    PubMed

    Luurila, H; Olkkola, K T; Neuvonen, P J

    1995-04-01

    Interaction between erythromycin, a strong inhibitor of CYP3A4, and nitrazepam, a long-acting benzodiazepine, was investigated in a double-blind and randomized cross-over study of two phases. Ten healthy volunteers received erythromycin (500 mg x 3) orally or placebo for 6 days. On the fourth day they were given a challenge dose of 5 mg nitrazepam. Plasma samples were collected and psychomotor effects were measured during 42 hr after intake of nitrazepam. There was a statistically significant pharmacokinetic interaction between erythromycin and nitrazepam. Erythromycin increased the area under the nitrazepam concentration-time curve by 25% (P < 0.05) and the peak concentration by 30% (P < 0.05). The concentration peak time of nitrazepam was shortened by over 50% (P < 0.05). The elimination half-lives did not change. Accordingly, as far as the metabolism of nitrazepam is concerned, erythromycin does not cause any major changes in the metabolism of nitrazepam. In psychomotor performance only minor differences were seen. It is concluded that the interaction between erythromycin and nitrazepam is of little clinical significance.

  2. Bioequivalence Study of Donepezil Hydrochloride Tablets in Healthy Male Volunteers

    PubMed Central

    Rojanasthien, Noppamas; Aunmuang, Siriluk; Hanprasertpong, Nutthiya; Roongapinun, Sukit; Teekachunhatean, Supanimit

    2012-01-01

    The objective of this study was to investigate the bioequivalence of two formulations of 5 mg donepezil HCL tablets: Tonizep as the test and Aricept as the reference. The two products were administered as a single oral dose according to a randomized two-phase crossover with a 3-week washout period in 20 healthy Thai Male volunteers. After drug administration, serial blood samples were collected over a period of 216 hours. Plasma donepezil concentrations were measured by high performance liquid chromatography with UV detection. Pharmacokinetic parameters were analyzed based on noncompartmental analysis. The logarithmically transformed data of AUC0–∞ and Cmax were analyzed for 90% confidence intervals (CI) using ANOVA. The mean (90% CI) values for the ratio of AUC0–∞ and Cmax values of the test product over those of the reference product were 1.08 (1.02–1.14) and 1.08 (0.99–1.17), respectively (within the bioequivalence range of 0.8–1.25). The median Tmax for the test product was similar to that of the reference product (2.0 hr), and the 90% CI for the Tmax difference between the two preparations was –0.19 to 0.29 hr and within the bioequivalence range of ± 20% of the Tmax of the reference formulation. Our study demonstrated the bioequivalence of the two preparations. PMID:23209934

  3. Pharmacokinetics/pharmacodynamics of desloratadine and fluoxetine in healthy volunteers.

    PubMed

    Gupta, Samir; Banfield, Christopher; Kantesaria, Bhavna; Flannery, Brian; Herron, Jerry

    2004-11-01

    The authors assessed the potential for a pharmacokinetic/pharmacodynamic interaction between desloratadine and fluoxetine. This randomized, placebo-controlled, open-label study was conducted in 54 healthy volunteers. Subjects received 1 of 3 treatments: desloratadine 5 mg plus fluoxetine 20 mg, desloratadine 5 mg plus placebo, or fluoxetine 20 mg plus placebo. Serial electrocardiograms (ECGs) were performed at baseline and day 35. Treatment effects on C(max) and AUC were assessed. During coadministration of desloratadine with fluoxetine, the ratio of the mean log-transformed C(max) and AUC values for desloratadine following concomitant fluoxetine therapy revealed a small increase in C(max) values of 15% (90% confidence interval [CI], 95%-139%) but no increase for AUC values (90% CI, 82%-123%). Corresponding values for 3-OH desloratadine demonstrated small increases in mean log-transformed C(max) and AUC ratios: 17% (90% CI, 100%-136%) and 13% (90% CI, 96%-132%), respectively. Statistical evaluation of the ratio of the mean C(max) and AUC values for fluoxetine following concomitant desloratadine therapy revealed small decreases of 9% (90% CI, 72%-115%) and 11% (90% CI, 69%-113%), respectively. Corresponding values for norfluoxetine demonstrated modest increases in mean log-transformed C(max) and AUC ratios: 22% (90% CI, 100%-139%) and 18% (90% CI, 101%-136%), respectively. Coadministration of desloratadine with a potent inhibitor of CYP2D6 did not result in clinically relevant changes in its pharmacokinetic parameters. Desloratadine administration was not associated with clinically important changes in the pharmacokinetics of fluoxetine, a drug metabolized by CYP2D6. The most common adverse event in all groups was headache (65%). Desloratadine plus fluoxetine caused no significant changes in ECGs or ventricular rate.

  4. Moderate red wine consumption improves hemorheological parameters in healthy volunteers.

    PubMed

    Toth, A; Sandor, B; Papp, J; Rabai, M; Botor, D; Horvath, Zs; Kenyeres, P; Juricskay, I; Toth, K; Czopf, L

    2014-01-01

    Pieces of epidemiological evidence have supported that moderate red wine consumption reduces the risk of cardiovascular diseases (French-paradox). Our previous in vitro experiment has demonstrated favourable hemorheological effects of red wine, alcohol-free red wine extract and ethanol. Thirty-nine healthy, non-smoking male volunteers between 18-40 years were assigned into two groups: control group had drunk water, while red wine group had consumed 2 dl of red wine each day at dinner for 3 weeks. No alcohol had been drunk for one week prior to the study. Blood was obtained in the morning of the first and last day. Hematocrit (Hct), plasma (PV) and whole blood viscosity (WBV) (Hevimet 40 capillary viscometer), red blood cell (RBC) aggregation (Myrenne and LORCA aggregometer) and deformability (LORCA ektacytometer) were measured and Hct/WBV ratio was calculated to determine oxygen carrying capacity. Hct was adjusted to 40%. Hct and PV were not affected. WBV remained unchanged in controls, but it considerably decreased in the red wine group compared to the 3-week control group, while Hct/WBV ratio became significantly higher in the red wine group compared to the control (p < 0.05). RBC aggregation significantly decreased in the red wine group and became significantly lower compared to the 3-week controls (p < 0.05). Red wine significantly increased RBC deformability (p < 0.05) at high shear stress. Our results show that moderate red wine consumption has beneficial effects on hemorheological parameters which may contribute to the French-paradox.

  5. Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers

    PubMed Central

    Weiner, Marc; Egelund, Eric F.; Engle, Melissa; Kiser, Melissa; Prihoda, Thomas J.; Gelfond, Jonathan A. L.; Mac Kenzie, William; Peloquin, Charles A.

    2014-01-01

    Objectives Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated the effect of rifapentine on the pharmacokinetic properties of raltegravir. Methods In this open-label, fixed-sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1–4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12–15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4–8 and 11–14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11–14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718. Results In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0–12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0–12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated. Conclusions The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV. PMID:24343893

  6. In vivo interaction of ketoconazole and sucralfate in healthy volunteers.

    PubMed Central

    Carver, P L; Berardi, R R; Knapp, M J; Rider, J M; Kauffman, C A; Bradley, S F; Atassi, M

    1994-01-01

    Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 +/- 12.20 versus 59.32 +/- 13.61 micrograms.h/ml and 12.34 +/- 3.07 versus 8.92 +/- 2.57 micrograms/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h. PMID:7910724

  7. Characterization of Physiologic (18)F FSPG Uptake in Healthy Volunteers.

    PubMed

    Mosci, Camila; Kumar, Meena; Smolarz, Kamilla; Koglin, Norman; Stephens, Andrew W; Schwaiger, Markus; Gambhir, Sanjiv S; Mittra, Erik S

    2016-06-01

    Purpose To evaluate the normal biodistribution and kinetics of (S)-4-(3-[18F]fluoropropyl)-l-glutamic acid ((18)F FSPG) in healthy volunteers and to compare (18)F FSPG mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) with those of (18)F fluorodeoxyglucose (FDG) across a variety of organs. Materials and Methods This protocol was reviewed and approved by all appropriate regulatory authorities. An 8-mCi (±10%) dose of (18)F FSPG was given to five subjects (three women, two men), and seven whole-body positron emission tomography (PET) scans were performed 5, 10, 20, 30, 45, 150, and 240 minutes after injection. Regions of interest were analyzed on the resultant (18)F FSPG images to evaluate the kinetics of this radiotracer. The images obtained 45 minutes after injection were used to measure SUVmean and SUVmax in additional regions of the body. These values were compared with similar values obtained with (18)F FDG PET published previously. Descriptive statistics, including average and standard deviation across the five subjects, were used. (18)F FSPG SUVmean and SUVmax were compared. Results On the (18)F FSPG images obtained 45 minutes after injection, there was only low-grade background activity in the majority of analyzed regions. Prominent activity was seen throughout the pancreas. Clearance of the radiotracer through the kidneys and collection in the bladder also were seen. SUV quantification shows notable differences between (18)F FSPG and (18)F FDG in the pancreas ((18)F FSPG SUVmean, 8.2; (18)F FDG SUVmean, 1.3), stomach ((18)F FSPG SUVmax, 3.6; (18)F FDG SUVmax, 1.6), and brain ((18)F FSPG SUVmean, 0.08; (18)F FDG SUVmean, 7.8). The kinetic data showed rapid clearance of the radiotracer from the blood pool and most organs, except the pancreas. Conclusion (18)F FSPG is a PET radiopharmaceutical characterized by rapid clearance from most healthy tissues, except the pancreas and kidneys. A consistent biodistribution pattern was

  8. Pharmacokinetics and safety of eszopiclone in healthy Chinese volunteers.

    PubMed

    Wu, F; Zhao, X L; Wei, M J; Wang, S M; Zhou, H; Guo, S J; Zhang, P

    2012-12-01

    The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers.In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6 mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3 mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24 h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings.The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6 mg; Cmax of 18.08±4.65, 38.29±15.41 and 76.38±23.34 ng/ml; Tmax of 0.94±0.39, 1.04±0.63 and 1.08±0.51 h; AUC0-24 of 110.90±23.06, 227.36±62.41 and 504.10±140.13 ng*h/ml; elimination half-lives of 5.84±1.03, 5.53±1.91 and 6.17±1.23 h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css_max at 33.43±5.63 ng/ml and AUCss (0-24) at 263.30±51.21 ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication.The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5-6 mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated.

  9. CONCENTRATED AMBIENT AIR PARTICLES INDUCE PULMONARY INFLAMMATION IN HEALTHY HUMAN VOLUNTEERS

    EPA Science Inventory


    We tested the hypothesis that exposure of healthy volunteers to concentrated ambient particles (CAPS) is associated with an influx of inflammatory cells into the lower respiratory tract. Thirty-eight volunteers were exposed to either filtered air or particles concentrated fro...

  10. Exposure to wood smoke particles produces an inflammation in healthy volunteers

    EPA Science Inventory

    Background. Human exposure to wood smoke particles (WSP) is of consequence in indoor air quality, exposures from wild fires, burning ofbiomass, and air pollution. This investigation tested the postulate that healthy volunteers exposed to WSP would demonstrate pulmonary and cardio...

  11. Giving monoclonal antibodies to healthy volunteers in phase 1 trials: is it safe?

    PubMed Central

    Tranter, Elizabeth; Peters, Gary; Boyce, Malcolm; Warrington, Steve

    2013-01-01

    Many monoclonal antibodies (MAbs) have been studied in healthy volunteers in phase 1, but few data have been published on the safety of that practice. We aimed to review the available data, and thereby to estimate the risks of participation in phase 1 trials of MAbs. We searched PubMed, the ClinicalTrials.gov database and Google, using the search terms ‘monoclonal antibody’, ‘phase 1’ and ‘healthy volunteers’. We identified 70 completed trials of MAbs in healthy volunteers, but the published data were too sparse to allow confident assessment of the risks of MAbs in healthy volunteers. Our best estimate of risk of a life-threatening adverse event was between 1 : 425 and 1 : 1700 volunteer-trials, but all such events occurred in a single trial (of TGN1412). In a phase 1 trial of a small molecule, the risk of death or a life-threatening adverse event appears to be 1 : 100 000–1 000 000 volunteer-trials, which is similar to the risk of many ordinary daily activities. Most people would consider that level of risk to be ‘minimal’ or ‘negligible’ and, therefore, acceptable. On that basis, the safety record of MAbs in healthy volunteers has been ruined by the TGN1412 disaster. However, that experience is unlikely to be repeated, because of improvements in governance and practice of phase 1 trials. If the experience of TGN1412 is disregarded, it seems reasonable to continue using healthy volunteers in phase 1 trials of MAbs, provided that there are scientific and medical reasons to conclude that the risk is truly minimal. PMID:23438102

  12. Diffusion tensor imaging reliably differentiates patients with schizophrenia from healthy volunteers.

    PubMed

    Ardekani, Babak A; Tabesh, Ali; Sevy, Serge; Robinson, Delbert G; Bilder, Robert M; Szeszko, Philip R

    2011-01-01

    The objective of this research was to determine whether fractional anisotropy (FA) and mean diffusivity (MD) maps derived from diffusion tensor imaging (DTI) of the brain are able to reliably differentiate patients with schizophrenia from healthy volunteers. DTI and high resolution structural magnetic resonance scans were acquired in 50 patients with schizophrenia and 50 age- and sex-matched healthy volunteers. FA and MD maps were estimated from the DTI data and spatially normalized to the Montreal Neurologic Institute standard stereotactic space. Individuals were divided randomly into two groups of 50, a training set, and a test set, each comprising 25 patients and 25 healthy volunteers. A pattern classifier was designed using Fisher's linear discriminant analysis (LDA) based on the training set of images to categorize individuals in the test set as either patients or healthy volunteers. Using the FA maps, the classifier correctly identified 94% of the cases in the test set (96% sensitivity and 92% specificity). The classifier achieved 98% accuracy (96% sensitivity and 100% specificity) when using the MD maps as inputs to distinguish schizophrenia patients from healthy volunteers in the test dataset. Utilizing FA and MD data in combination did not significantly alter the accuracy (96% sensitivity and specificity). Patterns of water self-diffusion in the brain as estimated by DTI can be used in conjunction with automated pattern recognition algorithms to reliably distinguish between patients with schizophrenia and normal control subjects.

  13. Diffusion Tensor Imaging Reliably Differentiates Patients With Schizophrenia from Healthy Volunteers

    PubMed Central

    Ardekani, Babak A.; Tabesh, Ali; Sevy, Serge; Robinson, Delbert G.; Bilder, Robert M.; Szeszko, Philip R.

    2010-01-01

    The objective of this research was to determine whether fractional anisotropy (FA) and mean diffusivity (MD) maps derived from diffusion tensor imaging (DTI) of the brain are able to reliably differentiate patients with schizophrenia from healthy volunteers. DTI and high resolution structural magnetic resonance scans were acquired in 50 patients with schizophrenia and 50 age- and sex-matched healthy volunteers. FA and MD maps were estimated from the DTI data and spatially normalized to the Montreal Neurologic Institute standard stereotactic space. Individuals were divided randomly into two groups of 50, a training set and a test set, each comprising 25 patients and 25 healthy volunteers. A pattern classifier was designed using Fisher’s linear discriminant analysis based on the training set of images to categorize individuals in the test set as either patients or healthy volunteers. Using the FA maps the classifier correctly identified 94% of the cases in the test set (96% sensitivity and 92% specificity). The classifier achieved 98% accuracy (96% sensitivity and 100% specificity) when using the MD maps as inputs to distinguish schizophrenia patients from healthy volunteers in the test dataset. Utilizing FA and MD data in combination did not significantly alter the accuracy (96% sensitivity and specificity). Patterns of water self-diffusion in the brain as estimated by DTI can be used in conjunction with automated pattern recognition algorithms to reliably distinguish between patients with schizophrenia and normal control subjects. PMID:20205252

  14. Accumulation of caffeine in healthy volunteers treated with furafylline.

    PubMed Central

    Tarrus, E; Cami, J; Roberts, D J; Spickett, R G; Celdran, E; Segura, J

    1987-01-01

    The pharmacokinetics and tolerance of repeated oral doses of furafylline were investigated in normal volunteers. In accord with predictions from single dose studies, steady state was achieved on the first day following the administration of 90 mg and maintained by subsequent daily doses of 30 mg. When corrected for body weight there were no significant differences in minimum and maximum plateau levels of furafylline between males (1.2-2.0 micrograms ml-1; mean body weight 67.2 kg) and females (1.6-2.6 micrograms ml-1; mean body weight 54.9 kg). The half-life of elimination was less when the plasma concentration was lower than 600 ng ml-1 than during the stationary phase of treatment. Despite constant plasma levels the repeated administration of furafylline appeared to be associated with the onset of adverse xanthine-like side effects, a finding which was subsequently traced to the presence of, and possible synergism with, accumulating serum levels of caffeine in those volunteers drinking caffeine containing beverages. Subsequent studies showed that a single dose (90 mg) of furafylline results in a rapid accumulation of caffeine given orally (100 mg twice daily) and that this is accompanied by an elimination half-life of some 50 h and an abrupt decrease in metabolite levels. The furafylline-induced accumulation of caffeine was not influenced by the smoking habits of the subjects, implying that the metabolite pathway blocked by furafylline is the demethylation of caffeine in position 3, an implication confirmed by the reduced formation of paraxanthine. This demonstration of an unacceptable level of adverse side effects resulting from a potent inhibiting effect of furafylline on the metabolism of a normal dietary constituent has obvious implications in the interpretation of drug-induced toxicity. PMID:3814465

  15. An integrated glucose-insulin model to describe oral glucose tolerance test data in healthy volunteers.

    PubMed

    Silber, Hanna E; Frey, Nicolas; Karlsson, Mats O

    2010-03-01

    The extension of the previously developed integrated models for glucose and insulin (IGI) to include the oral glucose tolerance test (OGTT) in healthy volunteers could be valuable to better understand the differences between healthy individuals and those with type 2 diabetes mellitus (T2DM). Data from an OGTT in 23 healthy volunteers were used. Analysis was based on the previously developed intravenous model with extensions for glucose absorption and incretin effect on insulin secretion. The need for additional structural components was evaluated. The model was evaluated by simulation and a bootstrap. Multiple glucose and insulin concentration peaks were observed in most individuals as well as hypoglycemic episodes in the second half of the experiment. The OGTT data were successfully described by the extended basic model. An additional control mechanism of insulin on glucose production improved the description of the data. The model showed good predictive properties, and parameters were estimated with good precision. In conclusion, a previously presented integrated model has been extended to describe glucose and insulin concentrations in healthy volunteers following an OGTT. The characterization of the differences between the healthy and diabetic stages in the IGI model could potentially be used to extrapolate drug effect from healthy volunteers to T2DM.

  16. [Profile of sex steroids in healthy volunteers' urine during experiment in isolated object].

    PubMed

    Larina, I M; Kochnova, E A; Pastushkova, L Kh; Rodchenkov, G M; Nosovskiĭ, A M; Nikolaev, E N

    2011-01-01

    The quantitative determination a number of endogenous steroids and their metabolites in urine of healthy volunteers by means of gas chromatography - mass spectrometry was performed. The dynamic of steroid profile of healthy individuals as well as possible ranges of several endogenous steroid parameters have been investigated. Samples were obtained during 105-days experiment with 6 volunteers in isolated on ground modules where were modeling the main life conditions which could influence the steroid profile: meal volume and composition, water consumption, motion activity, air composition and temperature, rate sleep - wakefulness and emotional tension. The parameters of urine steroid profile of healthy volunteer which were affected by life conditions in isolated object were revealed. The parameters of individual and group variability of steroid profile and its dependence from definite experiment conditions - change of salt consumption periods, autonomy of vital activity were detected.

  17. Experimental manipulations of pain catastrophizing influence pain levels in patients with chronic pain and healthy volunteers.

    PubMed

    Kjøgx, Heidi; Kasch, Helge; Zachariae, Robert; Svensson, Peter; Jensen, Troels S; Vase, Lene

    2016-06-01

    Pain catastrophizing (PC) has been related to pain levels in both patients experiencing acute or chronic pain and in healthy volunteers exposed to experimental pain. Still, it is unclear whether high levels of pain catastrophizing lead to high levels of pain or vice versa. We therefore tested whether levels of pain catastrophizing could be increased and decreased in the same participant through hypnotic suggestions and whether the altered level of situation-specific pain catastrophizing was related to increased and decreased pain levels, respectively. Using the spontaneous pain of 22 patients with chronic tension-type headache and experimentally induced pain in 22 healthy volunteers, participants were tested in 3 randomized sessions where they received 3 types of hypnotic suggestions: Negative (based on the 13 items in the Pain Catastrophizing Scale), Positive (coping-oriented reversion of the Pain Catastrophizing Scale), and Neutral (neutral sentence) hypnotic suggestions. The hypnotic suggestions significantly increased and decreased situation-specific PC in both patients and healthy volunteers (P < 0.001). Also, the levels of pain intensity and pain unpleasantness were significantly altered in both patients and healthy volunteers (P < 0.001). Furthermore, regression analyses showed that changes in pain catastrophizing predicted changes in pain in patients (R = 0.204-0.304; P < 0.045) and in healthy volunteers (R = 0.328-0.252; P < 0.018). This is the first study to successfully manipulate PC in positive and negative directions in both patients with chronic pain and healthy volunteers and to show that these manipulations significantly influence pain levels. These findings may have important theoretical and clinical implications.

  18. Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers.

    PubMed

    Hostler, David; Zhou, Jiangquan; Tortorici, Michael A; Bies, Robert R; Rittenberger, Jon C; Empey, Philip E; Kochanek, Patrick M; Callaway, Clifton W; Poloyac, Samuel M

    2010-05-01

    The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4 degrees C saline infusions and 4 degrees C saline + magnesium) and two normothermia groups (37 degrees C saline infusions and 37 degrees C saline + magnesium). The lowest temperatures achieved in the 4 degrees C saline + magnesium and 4 degrees C saline infusions were 35.4 +/- 0.4 and 35.8 +/- 0.3 degrees C, respectively. A significant decrease in the formation clearance of the major metabolite 1'-hydroxymidazolam was observed during the 4 degrees C saline + magnesium compared with that in the 37 degrees C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5 degrees C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted.

  19. Quantitative Analysis of Cerebrospinal Fluid Pressure Gradients in Healthy Volunteers and Patients with Normal Pressure Hydrocephalus

    PubMed Central

    HAYASHI, Naokazu; MATSUMAE, Mitsunori; YATSUSHIRO, Satoshi; HIRAYAMA, Akihiro; ABDULLAH, Afnizanfaizal; KURODA, Kagayaki

    2015-01-01

    Magnetic resonance imaging (MRI) can depict not only anatomical information, but also physiological factors such as velocity and pressure gradient. Measurement of these physiological factors is necessary to understand the cerebrospinal fluid (CSF) environment. In this study we quantified CSF motion in various parts of the CSF space, determined changes in the CSF environment with aging, and compared CSF pressure gradient between patients with idiopathic normal pressure hydrocephalus (iNPH) and healthy elderly volunteers. Fifty-seven healthy volunteers and six iNPH patients underwent four-dimensional (4D) phase-contrast (PC) MRI. CSF motion was observed and the pressure gradient of CSF was quantified in the CSF space. In healthy volunteers, inhomogeneous CSF motion was observed whereby the pressure gradient markedly increased in the center of the skull and gradually decreased in the periphery of the skull. For example, the pressure gradient at the ventral surface of the brainstem was 6.6 times greater than that at the convexity of the cerebrum. The pressure gradient was statistically unchanged with aging. The pressure gradient of patients with iNPH was 3.2 times greater than that of healthy volunteers. The quantitative analysis of 4D-PC MRI data revealed that the pressure gradient of CSF can be used to understand the CSF environment, which is not sufficiently given by subjective impression of the anatomical image. PMID:26226976

  20. Diesel Exhaust Modulates Ozone-induced Lung Function Decrements in Healthy Human Volunteers

    EPA Science Inventory

    The potential effects of combinations of dilute whole diesel exhaust (DE) and ozone (03), each a common component of ambient airborne pollutant mixtures, on lung function were examined. Healthy young human volunteers were exposed for 2 hr to pollutants while exercising (~50 L/min...

  1. Early effects of duloxetine on emotion recognition in healthy volunteers

    PubMed Central

    Bamford, Susan; Penton-Voak, Ian; Pinkney, Verity; Baldwin, David S; Munafò, Marcus R; Garner, Matthew

    2015-01-01

    The serotonin-noradrenaline reuptake inhibitor (SNRI) duloxetine is an effective treatment for major depression and generalised anxiety disorder. Neuropsychological models of antidepressant drug action suggest therapeutic effects might be mediated by the early correction of maladaptive biases in emotion processing, including the recognition of emotional expressions. Sub-chronic administration of duloxetine (for two weeks) produces adaptive changes in neural circuitry implicated in emotion processing; however, its effects on emotional expression recognition are unknown. Forty healthy participants were randomised to receive either 14 days of duloxetine (60 mg/day, titrated from 30 mg after three days) or matched placebo (with sham titration) in a double-blind, between-groups, repeated-measures design. On day 0 and day 14 participants completed a computerised emotional expression recognition task that measured sensitivity to the six primary emotions. Thirty-eight participants (19 per group) completed their course of tablets and were included in the analysis. Results provide evidence that duloxetine, compared to placebo, may reduce the accurate recognition of sadness. Drug effects were driven by changes in participants’ ability to correctly detect subtle expressions of sadness, with greater change observed in the placebo relative to the duloxetine group. These effects occurred in the absence of changes in mood. Our preliminary findings require replication, but complement recent evidence that sadness recognition is a therapeutic target in major depression, and a mechanism through which SNRIs could resolve negative biases in emotion processing to achieve therapeutic effects. PMID:25759400

  2. Enforced physical inactivity increases endothelial microparticle levels in healthy volunteers.

    PubMed

    Navasiolava, Nastassia M; Dignat-George, Françoise; Sabatier, Florence; Larina, Irina M; Demiot, Claire; Fortrat, Jacques-Olivier; Gauquelin-Koch, Guillemette; Kozlovskaya, Inesa B; Custaud, Marc-Antoine

    2010-08-01

    A sedentary lifestyle has adverse effects on the cardiovascular system, including impaired endothelial functions. Subjecting healthy men to 7 days of dry immersion (DI) presented a unique opportunity to analyze the specific effects of enhanced inactivity on the endothelium. We investigated endothelial properties before, during, and after 7 days of DI involving eight subjects. Microcirculatory functions were assessed with laser Doppler in the skin of the calf. We studied basal blood flow and endothelium-dependent and -independent vasodilation. We also measured plasma levels of microparticles, a sign of cellular dysfunction, and soluble endothelial factors, reflecting the endothelial state. Basal flow and endothelium-dependent vasodilation were reduced by DI (22 + or - 4 vs. 15 + or - 2 arbitrary units and 29 + or - 6% vs. 12 + or - 6%, respectively, P < 0.05), and this was accompanied by an increase in circulating endothelial microparticles (EMPs), which was significant on day 3 (42 + or - 8 vs. 65 + or - 10 EMPs/microl, P < 0.05), whereas microparticles from other cell origins remained unchanged. Plasma soluble VEGF decreased significantly during DI, whereas VEGF receptor 1 and soluble CD62E were unchanged, indicating that the increase in EMPs was associated with a change in antiapoptotic tone rather than endothelial activation. Our study showed that extreme physical inactivity in humans induced by 7 days of DI causes microvascular impairment with a disturbance of endothelial functions, associated with a selective increase in EMPs. Microcirculatory endothelial dysfunction might contribute to cardiovascular deconditioning as well as to hypodynamia-associated pathologies. In conclusion, the endothelium should be the focus of special care in situations of acute limitation of physical activity.

  3. The OxyMask™ development and performance in healthy volunteers

    PubMed Central

    Paul, James E; Hangan, Horia; Hajgato, Julius

    2009-01-01

    Background The OxyMask™ is a unique, open-style, oxygen mask that was originally developed in 2005. The original mask was modified, using computational fluid dynamics numerical simulations, with the goal of allowing it to produce a wider range of FiO2. This analysis was used to guide the modification of the mask shell and the location for the oxygen diffuser. Methods The new OxyMask was attached to 10 healthy subjects and used to deliver escalating levels of oxygen (1.5, 2, 2.5, 3, 5, 10, 15, 20, 25 and 30 LPM) for 90 seconds at each level and the resulting FiO2 was recorded (at the lips) from 5 consecutive measurements at each oxygen flow rate. Results Mean FiO2 was 25.4% at 1.5 LPM of oxygen, 30.1% at 2 LPM, 36.5% at 2.5 LPM, 41.8% at 3 LPM, 57.6% at 5 LPM, 74.4% at 10 LPM, and 80.1% at 15 LPM. Each FiO2 achieved at these escalating oxygen levels was significantly greater than all the previous levels. The mean FiO2 was 82.8 at 20 LPM, 84.2% at 25 LPM and 84.3% at 30 LPM. All of these values on average were not significantly greater than the FiO2 achieved with 15 LPM. In a few subjects a maximum FiO2 of 90% was reached. Conclusion The original OxyMask was successfully modified so that the second generation of the mask can provide a wide range of FiO2, from 25% to 90%, while keeping its unique open design. PMID:22915909

  4. Biomarkers of the Hedgehog/Smoothened pathway in healthy volunteers.

    PubMed

    Kadam, Sunil K; Patel, Bharvin K R; Jones, Emma; Nguyen, Tuan S; Verma, Lalit K; Landschulz, Katherine T; Stepaniants, Sergey; Li, Bin; Brandt, John T; Brail, Leslie H

    2012-01-01

    The Hedgehog (Hh) pathway is involved in oncogenic transformation and tumor maintenance. The primary objective of this study was to select surrogate tissue to measure messenger ribonucleic acid (mRNA) levels of Hh pathway genes for measurement of pharmacodynamic effect. Expression of Hh pathway specific genes was measured by quantitative real time polymerase chain reaction (qRT-PCR) and global gene expression using Affymetrix U133 microarrays. Correlations were made between the expression of specific genes determined by qRT-PCR and normalized microarray data. Gene ontology analysis using microarray data for a broader set of Hh pathway genes was performed to identify additional Hh pathway-related markers in the surrogate tissue. RNA extracted from blood, hair follicle, and skin obtained from healthy subjects was analyzed by qRT-PCR for 31 genes, whereas 8 samples were analyzed for a 7-gene subset. Twelve sample sets, each with ≤500 ng total RNA derived from hair, skin, and blood, were analyzed using Affymetrix U133 microarrays. Transcripts for several Hh pathway genes were undetectable in blood using qRT-PCR. Skin was the most desirable matrix, followed by hair follicle. Whether processed by robust multiarray average or microarray suite 5 (MAS5), expression patterns of individual samples showed co-clustered signals; both normalization methods were equally effective for unsupervised analysis. The MAS5- normalized probe sets appeared better suited for supervised analysis. This work provides the basis for selection of a surrogate tissue and an expression analysis-based approach to evaluate pathway-related genes as markers of pharmacodynamic effect with novel inhibitors of the Hh pathway.

  5. Novel bacterial immobilization compound effectively decreases bacterial counts in healthy volunteers.

    PubMed

    Pabon, Diego F; Yost, Michael J; Melendez, Giselle C; Durand, Tamsin M; Brock, Timothy Z; Felice, Peter A; Campbell, Katherine; Bynoe, Raymond P; Fann, Stephen A

    2010-01-01

    Skin flora immobilization technology is similar in efficacy to Iodine-Povidone in healthy volunteers. We did a prospective study in a university clinic with 60 healthy volunteers. Right inguinal skin area on healthy volunteers was used to compare the antimicrobial properties of cyanoacrylate sealant (FloraSeal, Adhesion Biomedical, Wyomissing, PA) versus standard surgical preparation Povidone-iodine (Betadine, Purdue Productions, Stamford, CT). Bacterial counts were measured at different time intervals: 15 minutes, 4 hours, and 24 hours. Bacterial colony forming units were compared between Povidone-iodine and cyanoacrylate sealant. The absolute log reduction was 5.568 for Povidone-iodine (7 absolute CFU); 5.028 for cyanoacrylate (59 absolute CFU); and 5.568 for Povidone-iodine and cyanoacrylate combined (21 absolute CFU). Cyanoacrylate was able to sustain a reduction on bacterial counts at 4 hours and 24 hours of more than 99.8 per cent as compared with the control group. Cyanoacrylate microbial sealant successfully reduces bacterial counts on normal healthy skin. The results were similar to Povidone-iodine alone. We believe this technology may be an excellent means of mitigating incisional surgical site infection by reducing the risk of contamination by skin flora and warrants further testing.

  6. Differences in gluten metabolism among healthy volunteers, coeliac disease patients and first-degree relatives.

    PubMed

    Caminero, Alberto; Nistal, Esther; Herrán, Alexandra R; Pérez-Andrés, Jénifer; Ferrero, Miguel A; Vaquero Ayala, Luis; Vivas, Santiago; Ruiz de Morales, José M G; Albillos, Silvia M; Casqueiro, Francisco Javier

    2015-10-28

    Coeliac disease (CD) is an immune-mediated enteropathy resulting from exposure to gluten in genetically predisposed individuals. Gluten proteins are partially digested by human proteases generating immunogenic peptides that cause inflammation in patients carrying HLA-DQ2 and DQ8 genes. Although intestinal dysbiosis has been associated with patients with CD, bacterial metabolism of gluten has not been studied in depth thus far. The aim of this study was to analyse the metabolic activity of intestinal bacteria associated with gluten intake in healthy individuals, CD patients and first-degree relatives of CD patients. Faecal samples belonging to twenty-two untreated CD patients, twenty treated CD patients, sixteen healthy volunteers on normal diet, eleven healthy volunteers on gluten-free diet (GFD), seventy-one relatives of CD patients on normal diet and sixty-nine relatives on GFD were tested for several proteolytic activities, cultivable bacteria involved in gluten metabolism, SCFA and the amount of gluten in faeces. We detected faecal peptidasic activity against the gluten-derived peptide 33-mer. CD patients showed differences in faecal glutenasic activity (FGA), faecal tryptic activity (FTA), SCFA and faecal gluten content with respect to healthy volunteers. Alterations in specific bacterial groups metabolising gluten such as Clostridium or Lactobacillus were reported in CD patients. Relatives showed similar parameters to CD patients (SCFA) and healthy volunteers (FTA and FGA). Our data support the fact that commensal microbial activity is an important factor in the metabolism of gluten proteins and that this activity is altered in CD patients.

  7. Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers

    PubMed Central

    Bielefeldt, Andreas Ø; Danborg, Pia B

    2016-01-01

    Objective To quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no signs of a mental disorder. Design Systematic review and meta-analysis. Main outcome measure Harms related to suicidality, hostility, activation events, psychotic events and mood disturbances. Setting Published trials identified by searching PubMed and Embase and clinical study reports obtained from the European and UK drug regulators. Participants Double-blind, placebo-controlled trials in adult healthy volunteers that reported on suicidality or violence or precursor events to suicidality or violence. Results A total of 5787 publications were screened and 130 trials fulfilled our inclusion criteria. The trials were generally uninformative; 97 trials did not report the randomisation method, 75 trials did not report any discontinuations and 63 trials did not report any adverse events or lack thereof. Eleven of the 130 published trials and two of 29 clinical study reports we received from the regulatory agencies presented data for our meta-analysis. Treatment of adult healthy volunteers with antidepressants doubled their risk of harms related to suicidality and violence, odds ratio 1.85 (95% confidence interval 1.11 to 3.08, p = 0.02, I2 = 18%). The number needed to treat to harm one healthy person was 16 (95% confidence interval 8 to 100; Mantel-Haenszel risk difference 0.06). There can be little doubt that we underestimated the harms of antidepressants, as we only had access to the published articles for 11 of our 13 trials. Conclusions Antidepressants double the occurrence of events in adult healthy volunteers that can lead to suicide and violence. PMID:27729596

  8. Neuropsychological test performance in healthy volunteers before and after donepezil administration.

    PubMed

    Beglinger, Leigh J; Gaydos, Brenda L; Kareken, David A; Tangphao-Daniels, Oranee; Siemers, Eric R; Mohs, Richard C

    2004-03-01

    Participants in early Phase I clinical trials for drugs designed to enhance cognition are typically healthy volunteers. If improvement can be detected with a battery of cognitive tests in healthy volunteers, such a battery could be a pharmacodynamic marker in the future development of the compound for treatment of cognitive disorders. In the present exploratory study, a battery of neuropsychological (NP) tests was used to determine if changes in cognition from a pharmacological intervention could be detected in healthy volunteers. A drug with known cognitive-enhancing effects in Alzheimer's disease, donepezil, was compared with placebo and no treatment arms. Carry-over effects of repeated test administration were also assessed. In this double-blind study, 27 healthy adults were randomized into one of three arms (eight donepezil, nine placebo and 10 no treatment) and completed 14 days of donepezil (5 mg q.h.s.) or placebo (q.h.s.). A battery of NP tests was administered on days 0, 7, 14 (randomization), 21, 28 (end of treatment) and 42 (washout). There were no differences in performance between the placebo and the no treatment arms. However, on day 21, subjects in the donepezil group performed slightly but significantly worse on some tests of speed, attention and memory (p < 0.05) compared to the pooled control group (placebo and no treatment arms). No improvement in performance was present while on donepezil at days 21 or 28. While the results are counter to expectations, some tests in the battery did detect a cognitive change (transient mild worsening during drug administration) in healthy volunteers.

  9. Assessing change in health professions volunteers' perceptions after participating in Special Olympics healthy athlete events.

    PubMed

    Freudenthal, Jacqueline J; Boyd, Linda D; Tivis, Rick

    2010-09-01

    This study assessed perceptions of health professions student and faculty volunteers who participated with athletes at the 2009 Special Olympics World Winter Games in Healthy Athlete venues. The volunteers' perceptions and expectations of the abilities of intellectually disabled athletes were measured by administering pre-event and post-event questionnaires consisting of demographic questions and the Prognostic Belief Scale (PBS). Invitations to participate in the study were sent to 165 students and faculty members; of those, eighty (48.5 percent response rate) responded to the pre-event questionnaire, and sixty-seven (40.6 percent response rate) responded to the post-event questionnaire. Of the eighty respondents to the pre-event questionnaire, fifty-five (68.7 percent) also completed the post-event questionnaire. The ANOVA comparing pre- and post-event PBS scores between groups found a trend towards higher scores among the volunteers, but analysis did not demonstrate a significant effect in either group (p=.68) or the interaction of group by time (p=.46). Despite the findings from the PBS, participants' statements suggest the experience had an impact on their perceptions and expectations. Although not statistically significant, this study found a positive trend pre- to post-event in the volunteers' perceptions of the abilities of athletes with intellectual disabilities. In addition to didactic and clinical education, volunteer experiences may enhance care providers' knowledge, skill, and confidence levels for treating clients with intellectual disabilities.

  10. Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers

    PubMed Central

    Tang, Yong-Jun; Hu, Kai; Liu, Zhi; Chen, Yao; Ouyang, Dong-Sheng; Zhou, Hong-Hao

    2017-01-01

    Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D′ = 0.977, r2 = 0.944). The mean values of Cmax, AUC0–24, and AUC0–∞ of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P < 0.05), while the pharmacokinetic parameters except Tmax of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers. PMID:28331852

  11. Oxytocin enhances processing of positive versus negative emotional information in healthy male volunteers.

    PubMed

    Di Simplicio, M; Massey-Chase, R; Cowen, P J; Harmer, Catherine J

    2009-05-01

    Animal studies have shown the role of oxytocin in affiliation and attachment, and recent evidence suggests that oxytocin is also involved in human models of approach behaviour, possibly by modulating the processing of emotionally valenced stimuli. Although oxytocin administration has been reported to decrease neural responses to facial emotional information, the effects on a wider range of behavioural measures of emotional processing shown to be sensitive to antidepressant manipulation have not been examined. The aim of this study was to investigate whether intranasally administered oxytocin affects the processing of positive and negative affective information in healthy male volunteers across tasks measuring attention, perception and memory. Twenty-nine male healthy volunteers were randomly allocated to receive a single dose of oxytocin nasal spray (24 UI) or placebo. 50 min later, participants completed a battery of psychological tests measuring emotional processing. A single dose of intranasally administered oxytocin slowed reaction time to correctly identify fearful facial expressions and reduced the misclassification of positive emotions as negative ones. These effects occurred in the absence of significant differences in subjective ratings of mood and anxiety. These results suggest that oxytocin modulates emotion processing in healthy male volunteers. This action may contribute to the emerging role of the neuropeptide in promoting affiliative and approach behaviours by reducing the salience of potentially ambiguous and threatening social stimuli.

  12. Soluble BACE-1 Activity and sAβPPβ Concentrations in Alzheimer's Disease and Age-Matched Healthy Control Cerebrospinal Fluid from the Alzheimer's Disease Neuroimaging Initiative-1 Baseline Cohort.

    PubMed

    Savage, Mary J; Holder, Daniel J; Wu, Guoxin; Kaplow, June; Siuciak, Judith A; Potter, William Z

    2015-01-01

    β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays an important role in the development of Alzheimer's disease (AD), freeing the amyloid-β (Aβ) N-terminus from the amyloid-β protein precursor (AβPP), the first step in Aβ formation. Increased BACE1 activity in AD brain or cerebrospinal fluid (CSF) has been reported. Other studies, however, found either no change or a decrease with AD diagnosis in either BACE1 activity or sAβPPβ, the N-terminal secreted product of BACE1 (sBACE1) activity on AβPP. Here, sBACE1 enzymatic activity and secreted AβPPβ (sAβPPβ) were measured in Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1) baseline CSF samples and no statistically significant changes were found in either measure comparing healthy control, mild cognitively impaired, or AD individual samples. While CSF sBACE1 activity and sAβPPβ demonstrated a moderate yet significant degree of correlation with each other, there was no correlation of either analyte to CSF Aβ peptide ending at residue 42. Surprisingly, a stronger correlation was demonstrated between CSF sBACE1 activity and tau, which was comparable to that between CSF Aβ₄₂ and tau. Unlike for these latter two analytes, receiver-operator characteristic curves demonstrate that neither CSF sBACE1 activity nor sAβPPβ concentrations can be used to differentiate between healthy elderly and AD individuals.

  13. Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera) in healthy volunteers

    PubMed Central

    Raut, Ashwinikumar A.; Rege, Nirmala N.; Tadvi, Firoz M.; Solanki, Punita V.; Kene, Kirti R.; Shirolkar, Sudatta G.; Pandey, Shefali N.; Vaidya, Rama A.; Vaidya, Ashok B.

    2012-01-01

    Ashwagandha (Withania somnifera) (WS), a “rasayana” drug, is recommended for balavardhan and mamsavardhan. The study was intended to evaluate dose-related tolerability, safety, and activity of WS formulation in normal individuals. The design was prospective, open-labeled, variable doses in volunteers. Eighteen apparently healthy volunteers (12M:6F, age:18-30 years, and BMI: 19-30) were enrolled. After baseline investigations, they received WS capsules (Rx) (aqueous extract, 8:1) daily in two divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day ×10 days, 1 000 mg/day × 10 days, 1 250 mg/day × 10 days). Volunteers were assessed for symptoms/signs, vital functions, hematological and biochemical organ function tests. Muscle activity was measured by hand grip strength, quadriceps strength, and back extensor force. Exercise tolerance was determined using cycle ergometry. Lean body weight and fat% were computed from skin fold thickness measurement. Adverse events were recorded, as volunteered by the subjects. Repeated measures ANOVA, McNemar's test, and paired t test were employed. All but one volunteer tolerated WS without any adverse event. One volunteer showed increased appetite, libido, and hallucinogenic effects with vertigo at the lowest dose and was withdrawn from study. In six subjects, improvement in quality of sleep was found. Organ function tests were in normal range before and after the intervention. Reduction in total- and LDL- cholesterol and increase of strength in muscle activity was significant. Total body fat percentage showed a reduction trend. WS, in escalated dose, was tolerated well. The formulation appeared safe and strengthened muscle activity. In view of its traditional Rasayana use, further studies are planned to evaluate potential of this drug in patients of sarcopenia. PMID:23125505

  14. Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera) in healthy volunteers.

    PubMed

    Raut, Ashwinikumar A; Rege, Nirmala N; Tadvi, Firoz M; Solanki, Punita V; Kene, Kirti R; Shirolkar, Sudatta G; Pandey, Shefali N; Vaidya, Rama A; Vaidya, Ashok B

    2012-07-01

    Ashwagandha (Withania somnifera) (WS), a "rasayana" drug, is recommended for balavardhan and mamsavardhan. The study was intended to evaluate dose-related tolerability, safety, and activity of WS formulation in normal individuals. The design was prospective, open-labeled, variable doses in volunteers. Eighteen apparently healthy volunteers (12M:6F, age:18-30 years, and BMI: 19-30) were enrolled. After baseline investigations, they received WS capsules (Rx) (aqueous extract, 8:1) daily in two divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day ×10 days, 1 000 mg/day × 10 days, 1 250 mg/day × 10 days). Volunteers were assessed for symptoms/signs, vital functions, hematological and biochemical organ function tests. Muscle activity was measured by hand grip strength, quadriceps strength, and back extensor force. Exercise tolerance was determined using cycle ergometry. Lean body weight and fat% were computed from skin fold thickness measurement. Adverse events were recorded, as volunteered by the subjects. Repeated measures ANOVA, McNemar's test, and paired t test were employed. All but one volunteer tolerated WS without any adverse event. One volunteer showed increased appetite, libido, and hallucinogenic effects with vertigo at the lowest dose and was withdrawn from study. In six subjects, improvement in quality of sleep was found. Organ function tests were in normal range before and after the intervention. Reduction in total- and LDL- cholesterol and increase of strength in muscle activity was significant. Total body fat percentage showed a reduction trend. WS, in escalated dose, was tolerated well. The formulation appeared safe and strengthened muscle activity. In view of its traditional Rasayana use, further studies are planned to evaluate potential of this drug in patients of sarcopenia.

  15. Sufentanil does not increase cerebral blood flow in healthy human volunteers

    SciTech Connect

    Mayer, N.; Weinstabl, C.; Podreka, I.; Spiss, C.K. )

    1990-08-01

    The effect of sufentanil on human cerebral blood flow (CBF) was studied in seven unpremedicated, healthy volunteers 31 +/- 3.5 yr of age (mean +/- SD) and either sex. CBF (ml.100 g-1.min-1) was measured noninvasively with the 133Xe clearance technique and a scintillation camera before and after sufentanil 0.5 micrograms/kg administered intravenously. This technique provides values for global blood flow and for gray and white matter blood flow, and from 13 preselected regions in one hemisphere. After the administration of sufentanil, the volunteers were stimulated verbally in order to prevent their loss of consciousness and hypercarbia. Heart rate (HR), arterial pressure, oxyhemoglobin saturation, and end-tidal CO2 ETCO2 were recorded during the measurements. Neither global CBF (46.1 +/- 1.6 control and 43 +/- 1.9 after sufentanil, mean +/- SEM) nor gray (76.5 +/- 3.2 and 70.9 +/- 6.1) or white (22.7 +/- 1.5 and 24.2 +/- 1.6) matter blood flow changed significantly after sufentanil administration. As well, no significant differences in HR (72 +/- 4 control and 79 +/- 4 beats per min after sufentanil) and ETCO2 (39.8 +/- 1.4 and 41.1 +/- 1.1 mmHg) were observed. It is concluded that sufentanil has no significant effect on CBF in healthy human volunteers.

  16. Reference values for cardiopulmonary exercise testing in healthy volunteers: the SHIP study.

    PubMed

    Koch, B; Schäper, C; Ittermann, T; Spielhagen, T; Dörr, M; Völzke, H; Opitz, C F; Ewert, R; Gläser, S

    2009-02-01

    Cardiopulmonary exercise testing (CPET) is a widely applied clinical procedure. The aim of the present study was to acquire a comprehensive set of reference values for cardiopulmonary responses to exercise and to evaluate possible associations with sex, age and body mass index (BMI). A standardised progressive incremental exercise protocol on a cycle ergometer was applied to 1,708 volunteers of a cross-sectional epidemiologic survey, called "Study of Health in Pomerania". Individuals with cardiopulmonary disorders, or echocardiographic or lung function pathologies, were excluded. The influence of potential confounding factors, such as smoking, taking beta-blockers, hypertension, diastolic dysfunction, BMI and physical activity, were analysed for their influencing power. Reference values of CPET parameters were determined by regression analyses. Of the volunteers, 542 current smokers and obese individuals were excluded for not being representative of a healthy population. The final sample size was 534 (253 males), with age 25-80 yrs. The current study provides a representative set of reference values for CPET parameters based on age and weight. Sex and age have a significant influence on exercise parameters. While addressing the problem of a selection bias, the current study provides the first comprehensive set of reference values obtained in a large number of healthy volunteers within a population-based survey.

  17. Safety evaluation of BacoMind in healthy volunteers: a phase I study.

    PubMed

    Pravina, K; Ravindra, K R; Goudar, K S; Vinod, D R; Joshua, A J; Wasim, P; Venkateshwarlu, K; Saxena, V S; Amit, A

    2007-05-01

    BacoMind is an enriched phytochemical composition of Bacopa monniera (B. monniera), a common medicinal plant used in the traditional systems of medicine as a memory-enhancing agent. BacoMind was standardized with reference to bioactive compounds and was evaluated for short-term safety and tolerability in healthy adult volunteers. The study plan employed randomized, open label, dose escalation design. Each of 23 participants were orally given one single capsule of BacoMind daily for 30 days, i.e., 300 mg for first 15 days and 450 mg for next 15 days. Detailed examination of clinical, hematological, biochemical and electrocardiographic parameters done in pre and post-treatment periods did not indicate any untoward effects in any of the treated volunteers. Mild adverse events related to gastrointestinal system were observed in the trial, which subsided spontaneously. BacoMind was found to meet the safety criteria at the dose administered for the given duration of trial period in healthy adult volunteers.

  18. Lanreotide inhibits human jejunal secretion induced by prostaglandin E1 in healthy volunteers.

    PubMed

    Sobhani, I; René, E; Ramdani, A; Bayod, F; Sabbagh, L C; Thomas, F; Mignon, M

    1996-02-01

    1. Somatostatin inhibits hormonal secretions in the gastrointestinal tract. Somatostatin analogues are used in the treatment of VIPome-related watery diarrhoea. In addition, more than 10% of patients with AIDS suffer from diarrhoea likely due to the increased intestinal secretion of water and ions. However, the direct effect of somatostatin on the flux of water and ions in the intestine has not been, so far, analyzed in vivo. The aim of the present study was to evaluate the effect of lanreotide, a somatostatin analogue, on the movements of water and ions in the jejunum in man. 2. Accordingly, 10 healthy volunteers (age 18-35 years, mean 27) and two patients with AIDS (26 and 33 years) suffering from water diarrhoea (> 800 ml day-1) underwent intestinal perfusion using a four lumen tube with proximal occluding balloon. The segment tested was 25 cm long. The jejunum was infused by an isotonic control saline solution containing polyethylene glycol (PEG) as nonabsorbable marker. Basal jejunal secretions were measured in all subjects. Prostaglandin E1 (PGE1) was administered intraluminally to stimulate jejunal secretion in healthy volunteers. The effect of intravenous lanreotide on the jejunal PGE1-induced secretions of water and electrolytes was analysed in healthy subjects and on the basal secretions in AIDS patients. Each period was analyzed on the basis of three (10 min) successive intestinal juice collections after 20-30 min equilibration time. The antisecretory effect of lanreotide was evaluated in each subject as the difference between fluxes compared to the control period. 3. In healthy volunteers, PGE1 induced secretion of H2O, Na+, K+ and Cl- in the jejunum and lanreotide reduced significantly PGE1-induced response. In both AIDS patients basal fluxes of water and ions were reduced by lanreotide in a dose-dependent manner. 4. Somatostatin can reduce stimulated-jejunal secretion of ions and water in normal subjects and may improve water diarrhoea in AIDS

  19. Feeding and Bleeding: The Institutional Banalization of Risk to Healthy Volunteers in Phase I Pharmaceutical Clinical Trials.

    PubMed

    Fisher, Jill A

    2015-03-01

    Phase I clinical trials are the first stage of testing new pharmaceuticals in humans. The majority of these studies are conducted under controlled, inpatient conditions using healthy volunteers who are paid for their participation. This article draws on an ethnographic study of six phase I clinics in the United States, including 268 semistructured interviews with research staff and healthy volunteers. In it, I argue that an institutional banalization of risk structures the perceptions of research staff and healthy volunteers participating in the studies. For research staff, there are three mechanisms by which risk becomes banal: a perceived homogeneity of studies, Fordist work regimes, and data-centric discourse. For healthy volunteers, repeat study participation contributes to the institutional banalization of risk both through the process of desensitization to risk and the formation of trust in the clinics. I argue that the institutional banalization of risk also renders invisible ethical concerns about exploitation of underprivileged groups in pharmaceutical research.

  20. Feeding and Bleeding: The Institutional Banalization of Risk to Healthy Volunteers in Phase I Pharmaceutical Clinical Trials

    PubMed Central

    Fisher, Jill A.

    2015-01-01

    Phase I clinical trials are the first stage of testing new pharmaceuticals in humans. The majority of these studies are conducted under controlled, inpatient conditions using healthy volunteers who are paid for their participation. This article draws on an ethnographic study of six phase I clinics in the United States, including 268 semistructured interviews with research staff and healthy volunteers. In it, I argue that an institutional banalization of risk structures the perceptions of research staff and healthy volunteers participating in the studies. For research staff, there are three mechanisms by which risk becomes banal: a perceived homogeneity of studies, Fordist work regimes, and data-centric discourse. For healthy volunteers, repeat study participation contributes to the institutional banalization of risk both through the process of desensitization to risk and the formation of trust in the clinics. I argue that the institutional banalization of risk also renders invisible ethical concerns about exploitation of underprivileged groups in pharmaceutical research. PMID:25914430

  1. Bioequivalence studies of two brands of meloxicam tablets in healthy Pakistani volunteers.

    PubMed

    Hasan, Syed Muhammad Farid; Shoaib, Muhammad Harris; Hassan, Fouzia; Rehman, Inam-Ur

    2009-04-01

    The pharmacokinetic parameters of two oral formulations of meloxicam tablets were compared in a randomized, single oral dose; two treatments cross over design in 12 healthy male volunteers belonging to Pakistan under fasting conditions. After an overnight fast, the volunteers received 30 mg meloxicam and the blood samples were collected up to 96 hours and drug concentrations were determined by a validated HPLC method. Various pharmacokinetic parameters were determined from the plasma concentration-time curves of both formulations. The 90% confidence intervals obtained by analysis of variance were 87-94% for C(max) and 88-97% for AUC(0-t), that fell well within the acceptance range of 80-125%. Also, no significant difference (a=0.05, Wilcoxon Signed rank test) were detected between T(max) of both formulations. The two formulations were well tolerated and no adverse effect was reported during the study.

  2. Effects of acute CDP-choline treatment on resting state brain oscillations in healthy volunteers.

    PubMed

    Knott, Verner; de la Salle, Sara; Smith, Dylan; Choueiry, Joelle; Impey, Danielle; Smith, Meaghan; Beaudry, Elise; Saghir, Salman; Ilivitsky, Vadim; Labelle, Alain

    2015-03-30

    CDP-choline (cytidine-5'-diphosphocholine) is a phospholipid used to treat cognitive disorders, presumably repairing and maintaining brain cell membranes. Additional mechanisms may include enhanced cholinergic neurotransmission as the α7 nicotinic receptor actions of choline and increased acetylcholine synthesis accompanying CDP-choline administration may modulate brain oscillations underlying cognitive processes. This study utilizes electroencephalographic (EEG) recordings in healthy volunteers to evaluate CDP-choline induction of an oscillatory response profile associated with nicotinic stimulation. Resting state EEG was acquired in 24 male volunteers administered low (500mg) and moderate (1000mg) doses of CDP-choline in a randomized placebo-controlled, crossover trial. Consistent with nicotinic agonist treatment, spectral analysis showed dose-dependent reductions in delta and increases in alpha oscillations, which were also accompanied by decreases in beta and gamma oscillatory activity. These findings support the posit that CDP-choline cognitive enhancement involves multiple mechanisms including facilitated nicotinic cholinergic action.

  3. Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity

    PubMed Central

    Lima, Renata Monteiro; Ferreira, Maria Augusta Drago; de Jesus Ponte Carvalho, Teresa Maria; Dumêt Fernandes, Bruno José; Takayanagui, Osvaldo Massaiti; Garcia, Hector Hugo; Coelho, Eduardo Barbosa; Lanchote, Vera Lucia

    2011-01-01

    AIM This study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers. METHODS A randomized crossover study was carried out in three phases (n = 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0–48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P≤ 0.05. RESULTS The administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 µg ml−1 h), (−)-ASOX by 358% (0.14 vs. 0.50 µg ml−1 h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 µg ml−1 h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (–)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (–)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 µg ml−1 h). CONCLUSIONS The pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (–)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination. PMID:21395645

  4. Pharmacokinetics of the antiepileptic drug levetiracetam in healthy Japanese and Caucasian volunteers following intravenous administration.

    PubMed

    Toublanc, Nathalie; Okagaki, Takuya; Boyce, Malcolm; Chan, Robert; Mugitani, Ayumi; Watanabe, Shikiko; Yamamoto, Katsumi; Yoshida, Katsumi; Andreas, Jens-Otto

    2015-12-01

    The intravenous (iv) formulation of levetiracetam has been available in clinical practice worldwide for several years, but not in Japan. Two open-label studies were conducted: Study A evaluated the bioequivalence of iv and oral tablet formulations in healthy Japanese volunteers; and Study B subsequently compared the pharmacokinetics of iv levetiracetam in healthy Japanese and Caucasian volunteers. Study A had a randomised, two-way crossover design; a single 1,500 mg levetiracetam dose was administered as a 15-min iv infusion and as 3 × 500 mg oral tablets to Japanese volunteers. In Study B, 1,500 mg levetiracetam was administered as single and repeated 15-min iv infusions to Japanese and Caucasian volunteers. Overall, 26/27 volunteers completed Study A and 32/32 (16 Japanese; 16 Caucasian) completed Study B. In Study A, the point estimate and 90 % confidence interval (CI) for the geometric least squares mean (LSM) ratio (iv vs oral) were fully included within the acceptance range for bioequivalence (0.85-1.25) for the area under plasma concentration-time curve from 0 to last quantifiable observation (AUClast 0.97 [0.95, 0.99]), but not for the maximum plasma concentration (C max 1.64 [1.47, 1.83]). In Study B, after a single iv infusion, the point estimates (90 % CI) for the geometric LSM ratio (Japanese vs Caucasian) for body weight-normalised C max and AUClast were 1.21 (1.07, 1.36) and 0.97 (0.90, 1.04), respectively. Corresponding values after repeated iv infusions were C max,ss 1.01 (0.91, 1.12) and AUCτ,ss 0.89 (0.83, 0.96). Levetiracetam was well tolerated in both studies. Study A did not demonstrate the bioequivalence of single doses of levetiracetam 1,500 mg administered as an iv infusion and as oral tablets in healthy Japanese adults. Study B, however, showed that pharmacokinetic profiles were generally similar between Japanese and Caucasian adults after single and repeated iv infusions of levetiracetam 1,500 mg.

  5. A single consumption of high amounts of the Brazil nuts improves lipid profile of healthy volunteers.

    PubMed

    Colpo, Elisângela; Vilanova, Carlos Dalton de Avila; Brenner Reetz, Luiz Gustavo; Medeiros Frescura Duarte, Marta Maria; Farias, Iria Luiza Gomes; Irineu Muller, Edson; Muller, Aline Lima Hermes; Moraes Flores, Erico Marlon; Wagner, Roger; da Rocha, João Batista Teixeira

    2013-01-01

    Background. This study investigates the effects of Brazil nut ingestion on serum lipid profile in healthy volunteers. Methods. Ten healthy subjects were enrolled in the study. Each subject was tested 4 times in a randomized crossover in relation to the ingestion of different serving sizes of the Brazil nut: 0, 5, 20, or 50 g. At each treatment point, peripheral blood was drawn before and at 1, 3, 6, 9, 24, and 48 hours and 5 and 30 days. Blood samples were tested for total cholesterol, high- and low-density lipoprotein cholesterol (HDL-c and LDL-c, resp.), triglycerides, selenium, aspartate and alanine aminotransferases, albumin, total protein, alkaline phosphatase, gamma GT, urea, creatinine, and C-reactive protein. Results. A significant increase of the plasma selenium levels was observed at 6 hours within the groups receiving the nuts. Serum LDL-c was significantly lower, whereas HDL-c was significantly higher 9 hours after the ingestion of 20 or 50 g of nuts. The biochemical parameters of liver and kidney function were not modified by ingestion of nuts. Conclusions. This study shows that the ingestion of a single serving of Brazil nut can acutely improve the serum lipid profile of healthy volunteers.

  6. A Single Consumption of High Amounts of the Brazil Nuts Improves Lipid Profile of Healthy Volunteers

    PubMed Central

    Colpo, Elisângela; Vilanova, Carlos Dalton de Avila; Medeiros Frescura Duarte, Marta Maria; Farias, Iria Luiza Gomes; Irineu Muller, Edson; Muller, Aline Lima Hermes; Moraes Flores, Erico Marlon; da Rocha, João Batista Teixeira

    2013-01-01

    Background. This study investigates the effects of Brazil nut ingestion on serum lipid profile in healthy volunteers. Methods. Ten healthy subjects were enrolled in the study. Each subject was tested 4 times in a randomized crossover in relation to the ingestion of different serving sizes of the Brazil nut: 0, 5, 20, or 50 g. At each treatment point, peripheral blood was drawn before and at 1, 3, 6, 9, 24, and 48 hours and 5 and 30 days. Blood samples were tested for total cholesterol, high- and low-density lipoprotein cholesterol (HDL-c and LDL-c, resp.), triglycerides, selenium, aspartate and alanine aminotransferases, albumin, total protein, alkaline phosphatase, gamma GT, urea, creatinine, and C-reactive protein. Results. A significant increase of the plasma selenium levels was observed at 6 hours within the groups receiving the nuts. Serum LDL-c was significantly lower, whereas HDL-c was significantly higher 9 hours after the ingestion of 20 or 50 g of nuts. The biochemical parameters of liver and kidney function were not modified by ingestion of nuts. Conclusions. This study shows that the ingestion of a single serving of Brazil nut can acutely improve the serum lipid profile of healthy volunteers. PMID:23840948

  7. The effect of selective head-neck cooling on physiological and cognitive functions in healthy volunteers

    PubMed Central

    Jackson, Kevin; Rubin, Rachael; Van Hoeck, Nicole; Hauert, Tommy; Lana, Valentina; Wang, Huan

    2015-01-01

    In general, brain temperatures are elevated during physical sporting activities; therefore, reducing brain temperature shortly after a sports-related concussion (SRC) could be a promising intervention technique. The main objective of this study was to examine the effects of head and neck cooling on physiological and cognitive function in normal healthy volunteers. Twelve healthy volunteers underwent two different sessions of combined head and neck cooling, one session with a cold pack and one session with a room temperature pack. Physiological measurements included: systolic/diastolic blood pressure, pulse oximetry, heart rate, and sublingual and tympanic temperature. Cognitive assessment included: processing speed, executive function, and working memory tasks. Physiological measurements were taken pre-, mid- and post-cooling, while cognitive assessments were done before and after cooling. The order of the sessions was randomized. There was a significant decrease in tympanic temperature across both sessions; however more cooling occurred when the cold pack was in the device. There was no significant decrease in sublingual temperature across either session. The observed heart rates, pulse oximetry, systolic and diastolic blood pressure during the sessions were all within range of a normal healthy adult. Cognitive assessment remained stable across each session for both pre- and post-cooling. We propose that optimizing brain temperature management after brain injury using head and neck cooling technology may represent a sensible, practical, and effective strategy to potentially enhance recovery and perhaps minimize the subsequent short and long term consequences from SRC. PMID:28123796

  8. Effects of dexamethasone coadministered with oseltamivir on the pharmacokinetics of oseltamivir in healthy volunteers

    PubMed Central

    Jang, Kyungho; Kim, Min-Kyoung; Oh, Jaeseong; Lee, SeungHwan; Cho, Joo-Youn; Yu, Kyung-Sang; Choi, Tai Kiu; Lee, Sang-Hyuk; Lim, Kyoung Soo

    2017-01-01

    Purpose Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1) to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK) of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers. Methods An open-label, two-period, one-sequence, multiple-dose study was conducted in 19 healthy male volunteers. Oseltamivir (75 mg) was orally administered on Day 1 and Day 8, and dexamethasone (1.5 mg) was administered once daily from Day 3 to Day 8. Serial blood and urine samples were collected for PK analysis of oseltamivir and oseltamivir carboxylate on Day 1 and Day 8. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography–tandem mass spectrometry. Results Area under the plasma concentration–time curve (AUC) of oseltamivir and oseltamivir carboxylate decreased after dexamethasone treatment for 6 days. The geometric mean ratio (90% confidence interval) of the metabolic ratio (oseltamivir carboxylate AUC0–48h/oseltamivir AUC0–48h) was 0.92 (0.87–0.97). The amount of unchanged oseltamivir excreted in urine increased by 14% after dexamethasone treatments. Conclusion Coadministration of dexamethasone with oseltamivir slightly decreased systemic exposure to oseltamivir and oseltamivir carboxylate in healthy volunteers. This result suggests that CES1 is inhibited by dexamethasone in humans. However, coadministration of oseltamivir and dexamethasone did not appear to have a clinically relevant effect on the PK of oseltamivir; based on these results, dexamethasone can be coadministered with oseltamivir. PMID

  9. Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

    PubMed Central

    Pickering, Gisèle; Macian, Nicolas; Dubray, Claude; Pereira, Bruno

    2016-01-01

    Background Acetaminophen (APAP, paracetamol) mechanism for analgesic and antipyretic outcomes has been largely addressed, but APAP action on cognitive function has not been studied in humans. Animal studies have suggested an improved cognitive performance but the link with analgesic and antipyretic modes of action is incomplete. This study aims at exploring cognitive tests in healthy volunteers in the context of antinociception and temperature regulation. A double-blind randomized controlled study (NCT01390467) was carried out from May 30, 2011 to July 12, 2011. Methods Forty healthy volunteers were included and analyzed. Nociceptive thresholds, core temperature (body temperature), and a battery of cognitive tests were recorded before and after oral APAP (2 g) or placebo: Information sampling task for predecisional processing, Stockings of Cambridge for spatial memory, reaction time, delayed matching of sample, and pattern recognition memory tests. Analysis of variance for repeated measures adapted to crossover design was performed and a two-tailed type I error was fixed at 5%. Results APAP improved information sampling task (diminution of the number of errors, latency to open boxes, and increased number of opened boxes; all P<0.05). Spatial planning and working memory initial thinking time were decreased (P=0.04). All other tests were not modified by APAP. APAP had an antinociceptive effect (P<0.01) and body temperature did not change. Conclusion This study shows for the first time that APAP sharpens decision making and planning strategy in healthy volunteers and that cognitive performance and antinociception are independent of APAP effect on thermogenesis. We suggest that cognitive performance mirrors the analgesic rather than thermic cascade of events, with possibly a central role for serotonergic and cannabinoid systems that need to be explored further in the context of pain and cognition. PMID:27980393

  10. Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers.

    PubMed

    Di Stefano, M; Papathanasopoulos, A; Blondeau, K; Vos, R; Boecxstaens, V; Farré, R; Rommel, N; Tack, J

    2012-07-01

    There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P < 0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P < 0.05) and duration (6.1 vs. 4.2 seconds, P < 0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P < 0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P < 0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P < 0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P < 0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility.

  11. Relative bioavailability of carbocysteine from three dosage forms, investigated in healthy volunteers.

    PubMed

    Bron, J

    1988-01-01

    The aim of the present study was to evaluate the bioavailability of a new tablet formulation of carbocysteine relative against two other oral carbocysteine containing dosage forms, viz. a syrup and capsules. Plasma levels and urine concentrations of carbocysteine were monitored, following oral administration of all three dosage forms to healthy human volunteers, by direct derivatization of carbocysteine using dabsylchloride and subsequent high performance liquid chromatography. There was no difference in bioavailability of carbocysteine from these dosage forms as expressed by the respective areas under the plasma concentration-time curves and total amounts of unchanged carbocysteine excreted in urine.

  12. Effect of Crocus sativus L. (saffron) on coagulation and anticoagulation systems in healthy volunteers.

    PubMed

    Ayatollahi, Hossein; Javan, Atefeh Ordoei; Khajedaluee, Mohammad; Shahroodian, Masood; Hosseinzadeh, Hossein

    2014-04-01

    Saffron showed some effects on blood coagulation and platelet aggregation in in vitro and in vivo studies. In a clinical trial with a limited number volunteers, saffron tablets influenced on bleeding time. In this study, the effect of saffron on plasma level of fibrinogen, factor VII (as coagulant agent), C and S protein (as anti-coagulant agent), PT and PTT in a larger sample size was evaluated. The study was a double-blind, placebo-controlled study consisting of 1 week treatment with 200 mg and 400 mg saffron tablets. Sixty healthy volunteers (age range 20-50 years) were selected for the study. The volunteers were divided into three groups of 20 each. Group 1 received placebo; Groups 2 and 3 received 200 mg and 400 mg saffron tablets, respectively, for 7 days (1 tablet per day). Before and after 7 days treatment and also 1 month after that, blood samples were taken. The plasma levels of fibrinogen, factor VII, C and S protein, PT and PTT were evaluated. Statistical analysis showed no difference between groups for any of evaluated factors. This study rejected any effect of saffron with dose of 200 and 400 mg for 1 week on coagulant and anticoagulant system.

  13. Clearance of soluble aggregates of human immunoglobulin G in healthy volunteers and chimpanzees.

    PubMed

    Lobatto, S; Daha, M R; Voetman, A A; Evers-Schouten, J H; Van Es, A A; Pauwels, E K; Van Es, L A

    1987-07-01

    Using aggregates of IgG (AIgG) obtained by heat aggregation of a 16 g% human IgG solution, we sought a method for measuring the function of the mononuclear phagocyte system with a probe that bears more resemblance to soluble immune complexes than erythrocytes coated with anti-rhesus IgG (EIgG). It was found that intravenous administration of 10 micrograms AIgG/kg body weight did not cause any detectable side effects in chimpanzees. In nine healthy volunteers, a dose of 10 micrograms AIgG/kg body weight was used without any adverse reactions. AIgG is cleared from the human circulation with a t1/2 of 26 +/- 8 min (mean +/- SD). The site of clearance is predominantly the liver, as shown by an average liver spleen uptake ratio of 230:100. In whole blood obtained from the volunteers, it was found that erythrocytes bound significant amounts of AIgG, suggesting that CR1 on erythrocytes is involved in the clearance of complement activating immune complexes in humans. In five of the volunteers, clearance studies with EIgG had been done in a previous study. EIgG was cleared from the circulation with a t1/2 of 30 +/- 6.2 min (mean +/- SD). The predominant site of clearance of EIgG was the spleen. These data indicate that sensitized red blood cells are cleared from the circulation differently from soluble IgG aggregates.

  14. Allium sativum L. Improves Visual Memory and Attention in Healthy Human Volunteers

    PubMed Central

    Tasnim, Sara; Haque, Parsa Sanjana; Bari, Md. Sazzadul; Hossain, Md. Monir; Islam, Sardar Mohd. Ashraful; Shahriar, Mohammad; Bhuiyan, Mohiuddin Ahmed; Bin Sayeed, Muhammad Shahdaat

    2015-01-01

    Studies have shown that Allium sativum L. (AS) protects amyloid-beta peptide-induced apoptosis, prevents oxidative insults to neurons and synapses, and thus prevent Alzheimer's disease progression in experimental animals. However, there is no experimental evidence in human regarding its putative role in memory and cognition. We have studied the effect of AS consumption by healthy human volunteers on visual memory, verbal memory, attention, and executive function in comparison to control subjects taking placebo. The study was conducted over five weeks and twenty volunteers of both genders were recruited and divided randomly into two groups: A (AS) and B (placebo). Both groups participated in the 6 computerized neuropsychological tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) twice: at the beginning and after five weeks of the study. We found statistically significant difference (p < 0.05) in several parameters of visual memory and attention due to AS ingestion. We also found statistically nonsignificant (p > 0.05) beneficial effects on verbal memory and executive function within a short period of time among the volunteers. Study for a longer period of time with patients suffering from neurodegenerative diseases might yield more relevant results regarding the potential therapeutic role of AS. PMID:26351508

  15. Comparative pharmacokinetics of different oral nifedipine preparations in healthy Brazilian volunteers.

    PubMed

    Vianna-Jorge, R; Sudo, R T; Melo, P A; Suarez-Kurtz, G

    1992-01-01

    1. The pharmacokinetics of different pharmaceutical preparations of oral nifedipine--Adalat (capsule), Oxcord and Cardalin (tablets)--was determined after administration of single oral doses of 10 mg to nine healthy young Brazilian volunteers (7 men). 2. There were no significant changes in heart rate or systolic and diastolic blood pressure measured in the sitting position within 8 h of nifedipine administration to these normotensive volunteers. No side effects were reported by the volunteers or observed by the attending physicians during the study. 3. No significant differences were observed among the three preparations in relation to the following pharmacokinetic parameters obtained from the plasma concentration-time curves: area under the curve (AUC), slope (beta) and half-life (T1/2) of the elimination phase, volume of distribution (Vd/F) and total body clearance (CL/F), both expressed as functions of the oral bioavailability (F) of nifedipine. 4. The peak plasma concentration of nifedipine (Cmax) and the time to reach Cmax (Tmax) were not different for the two tablet preparations. However, Cmax was significantly higher, and Tmax was significantly shorter for the capsule. These data indicate that the capsule and the tablet preparations are not bioequivalent.

  16. Effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin in healthy Chinese volunteers

    PubMed Central

    Zhang, Yi-fan; Dai, Xiao-jian; Yang, Yong; Chen, Xiao-yan; Wang, Ting; Tang, Yun-biao; Tsai, Cheng-yuan; Chang, Li-wen; Chang, Yu-ting; Zhong, Da-fang

    2016-01-01

    Purpose To investigate the effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin in humans. Methods Two independent, open-label, randomized, crossover studies were conducted in 24 (12 per study) healthy Chinese volunteers. In Study 1, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with 1.5 g of probenecid divided into three doses within 25 hours. In Study 2, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with multiple doses of cimetidine (400 mg thrice daily for 7 days). The plasma and urine nemonoxacin concentrations were determined using validated liquid chromatography–tandem mass spectrometry methods. Results Coadministration of nemonoxacin with probenecid reduced the renal clearance (CLr) of nemonoxacin by 22.6%, and increased the area under the plasma concentration–time curve from time 0 to infinity (AUC0−∞) by 26.2%. Coadministration of nemonoxacin with cimetidine reduced the CLr of nemonoxacin by 13.3% and increased AUC0−∞ by 9.4%. Coadministration of nemonoxacin with probenecid or cimetidine did not significantly affect the maximum concentration of nemonoxacin or the percentage of the administered dose recovered in the urine. Conclusion Although probenecid reduced the CLr and increased the plasma exposure of nemonoxacin, these effects are unlikely to be clinically meaningful at therapeutic doses. Cimetidine had weaker, clinically meaningless effects on the pharmacokinetics of nemonoxacin. PMID:26855561

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

    PubMed

    Wesnes, Keith A; Brooker, Helen; Watson, Anthony W; Bal, Wendy; Okello, Edward

    2017-02-01

    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.

  18. Evaluation of effects (symptoms and palatability) after ingestion of "Gran Soleil" in healthy volunteers.

    PubMed

    Gasbarrini, G; Gallo, A; Nicoletti, M; Montalto, M; Addolorato, G

    2008-01-01

    A good digestion is essential to maintain a healthy status. It is known that physiological digestive processes could be improved by the ingestion of some medicinal plants, while specific foods can facilitate the occurrence of gastrointestinal symptoms. Moreover, sensory properties of food seem to also influence digestion. We assessed the influence on physiological digestive processes of two Gran Soleil (GS) products containing a mixture of digestive plant extracts, citrus juices and liquors. We evaluated, in 10 healthy volunteers, the eventual occurrence of gastrointestinal symptoms after their ingestion and measured their palatability. Ingestion of GS did not cause significant gastrointestinal symptoms. Moreover, the palatability median score shows a good appreciation of the products. In conclusion, it is possible to suppose that a product with a good palatability, able to support and maintain a good digestive condition, derives from the mixture of digestive herbs, citrus juices, liquor and other ingredients.

  19. Prograf five milligrams versus Tacrolimus medis in healthy volunteers: a bioequivalence study.

    PubMed

    Masri, M; Rizk, S; Boujbel, L; Bellahirich, W; Baassoumi, D; Attia, M; Matha, V

    2013-01-01

    For FDA approval, bioequivalence of a generic version of Tacrolimus must be demonstrated in a randomized, two-treatments, two-periods, two-sequences, single-dose crossover study in healthy adult volunteers. Currently there are at least 3 differents generic equivalent for Tacrolimus, that are approved by the EMA and the FDA, with a USA market share of nearly 50%. However, the market share of generic immunosuppressive drugs in the Middle East region is still very low due to the reluctance of the physician to accept Tacrolimus generics, considered to be a narrow therapeutic window drug, that are approved using the standard bioequivalence criteria of 80% to 125%. Herein we present a bioequivalence study of a new Tacrolimus generic, Tacrolimus Medis 5 mg developed by Medis Tunisia batch number 12G3003 compared with Prograf® 5 mg batch number 7202 manufactured by Astellas Toyama Co., Ltd. Japan and HIKMA Pharmaceuticals, Amman-Jordan in healthy adult volunteers using the 90%-111% criteria recommended for drugs with narrow therapeutic window. The study was, balanced, randomized, two-treatments, two-periods, two-sequences, single dose, crossover, comparative oral bioavailability study in healthy adult human volunteers. The study was carried out in accordance with the Basic Principles defined in the U.S. 21 CFR Part 312.20, the principles enunciated in the Declaration of Helsinki (World Medical Association Declaration of Helsinki). Thirty six non-smoking healthy, as determined by medical history, volunteers, 18 years and older, were included. Following randomization using a computer software (pharma solution) the volunteers were given a single oral dose of 5 milligrams following a 12 hour fast with a wash out period of 7 days. Pharmacokinetics profile with blood levels at: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours were performed following each dose. Tacrolimus plasma level was determined using an HPLC validated method (Transmedical For Life S.A.R.L. Beirut

  20. Evaluation of antioxidant potential of Rasayana drugs in healthy human volunteers

    PubMed Central

    Kuchewar, Vaishali V.; Borkar, Mangal A.; Nisargandha, Milind A.

    2014-01-01

    Background: It is increasingly being realized that many of today's diseases are due to “oxidative stress” that results from an imbalance between formation and neutralization of free radicals. Rasayana Chikitsa is a unique branch of Ayurveda. The word Rasayana means the way for attaining excellent Rasadi Dhatus. Several medicinal plants have been described as Rasayanas in Ayurveda. Ashwagandha and Guduchi are the best among the Rasayanas described by Charaka. Aim: To study the efficacy of Ashwagandha and Guduchi in oxidative stress in healthy volunteers. Materials and Methods: The study was carried out on 30 healthy volunteers after obtaining written informed consent. They were randomly distributed in three groups. Each group was treated with three different colored capsules containing Ashwagandha, Guduchi and placebo in the dose of 1 capsule (500 mg) twice a day for 6 months. The parameters such as hemoglobin%, Erythorcyte Sedimentation Rate (ESR), Malondialdehyde (MDA), Super-Oxide Dismutase (SOD) level, etc., were assessed before and after treatment. The Student's t-test was applied to assess significant variations in all of the studied parameters. Results: In this study, there was a significant increase in SOD level and decrease in MDA level in Ashwagandha and Guduchi groups. Conclusion: Ashwagandha and Guduchi may be helpful in preventing the oxidative stress and premature aging. PMID:25364199

  1. Biomarkers for the effects of cannabis and THC in healthy volunteers

    PubMed Central

    Zuurman, Lineke; Ippel, Annelies E; Moin, Eduard; van Gerven, Joop M A

    2009-01-01

    An increasing number of novel therapeutic agents are targeted at cannabinoid receptors. Drug development programmes of new cannabinoid drugs may be facilitated by the identification of useful biomarkers. This systemic literature review aims to assess the usefulness of direct biomarkers for the effects of cannabis and tetrahydrocannabinol (THC) in healthy volunteers. One hundred and sixty-five useful articles were found that investigated the acute effects of cannabis or THC on the central nervous system (CNS) and heart rate in healthy volunteers. Three hundred and eighteen tests (or test variants) were grouped in test clusters and functional domains, to allow their evaluation as a useful biomarker and to study their dose–response effects. Cannabis/THC affected a wide range of CNS domains. In addition to heart rate, subjective effects were the most reliable biomarkers, showing significant responses to cannabis in almost all studies. Some CNS domains showed indications of depression at lower and stimulation at higher doses. Subjective effects and heart rate are currently the most reliable biomarkers to study the effect of cannabis. Cannabis affects most CNS domains, but too many different CNS tests are used to quantify the drug–response relationships reliably. Test standardization, particularly in motor and memory domains, may reveal additional biomarkers. PMID:19133057

  2. Bioequivalence study of 400 and 100 mg imatinib film-coated tablets in healthy volunteers.

    PubMed

    Ostrowicz, Andrzej; Mikołajczak, Przemysław L; Wierzbicka, Marzena; Boguradzki, Piotr

    2014-01-01

    The aim of the study was to investigate the bioavailability of a generic product of 100 mg and 400 mg imatinib film-coated tablets (test) as compared to that of a branded product (reference) at the same strength to determine bioequivalence. The secondary objective of the study was to evaluate tolerability of both products. An open-label, randomized, crossover, two-period, single-dose, comparative study was conducted in 43 (Imatynib-Biofarm 100 mg film-coated tablet) and in 42 (Imatynib-Biofarm 400 mg film-coated tablet), brand name Imatenil, Caucasian healthy volunteers in fed conditions. A single oral dose administration of the test or reference product was separated by 14-day washout period. The imatinib and its metabolite N-desmethyl imatinib concentrations were determined using a validated LC MS/MS method. The results of the single-dose study in healthy volunteers indicated that the film-coated tablets of Imatynib-Biofarm 100 mg and 400 mg film-coated tablets manufactured by Biofarm Sp. z o.o. (test products) are bioequivalent to those of Glivec 100 mg and 400 mg film-coated tablets manufactured by Novartis Pharma GmbH (reference products). Both products in the two doses of imatinib were well tolerated.

  3. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers

    PubMed Central

    Wang, Tingting; Cai, Guoxiang; Qiu, Yunping; Fei, Na; Zhang, Menghui; Pang, Xiaoyan; Jia, Wei; Cai, Sanjun; Zhao, Liping

    2012-01-01

    Despite a long-suspected role in the development of human colorectal cancer (CRC), the composition of gut microbiota in CRC patients has not been adequately described. In this study, fecal bacterial diversity in CRC patients (n=46) and healthy volunteers (n=56) were profiled by 454 pyrosequencing of the V3 region of the 16S ribosomal RNA gene. Both principal component analysis and UniFrac analysis showed structural segregation between the two populations. Forty-eight operational taxonomic units (OTUs) were identified by redundancy analysis as key variables significantly associated with the structural difference. One OTU closely related to Bacteroides fragilis was enriched in the gut microbiota of CRC patients, whereas three OTUs related to Bacteroides vulgatus and Bacteroides uniformis were enriched in that of healthy volunteers. A total of 11 OTUs belonging to the genera Enterococcus, Escherichia/Shigella, Klebsiella, Streptococcus and Peptostreptococcus were significantly more abundant in the gut microbiota of CRC patients, and 5 OTUs belonging to the genus Roseburia and other butyrate-producing bacteria of the family Lachnospiraceae were less abundant. Real-time quantitative PCR further validated the significant reduction of butyrate-producing bacteria in the gut microbiota of CRC patients by measuring the copy numbers of butyryl-coenzyme A CoA transferase genes (Mann–Whitney test, P<0.01). Reduction of butyrate producers and increase of opportunistic pathogens may constitute a major structural imbalance of gut microbiota in CRC patients. PMID:21850056

  4. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers

    PubMed Central

    Allen, A P; Hutch, W; Borre, Y E; Kennedy, P J; Temko, A; Boylan, G; Murphy, E; Cryan, J F; Dinan, T G; Clarke, G

    2016-01-01

    The emerging concept of psychobiotics—live microorganisms with a potential mental health benefit—represents a novel approach for the management of stress-related conditions. The majority of studies have focused on animal models. Recent preclinical studies have identified the B. longum 1714 strain as a putative psychobiotic with an impact on stress-related behaviors, physiology and cognitive performance. Whether such preclinical effects could be translated to healthy human volunteers remains unknown. We tested whether psychobiotic consumption could affect the stress response, cognition and brain activity patterns. In a within-participants design, healthy volunteers (N=22) completed cognitive assessments, resting electroencephalography and were exposed to a socially evaluated cold pressor test at baseline, post-placebo and post-psychobiotic. Increases in cortisol output and subjective anxiety in response to the socially evaluated cold pressor test were attenuated. Furthermore, daily reported stress was reduced by psychobiotic consumption. We also observed subtle improvements in hippocampus-dependent visuospatial memory performance, as well as enhanced frontal midline electroencephalographic mobility following psychobiotic consumption. These subtle but clear benefits are in line with the predicted impact from preclinical screening platforms. Our results indicate that consumption of B. longum 1714 is associated with reduced stress and improved memory. Further studies are warranted to evaluate the benefits of this putative psychobiotic in relevant stress-related conditions and to unravel the mechanisms underlying such effects. PMID:27801892

  5. Pharmacokinetics of ivermectin applied topically by whole-body bathing method in healthy volunteers.

    PubMed

    Miyajima, Atsushi; Hirota, Takashi; Tashiro, Mari; Noguchi, Wataru; Kawano, Yayoi; Hanawa, Takehisa; Kigure, Akira; Anata, Taichi; Yamamoto, Yosuke; Yuasa, Nae; Koshino, Machi; Shiraishi, Yumi; Yuzawa, Kaoru; Akagi, Keita; Yoshimasu, Takashi; Makigami, Kuniko; Komoda, Masayo

    2016-10-15

    As a novel administration method of ivermectin (IVM) for scabies treatment, we proposed a "whole-body bathing method (WBBM)". In this method, the patients would bathe themselves in a bathing fluid containing IVM at an effective concentration. Previously, we demonstrated that WBBM could deliver IVM to the skin but not to the plasma in rats. In the present study, to assess the clinical validity of the method an arm bathing examination (first trial) and a whole-body bathing examination (second trial) were conducted in healthy volunteers. In both the first and second trials, after bathing in fluid containing IVM, the exposure in the stratum corneum was higher compared with that after taking IVM p.o. as reported previously. IVM was not detected in plasma at any sampling point after the whole-body bathing in the second trial. Furthermore no serious adverse events were found. These results in both trials suggest that WBBM can deliver IVM to the human stratum corneum without systemic exposure or serious adverse effects in healthy volunteers, and at concentrations that would be adequate for scabies treatment.

  6. Neurobehavioral and Cognitive Changes Induced by Sleep Deprivation in Healthy Volunteers.

    PubMed

    Cassé-Perrot, Catherine; Lanteaume, Laura; Deguil, Julie; Bordet, Régis; Auffret, Alexandra; Otten, Lisa; Blin, Olivier; Bartrés-Faz, David; Micallef, Joëlle

    2016-01-01

    To this day, the pharmacological treatment of Alzheimer's disease remains limited to the temporary stabilisation of cognitive decline and the reduction of neuropsychiatric symptoms. It is moreover with great difficulty to predict and select promising drug candidates in the early stages of the discovery and developmental process. In this context, scientists have developed new experimental paradigms to artificially induce transient cognitive impairments in healthy volunteers akin to those observed in Alzheimer's disease, i.e. the Cognitive Challenge Models. In the last decade, a great amount of literature on Sleep Deprivation was published which mainly focused on the consequences of sleep loss for public health. However, sleep deprivation paradigm may also be regarded as a cognitive challenge model. It is commonly accepted that sleep deprivation induces cognitive impairments related to a global decrease in vigilance, while in fact, there is a controversial approach related to the selective effects on cognitive functions. The identification and validation of cognitive challenge models in healthy volunteers are suitable in early clinical development of drugs to determine the 'hint of efficacy' of drug candidates. The present review aims at exploring in detail the methods, designs and cognitive paradigms used in non pharmacological sleep deprivation studies. Sleep deprivation can be induced by different methods. Probing the four main cognitive functions will allow identifying the extent to which different sleep deprivation designs selectively compromise executive function, working memory, episodic memory and attention. Findings will be discussed in line with cognitive processing levels that are required according to the tasks.

  7. Caffeine and taurine containing energy drink increases left ventricular contractility in healthy volunteers.

    PubMed

    Doerner, Jonas M; Kuetting, Daniel L; Luetkens, Julian A; Naehle, Claas P; Dabir, Darius; Homsi, Rami; Nadal, Jennifer; Schild, Hans H; Thomas, Daniel K

    2015-03-01

    To investigate the impact of a caffeine and taurine containing energy drink (ED) on myocardial contractility in healthy volunteers using cardiac MR and cardiac MR based strain analysis. 32 healthy volunteers (mean age 28 years) were investigated before and 1 h after consumption of a caffeine and taurine containing ED. For assessment of global cardiac functional parameters balanced SSFP-Cine imaging was performed, whereas CSPAMM tagging was used to evaluate global and regional myocardial strain. In addition, ten randomly chosen subjects were investigated once more using a caffeine only protocol to further evaluate the effect of caffeine solely. Heart rate and blood pressure were recorded throughout all studies. ED consumption led to a significant increase in peak systolic strain (PSS) and peak systolic strain rate (PSSR) 1 h after consumption (PSS: w/o ED -22.8 ± 2.1%; w ED -24.3 ± 2.4%, P = <0.0001 and PSSR: w/o ED -1.2 ± 0.1 1/s; w ED -1.3 ± 0.2 1/s, P = 0.0056), which was not observed in the caffeine only group. In contrast, global left ventricular function was unchanged (P = 0.2076). No significant changes of vital parameters and diastolic filling pattern were detected 1 h after ED consumption. Consumption of a caffeine and taurine containing ED results in a subtle, but significant increase of myocardial contractility 1 h after consumption.

  8. Characterizing the Subjective and Psychomotor Effects of Carisoprodol in Healthy Volunteers

    PubMed Central

    Zacny, James P.; Paice, Judith A.; Coalson, Dennis W.

    2011-01-01

    Carisoprodol is a centrally acting drug used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions. There is evidence from different sources that this oral muscle relaxant is abused and that it is associated with impairment leading to arrests for “driving under the influence” as well as increased risk of automobile accidents. Its subjective and psychomotor effects in healthy volunteers at therapeutic and supratherapeutic doses have not been well-characterized, and form the basis of this report. Fifteen healthy volunteers (8 males, 7 females) were administered 0, 350, and 700 mg of carisoprodol in separate sessions and for 6 h afterwards they completed a battery of tests at fixed time intervals so as to assess the subjective and psychomotor effects of the drug. The supratherapeutic dose, 700 mg, increased visual analog scale ratings of terms that were more reflective of sedation (e.g., “sleepy,” “heavy, sluggish feeling”) than those of abuse liability, and produced impaired performance on several psychomotor tests. The therapeutic dose, 350 mg, while producing few and mild subjective effects, still produced psychomotor impairment. The fact that the therapeutic dose of carisoprodol produced minimal subjective effects while adversely affecting performance is of concern in that patients prescribed this drug may feel relatively normal and engage in tasks (driving) that could put themselves and others at risk. PMID:21884720

  9. High-performance liquid chromatographic analysis and pharmacokinetics of terazosin in healthy volunteers.

    PubMed

    Kang, B C; Yang, C Q; Rhee, J E; Suh, O K; Shin, W G

    2001-01-01

    A high-performance liquid chromatographic (HPLC) analysis of terazosin in 1 ml of human plasma was developed using prazosin as an internal standard. The plasma sample was extracted with dichloromethane and ethylether and a 100-microl aliquot was injected onto the reversed-phase column. The mobile phase, 0.02 M sodium phosphate buffer:acetonitrile:tetrahydrofuran = 720:220:60 (v/v/v), was run at a flow rate of 0.8 ml/min and the column effluent was monitored using a florescence detector set at 370 and 250 nm for the emission and excitation wave numbers, respectively. The retention times for terazosin and prazosin were approximately 6.4 and 9.8 min, respectively, and the coefficients of variation of terazosin were generally low, below 6.4%. The present HPLC method was successful for the pharmacokinetic study of terazosin in healthy volunteers. Following oral administration of terazosin, 2 mg, to 20 healthy male volunteers, the area under the plasma concentration-time curve from time zero to time infinity was 421 +/- 71.8 ng h/ml and terminal half-life was 9.83 +/- 1.29 h.

  10. Videomanometric analysis of supraglottic swallow, effortful swallow, and chin tuck in healthy volunteers.

    PubMed

    Bülow, M; Olsson, R; Ekberg, O

    1999-01-01

    Simultaneous videoradiography and solid-state manometry (videomanometry) was applied in eight healthy volunteers (four women, four men; age range 25-64 years, mean age 41 years) without swallowing problems. Three different swallowing techniques were tested; supraglottic swallow, effortful swallow, and chin tuck. Seven videoradiographic variables and six manometric variables were analyzed. The supraglottic swallowing technique did not differ significantly from that of the control swallows. The effortful swallow had a significantly (p = 0.0001) reduced hyoid-mandibular distance preswallow due to an elevation of the hyoid and the larynx, which caused a significantly (p = 0.007) reduced maximal hyoid movement and a significantly (p = 0.009) reduced laryngeal elevation during swallow. The chin tuck swallow had a significantly (p = 0. 001) reduced laryngohyoid distance and also a significantly (p = 0. 004) reduced hyoid-mandibular distance. The chin tuck swallow also displayed significantly (p = 0.003) weaker pharyngeal contractions. Videomanometry allows for analysis of bolus transport, movement of anatomical structures, and measurement of intraluminal pressures. These variables are important when evaluating swallowing techniques. In the present study, we made a few observations that never have been reported before. When healthy volunteers performed supraglottic swallow, they performed the technique somewhat differently. Therefore, we assume dysphagic patients would need a substantial period of training to perform a technique efficiently. Chin tuck could impair protection of the airways in dysphagic patients with weak pharyngeal constrictor muscles.

  11. The silicon content of beer and its bioavailability in healthy volunteers.

    PubMed

    Sripanyakorn, Supannee; Jugdaohsingh, Ravin; Elliott, Hazel; Walker, Caroline; Mehta, Payal; Shoukru, Sera; Thompson, Richard P H; Powell, Jonathan J

    2004-03-01

    Dietary Si, as soluble orthosilicic acid (OSA), may be important for the growth and development of bone and connective tissue. Beer appears to be a major contributor to Si intake, although the Si content of beer and its bioavailability in human subjects have not been well established. Here we investigated the Si content of different beers and then estimated Si absorption from beer in healthy volunteers. The Si content of seventy-six different beers was estimated using inductively coupled plasma optical emission spectrometry and one of the beers, used in the ingestion study, was ultrafiltered to determine OSA content. Next, following the ingestion of 0.6 litres beer (22.5 mg Si; 4.6 % (v/v) ethanol), serum and urinary Si levels were measured in nine healthy volunteers over a 6 h period. A solution of OSA was similarly investigated as a positive control and water and 4.6 % ethanol as negative controls. The mean Si level of beer was 19.2 (sd 6.6) mg/l; the median Si level was 18.0 mg/l. There was no significant difference in the Si levels of the different beers by geographical origin or type of beer. Serum and urinary Si levels increased considerably following the ingestion of beer or a solution of OSA but not with the ingestion of either 4.6 % ethanol or water. The ultrafilterability of Si from beer (about 80 %) and its absorption in volunteers (about 55 %) was comparable with that of a solution of OSA suggesting that Si in beer is present chiefly in a monomeric form and is readily bioavailable.

  12. Molecular characterization of skin microbiota between cancer cachexia patients and healthy volunteers.

    PubMed

    Li, Wei; Han, Lei; Yu, Pengbo; Ma, Chaofeng; Wu, Xiaokang; Moore, John E; Xu, Jiru

    2014-04-01

    Systemic inflammation contributes to both the development of cancer and of cachexia. The microenvironment of bacterial habitats might be changed during the progression of cancer cachexia. The aim of this study was to quantitatively and qualitatively compare the composition of the skin microbiota between cancer cachexia patients and healthy volunteers. Cutaneous bacteria were swabbed at the axillary fossa of 70 cancer cachexia patients and 34 healthy individuals from China. Nested-PCR-denaturing gradient gel electrophoresis (PCR-DGGE) with primers specifically targeting V3 region and quantitative PCR (qPCR) for total bacteria, Corynebacterium spp., Staphylococcus spp., and Staphylococcus epidermidis were performed on all samples. Barcoded 454 pyrosequencing of the V3-V4 regions was performed on 30 randomly selected samples. By comparing diversity and richness indices, we found that the skin microbiome of cachectic cancer patients is less diverse than that of healthy participants, though these differences were not significant. The main microbes that reside on human skin were divided into four phyla: Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes. Staphylococcus spp. and Corynebacterium spp. were the dominant bacteria at the genus level. Significantly fewer Corynebacterium spp. had been observed in cachexia patients compared to healthy subjects. These results suggest that the presence of cancer and cachexia alters human skin bacterial communities. Understanding the changes in microbiota during cancer cachexia may lead to new insights into the syndrome.

  13. Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers.

    PubMed

    Antypa, N; Van der Does, A J W; Smelt, A H M; Rogers, R D

    2009-09-01

    Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation may be beneficial in the treatment of several psychiatric disorders, including depression. A small number of studies have suggested that there may also be cognitive and mood effects in healthy samples. The purpose of the present study was to investigate the effects of n-3 PUFA on depression-relevant cognitive functioning in healthy individuals. Fifty-four healthy university students were randomized to receive either n-3 PUFA supplements or placebo for 4 weeks in a double-blind design. The test battery included measures of cognitive reactivity, attention, response inhibition, facial emotion recognition, memory and risky decision-making. Results showed few effects of n-3 PUFAs on cognition and mood states. The n-3 PUFA group made fewer risk-averse decisions than the placebo group. This difference appeared only in non-normative trials of the decision-making test, and was not accompanied by increased impulsiveness. N-3 PUFAs improved scores on the control/perfectionism scale of the cognitive reactivity measure. No effects were found on the other cognitive tasks and no consistent effects on mood were observed. The present findings indicate that n-3 PUFA supplementation may have a selective effect on risky decision making in healthy volunteers, which is unrelated to impulsiveness.

  14. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers.

    PubMed

    Gota, Vikram S; Maru, Girish B; Soni, Tejal G; Gandhi, Tejal R; Kochar, Nitin; Agarwal, Manish G

    2010-02-24

    Curcumin is the lipid-soluble antioxidant compound obtained from the rhizome of Curcuma longa Linn, also known as turmeric. Curcumin targets multiple chemotherapeutic and inflammatory pathways and has demonstrated safety and tolerability in humans, supporting its potential as a therapeutic agent; however, the clinical literature lacks conclusive evidence supporting its use as a therapeutic agent due to its low bioavailability in humans. The purpose of this study was to quantify plasma levels of free curcumin after dosing of a solid lipid curcumin particle (SLCP) formulation versus unformulated curcumin in healthy volunteers and to determine its tolerability and dose-plasma concentration relationship in late-stage osteosarcoma patients. Doses of 2, 3, and 4 g of SLCP were evaluated in 11 patients with osteosarcoma. Plasma curcumin levels were measured using a validated high-performance liquid chromatography method. The limit of detection of the assay was 1 ng/mL of curcumin. In healthy subjects, the mean peak concentration of curcumin achieved from dosing 650 mg of SLCP was 22.43 ng/mL, whereas plasma curcumin from dosing an equal quantity of unformulated 95% curcuminoids extract was not detected. In both healthy individuals and osteosarcoma patients, high interindividual variability in pharmacokinetics and nonlinear dose dependency was observed, suggesting potentially complex absorption kinetics. Overall, good tolerability was noted in both healthy and osteosarcoma groups.

  15. Noninvasive estimation of tissue edema in healthy volunteers and in patients suffering from heart failure

    NASA Astrophysics Data System (ADS)

    Gurfinkel, Yuri I.; Mikhailov, Valery M.; Kudutkina, Marina I.

    2004-06-01

    Capillaries play a critical role in cardiovascular function as the point of exchange of nutrients and waste products between tissues and circulation. A common problem for healthy volunteers examined during isolation, and for the patients suffering from heart failure is a quantitative estimation tissue oedema. Until now, objective assessment body fluids retention in tissues did not exist. Optical imaging of living capillaries is a challenging and medically important scientific problem. Goal of the investigation was to study dynamic of microcriculation parameters including tissue oedema in healthy volunteers during extended isolation and relative hypokinesia as a model of mission to the International Space Station. The other aim was to study dynamic of microcirculation parameters including tissue oedema in patients suffering from heart failure under treatment. Healthy volunteers and patients. We studied four healthy male subjects at the age of 41, 37, 40, and 48 before the experiment (June 1999), and during the 240-d isolation period starting from July3, 1999. Unique hermetic chambers with artidicial environmental parameters allowed performing this study with maximum similarity to real conditions in the International Space Station (ISS). With the regularity of 3 times a week at the same time, each subject recorded three video episodes with the total length of one-minute using the optical computerized capillaroscope for noninvasive measurement of the capillary diameters sizes, capillary blood velocity as well as the size of the perivascular zone. All this parameters of microcirculation determined during three weeks in 15 patients (10 male, 5 female, aged 62,2+/-8,8) suffering from heart failure under Furosemid 40 mg 2 times a week, as diuretic. Results. About 1500 episodes recorded on laser disks and analyzed during this experiment. Every subject had wave-like variations of capillary blood velocity within the minute, week, and month ranges. It was found that the

  16. Diversity of Duodenal and Rectal Microbiota in Biopsy Tissues and Luminal Contents in Healthy Volunteers.

    PubMed

    Li, Gangping; Yang, Min; Zhou, Kan; Zhang, Lei; Tian, Lugao; Lv, Shangze; Jin, Yu; Qian, Wei; Xiong, Hanhua; Lin, Rong; Fu, Yu; Hou, Xiaohua

    2015-07-01

    The diverse microbial communities that colonize distinct segments of the gastrointestinal tract are intimately related to aspects of physiology and the pathology of human health. However, most recent studies have focused on the rectal or fecal microbiota, and the microbial signature of the duodenum is poorly studied. In this study, we compared the microbiota in duodenal and rectal samples to illustrate the characteristic microbial signatures of the duodenum in healthy adults. Nine healthy volunteers donated biopsies and luminal contents from the duodenum and rectum. To determine the composition and diversity of the microbiota, 454- pyrosequencing of bacterial 16S rRNA was performed and multiple bioinformatics analyses were applied. The α-diversity and phylogenetic diversity of the microbiota in the duodenal samples were higher than those of the rectal samples. There was higher biodiversity among the microbiota isolated from rectal biopsies than feces. Proteobacteria were more highly represented in the duodenum than in the rectum, both in the biopsies and in the luminal contents from the healthy volunteers (38.7% versus 12.5%, 33.2% versus 5.0%, respectively). Acinetobacter and Prevotella were dominant in the duodenum, whereas Bacteroides and Prevotella were dominant in the rectum. Additionally, the percentage of OTUs shared in biopsy groups was far higher than in the luminal group (43.0% versus 26.8%) and a greater number of genera was shared among the biopsies than the luminal contents. Duodenal samples demonstrated greater biological diversity and possessed a unique microbial signature compared with the rectum. The mucosa-associated microbiota was more relatively conserved than luminal samples.

  17. Changing Geomagnetic Field and Heart Rates Variability in Healthy Volunteers: A Pilot Study

    NASA Astrophysics Data System (ADS)

    Jordanova, Malina; Zenchenko, Tatiana; Poskotinova, Lilia; Medvedeva, Anna; Uzunov, Todor; Alenikova, Alexandra

    Space Climate is an interdisciplinary science that deals with the long-term change in the Sun, and its effects in the near-Earth environment, including possible effects on human health. This paper will present the first results from simultaneous experiments performed at 3 different locations - Sofia, Bulgaria 42° 40' N 23° 20' E; Moscow, Russia 55° 45' N 37° 36‘ E and Arkhangelsk, Russia 64° 34' N / 40° 32' E. Subjects are 5 healthy volunteers, women, mean age 39,4 years. The experiments are part of the project “Heliobiology” (2011 - 2015) that reflects the intense interest towards the influence of solar activity and meteorology on the human health. The aim of the experiments is to study the degree of conjugation of the heart rate variability and the variations of the geomagnetic field. To minimize the experimental bias one and the same hard- and software were applied during the testing. ECG signals were recorder via "KARDI-2", the software package is "Ecosan-2007", both developed by "Medical Computer Systems", Zelenograd, Russia. The duration of the observations ranged from 60 to 120 minutes. A comparison of the dynamics of the minute variations of the heart rate with the horizontal components of the geomagnetic field vector revealed a synchronization of some of the research parameters as well as specific individual differences. Despite of the small sample size (5 subjects per 8 measures), in over 70% of the experimental data a similar patterns of variation of geophysical and heart rate variability were recorded. The experiments discussed involved healthy volunteers, i.e. people that have good adaptation reserves, and the response to variation of geomagnetic field will not push them beyond the physiological norms. The observed effect of synchronization of heart rate fluctuations of healthy subjects with fluctuations of geomagnetic field may give an effective tool to address further one especially interesting problems - the mechanism of geomagnetic

  18. Evaluation of Trigeminal Sensitivity to Ammonia in Asthmatics and Healthy Human Volunteers

    PubMed Central

    Petrova, Maja; Diamond, Jeanmarie; Schuster, Benno; Dalton, Pamela

    2009-01-01

    Background Asthmatics often report the triggering or exacerbation of respiratory symptoms following exposure to airborne irritants, which in some cases may result from stimulation of irritant receptors in the upper airways inducing reflexive broncho-constriction. Ammonia (NH3) is a common constituent of commercially available household products, and in high concentration has the potential to elicit sensory irritation in the eyes and upper respiratory tract of humans. The goal of the present study was to evaluate the irritation potential of ammonia in asthmatics and healthy volunteers and to determine whether differences in nasal or ocular irritant sensitivity to ammonia between these two groups could account for the exacerbation of symptoms reported by asthmatics following exposure to an irritant. Methods 25 healthy and 15 mild/moderate persistent asthmatic volunteers, with reported sensitivity to household cleaning products, were evaluated for their sensitivity to the ocular and nasal irritancy of NH3. Lung function was evaluated at baseline and multiple time points following exposure. Results Irritation thresholds did not differ between asthmatics and healthy controls, nor did ratings of odor intensity, annoyance and irritancy following exposure to NH3 concentrations at and above the irritant threshold for longer periods of time (30 sec).Importantly, no changes in lung function occurred following exposure to NH3 for any individuals in either group. Conclusion Despite heightened symptom reports to environmental irritants among asthmatics, the ocular and nasal trigeminal system of mild-moderate asthmatics does not appear to be more sensitive or more reactive than that of non-asthmatics, nor does short duration exposure to ammonia at irritant levels induce changes in lung function. At least in brief exposures, the basis for some asthmatics to experience adverse responses to volatile compounds in everyday life may arise from factors other than trigeminally

  19. Gastric Re-acidification with Betaine HCl in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria

    PubMed Central

    Yago, Marc Anthony R.; Frymoyer, Adam R.; Smelick, Gillian S.; Frassetto, Lynda A.; Budha, Nageshwar R.; Dresser, Mark J.; Ware, Joseph A.; Benet, Leslie Z.

    2013-01-01

    Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric re-acidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically-induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 minutes, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 hours. Betaine HCl significantly lowered gastric pH by 4.5 (±0.5) units from 5.2 (±0.5) to 0.6 (±0.2) (P <0.001) during the 30 minute interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (±4.3) minutes. The re-acidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (±33) and 77 (±30) minutes, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically-induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions. PMID:23980906

  20. Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria.

    PubMed

    Yago, Marc R; Frymoyer, Adam R; Smelick, Gillian S; Frassetto, Lynda A; Budha, Nageshwar R; Dresser, Mark J; Ware, Joseph A; Benet, Leslie Z

    2013-11-04

    Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (± 0.5) units from 5.2 (± 0.5) to 0.6 (± 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (± 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (± 33) and 77 (± 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions.

  1. Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers

    PubMed Central

    Xin, Hua-Wen; Wu, Xiao-Chun; Li, Qing; Yu, Ai-Rong; Zhu, Min; Shen, Yang; Su, Dan; Xiong, Lei

    2007-01-01

    What is already known about this subject Schisandra sphenanthera extract (SchE) and tacrolimus are often co-administrated in treating renal and liver transplant recipients in China. We discovered occasionally that blood tacrolimus concentrations are markedly increased in some patients who receive tacrolimus and concomitant SchE. This is the first study to investigate the effects of SchE on the pharmacokinetics of tacrolimus. What this study adds Following administration of SchE in healthy volunteers, the mean AUC, AUMC and Cmax of tacrolimus substantially increases, whereas its CL/F and V/F decreases significantly. Blood tacrolimus concentrations need to be closely monitored and dose adjustments of tacrolimus have to be made accordingly in the presence of SchE. Aim To assess the effect of Schisandra sphenanthera extract (SchE) on the pharmacokinetics of tacrolimus in healthy volunteers. Methods Twelve healthy male volunteers were orally treated with SchE, three capsules twice daily for 13 days. Pharmacokinetic investigations of oral tacrolimus administration at 2 mg were performed both before and at the end of the SchE treatment period. Whole blood tacrolimus concentrations were determined by enzyme-linked immunosorbent assay. Estimated pharmacokinetic parameters before and with SchE were calculated with noncompartmental techniques. Results Following administration of SchE, the average percentage increases of individual increases in AUC, AUMC and Cmax of tacrolimus were 164.2% [95% confidence interval (CI) 70.1, 258.4], 133.1% (95% CI 49.5, 261.3) and 227.1% (95% CI 155.8, 298.4), respectively (P< 0.01 or 0.05). On average, there was a 36.8% (95% CI 13.4, 60.2) increase in tacrolimus tmax (P< 0.01). The average percentage decreases in CL/F and V/F were 49.0% (95% CI 31.1, 66.9) and 53.7% (95% CI 40.1, 67.4), respectively (P< 0.01). Conclusions SchE can increase the oral bioavailability of tacrolimus. The results of this study will add important information to the

  2. Increase in body mass index from normal weight to overweight in a cross-sectional sample of healthy research volunteers.

    PubMed

    Courville, Amber B; DiVito, Meagan; Moyer, Lindsay; Rossinoff, Anna; Royster, Caitlin; Psota, Tricia; Ayres, Elaine; Zambell, Kirsten L

    2014-12-01

    Current literature provides limited information about healthy volunteers serving as controls for biomedical research. This study describes trends in body mass index (BMI), a ratio of weight to height (kilograms per square meter), of the population of healthy volunteers at the National Institutes of Health Clinical Center (NIH CC) and compares these trends to a nationally representative sample, as reported by the National Health and Nutrition Examination Survey. We hypothesized that BMI trends at the NIH CC would follow those of the US population. This cross-sectional study examined the BMI of healthy volunteers at the NIH CC from 1976 to 1980, 1981 to 1987, 1988 to 1994, 1995 to 1998 and for all subsequent two-year periods onward until 2012. Study data were extracted from the NIH Biomedical Translational Research Information System. Subjects were selected based on a discharge code of "volunteer." Descriptive statistics of volunteers at the NIH CC were calculated for height, weight, age-adjusted BMI, age, and sex, and associations between categorical variables were analyzed using the χ2 test. Differences between BMI categories or periods for continuous independent variables were assessed using Kruskal-Wallis and post hoc Tamhane T2 tests. The 13 898 healthy volunteers with median age of 34 years were 53% female and primarily non-Hispanic whites. Mean BMI was within the normal category from 1976 to 1987. From 1988 on, mean BMI fluctuated but increased overall. The BMI of healthy volunteers at the NIH CC appears to follow national trends as described by National Health and Nutrition Examination Survey data of increasing body weight during the past three decades followed by a recent plateau.

  3. Effect of food on the pharmacokinetics of dronabinol oral solution versus dronabinol capsules in healthy volunteers

    PubMed Central

    Oh, D Alexander; Parikh, Neha; Khurana, Varun; Cognata Smith, Christina; Vetticaden, Santosh

    2017-01-01

    Dronabinol is a pharmaceutical tetrahydrocannabinol originally developed as an oral capsule. A dronabinol oral solution was recently approved, and the effects of food on absorption and bioavailability of the oral solution versus capsules were compared in an open-label, single-dose, 3-period crossover study. Healthy volunteers were randomized to either dronabinol oral solution 4.25 mg (fed) or dronabinol capsule 5 mg (fed or fasted). Dosing was separated by a 7-day washout period. Plasma pharmacokinetics were evaluated for dronabinol and its major metabolite, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-Δ9-THC). Pharmacokinetic data were available for analysis in 54 volunteers. In the fed state, initial dronabinol absorption was faster with oral solution versus capsule (mean time to the first measurable concentration, 0.15 vs 2.02 hours, respectively), with 100% and 15% of volunteers, respectively, having detectable plasma dronabinol levels 30 minutes postdose. There was less interindividual variability in plasma dronabinol concentration during early absorption with oral solution versus capsule. Compared with the fasted state, mean area under the plasma concentration–time curve from time zero to the last measurable concentration (AUC0−t) increased by 2.1- and 2.4-fold for dronabinol oral solution and capsule, respectively, when taken with food. Mean time to maximum plasma concentration was similarly delayed for dronabinol oral solution with food (7.7 hours) and capsule with food (5.6 hours) versus capsule with fasting (1.7 hours). Under fed conditions, AUC0−t and area under the plasma concentration–time curve from time zero to infinity were similar for the oral solution versus capsule based on 11-OH-Δ9-THC levels. An appreciable food effect was observed for dronabinol oral solution and capsules. Dronabinol oral solution may offer therapeutic benefit to patients, given its rapid and lower interindividual absorption variability versus dronabinol capsule

  4. Effect of food on the pharmacokinetics of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

    PubMed

    Oh, D Alexander; Parikh, Neha; Khurana, Varun; Cognata Smith, Christina; Vetticaden, Santosh

    2017-01-01

    Dronabinol is a pharmaceutical tetrahydrocannabinol originally developed as an oral capsule. A dronabinol oral solution was recently approved, and the effects of food on absorption and bioavailability of the oral solution versus capsules were compared in an open-label, single-dose, 3-period crossover study. Healthy volunteers were randomized to either dronabinol oral solution 4.25 mg (fed) or dronabinol capsule 5 mg (fed or fasted). Dosing was separated by a 7-day washout period. Plasma pharmacokinetics were evaluated for dronabinol and its major metabolite, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-Δ9-THC). Pharmacokinetic data were available for analysis in 54 volunteers. In the fed state, initial dronabinol absorption was faster with oral solution versus capsule (mean time to the first measurable concentration, 0.15 vs 2.02 hours, respectively), with 100% and 15% of volunteers, respectively, having detectable plasma dronabinol levels 30 minutes postdose. There was less interindividual variability in plasma dronabinol concentration during early absorption with oral solution versus capsule. Compared with the fasted state, mean area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t ) increased by 2.1- and 2.4-fold for dronabinol oral solution and capsule, respectively, when taken with food. Mean time to maximum plasma concentration was similarly delayed for dronabinol oral solution with food (7.7 hours) and capsule with food (5.6 hours) versus capsule with fasting (1.7 hours). Under fed conditions, AUC0-t and area under the plasma concentration-time curve from time zero to infinity were similar for the oral solution versus capsule based on 11-OH-Δ9-THC levels. An appreciable food effect was observed for dronabinol oral solution and capsules. Dronabinol oral solution may offer therapeutic benefit to patients, given its rapid and lower interindividual absorption variability versus dronabinol capsule.

  5. Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

    PubMed Central

    Teng, Renli; Butler, Kathleen

    2013-01-01

    Objectives Two open-label, two-period, crossover studies in healthy volunteers were designed to determine the pharmacokinetic interactions between ticagrelor, a P2Y12 receptor antagonist, and a moderate (diltiazem) and a strong (ketoconazole) cytochrome P450 (CYP) 3A inhibitor. Methods Seventeen volunteers received diltiazem (240 mg once daily) for 14 days. In the second study, ketoconazole (n = 14) 200 mg twice daily was given for 10 days. A single oral 90-mg ticagrelor dose was administered on day 8 (diltiazem) or day 4 (ketoconazole). In each study, volunteers received a single 90-mg oral dose of ticagrelor before or after washout (≥14 days). Pharmacokinetic parameters for ticagrelor, AR-C124910XX (primary metabolite), diltiazem, and ketoconazole were assessed. Results Compared with ticagrelor alone, diltiazem co-administration significantly increased the mean maximum concentration (Cmax) and mean area under the plasma concentration–time curve (AUC) for ticagrelor by 69% and 174%, respectively. Diltiazem co-administration reduced Cmax by 38% but had no significant effect on AUC for AR-C124910XX. Cmax and AUC for ticagrelor were increased by 135% and 632%, respectively, by ketoconazole co-administration, whereas these parameters were reduced by 89% and 56%, respectively, for AR-C124910XX. Diltiazem and ketoconazole pharmacokinetic parameters were not significantly affected by the presence of ticagrelor. Conclusions These results suggest that ticagrelor can be co-administered with moderate CYP3A inhibitors. However, co-administration of strong CYP3A inhibitors with ticagrelor is not recommended. PMID:27536435

  6. Impact of Surotomycin on the Gut Microbiota of Healthy Volunteers in a Phase 1 Clinical Trial

    PubMed Central

    Tyrrell, Kerin L.; Dale, Suzanne E.; Chesnel, Laurent; Goldstein, Ellie J. C.

    2016-01-01

    Clostridium difficile-associated diarrhea has been associated with disruption of the normal intestinal microbiota, particularly the Bacteroides fragilis group and Prevotella species. Surotomycin is a bactericidal cyclic lipopeptide in development for treatment of Clostridium difficile-associated diarrhea that has selective and potent activity against C. difficile and other Gram-positive bacteria and a minimal impact on intestinal Gram-negative organisms. The impacts of ascending doses of surotomycin on major organism groups in the gut microbiota of healthy volunteers were evaluated during a randomized, double-blind, placebo-controlled, multiple-dose phase 1 study. Thirty volunteers were randomized into 3 cohorts, using a 4:1 ratio, to receive 250 mg, 500 mg, or 1,000 mg of surotomycin, or placebo, twice daily for 14 days. Stool samples collected at baseline (days 0 and 1) and at the end of treatment (days 13 to 15) were cultured quantitatively. The B. fragilis group, the Bacteroides/Prevotella group, and Enterobacteriaceae were also quantified by quantitative real-time PCR. Baseline and end-of-treatment stool samples showed 1- to 2-log10 CFU/g reductions in total bacterial counts for most volunteers. Various decreases in clostridial, Lactobacillus-Bifidobacterium group, and enterococcus-streptococcus group counts occurred while patients were receiving surotomycin, whereas the enterobacteria and the B. fragilis group persisted at the end of treatment. There was no change in enterococcus MICs of surotomycin, nor was vancomycin-resistant Enterococcus detected after exposure. Surotomycin at doses of up to 1,000 mg twice daily had only modest disruptive effects on the gut microbiota. The potential sparing of the gut microbiota by surotomycin may decrease the risk of disease recurrence. PMID:26787687

  7. Disposition kinetics of selenium in healthy volunteers following therapeutic shampoo treatment.

    PubMed

    Noisel, Nolwenn; Bouchard, Michèle; Carrier, Gaétan

    2010-05-01

    This study was aimed at documenting the kinetic time courses of selenium (Se) in accessible biological matrices of volunteers following controlled applications of therapeutic shampoo containing Se, to better elucidate the mechanisms by which shampoo-Se accumulates in hair and hence estimate the contribution of this source to total Se body burden. Ten healthy volunteers were exposed to Se-shampoo three times a week over a month. Blood, hair and toenail concentrations along with daily urinary excretions were repeatedly measured over an 18-month period following the onset of application. Over the entire study period, blood concentrations of Se (range: 127-233μg/l) and daily urinary excretions (range: 11.9-150μg/d) remained within baseline range of the general population. Conversely, during shampoo application, mean Se concentrations in hair reached transitional levels of 89μg/g while, following cessation of treatment, a mono-exponential decrease was observed with a mean half-life of 4.5 weeks. Two of the volunteers also exhibited an increase in toenail concentrations of Se during the study period. Results show that Se-shampoo does not contribute significantly to total Se body burden, as assessed from blood and urine levels. Differences observed between blood and urine time courses as compared to hair profiles and the presence of Se on hair grown before treatment indicates an adsorption on hair; however, the gradual decrease in Se concentrations in successive centimeters of hair grown following the application period suggests a concomitant absorption from the scalp during treatment with subsequent excretion in hair.

  8. Evaluation of the antimuscarinic activity of atropine, terfenadine and mequitazine in healthy volunteers.

    PubMed Central

    Brion, N; Beaumont, D; Advenier, C

    1988-01-01

    1 The anticholinergic effects of atropine and two antihistamines (terfenadine and mequitazine) were investigated vs placebo in a double-blind study. 2 Salivary secretion, basal pupil diameter, pilocarpine (0.25%) induced miosis and heart rate were determined in eight healthy volunteers, seven male and one female, aged between 23 and 35 years. Each volunteer received all four separate courses of treatment: i.e. terfenadine 60 mg or mequitazine 5 mg twice daily for 3 days, and one single dose on the day of the trial; for the placebo or atropine courses they received the placebo twice daily during 3 days and, on the morning of test day, either the placebo again or atropine 1 mg. Pupillary diameter was measured under standardized conditions using a pupil gauge (Smith and Nephew Pharmaceuticals Ltd). 3 Atropine significantly reduced salivary output (-2.25 +/- 0.36 ml from control values of 4.17 +/- 0.42 ml, P less than 0.001) and heart rate (-9.7 +/- 3.7 beats min-1 from 77.5 +/- 2.7, P less than 0.05). These maximal effects were observed 3 h after atropine dosing for salivary secretion and 1 h for heart rate. Atropine did not affect basal pupil diameter or pilocarpine-induced miosis. 4 Mequitazine and terfenadine did not affect salivary flow, heart rate or pilocarpine-induced miosis. 5 Terfenadine and mequitazine had no anticholinergic effect in these tests involving a limited number of subjects. PMID:3130890

  9. Piroxicam immediate release formulations: A fasting randomized open-label crossover bioequivalence study in healthy volunteers.

    PubMed

    Helmy, Sally A; El-Bedaiwy, Heba M

    2014-11-01

    Piroxicam is a NSAID with analgesic and antipyretic properties, used for the treatment of rheumatoid diseases. The aim of this study was to evaluate the bioequivalence of two brands of piroxicam capsules (20 mg) in 24 Egyptian volunteers. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, 2-period, 2-sequence, crossover study with a washout period of 3 weeks. Under fasting conditions, 24 healthy male volunteers were randomly selected to receive a single oral dose of one capsule (20 mg) of either test or reference product. Plasma samples were obtained over a 144-hour interval and analyzed for piroxicam by HPLC with UV detection. The pharmacokinetic parameters Cmax , tmax , AUC0-t , AUC0-∞ , Vd /F, Cl/F, and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUC0-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two piroxicam formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 20-mg piroxicam and both formulations were well-tolerated.

  10. Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

    PubMed Central

    Staahl, Camilla; Olesen, Anne Estrup; Andresen, Trine; Arendt-Nielsen, Lars; Drewes, Asbjørn Mohr

    2009-01-01

    AIM Experimental pain models may help to evaluate the mechanisms of action of analgesics and target the clinical indications for their use. This review addresses how the efficacy of opioids can be assessed in human volunteers using experimental pain models. The drawback with the different study designs is also discussed. METHOD A literature search was completed for randomized controlled studies which included human experimental pain models, healthy volunteers and opioids. RESULTS Opioids with a strong affinity for the µ-opioid receptor decreased the sensation in a variety of experimental pain modalities, but strong tonic pain was attenuated more than short lasting pain and non-painful sensations. The effects of opioids with weaker affinity for the µ-opioid receptor were detected by a more narrow range of pain models, and the assessment methods needed to be more sensitive. CONCLUSION The way the pain is induced, assessed and summarized is very important for the sensitivity of the pain models. This review gives an overview of how different opioids perform in experimental pain models. Generally experimental pain models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. This knowledge can aid the decisions needed to be taken when designing experimental pain studies for compounds entering phase 1 clinical trials. PMID:19694733

  11. The effect of titrated fentanyl on suppressed cough reflex in healthy adult volunteers.

    PubMed

    Kelly, H E; Shaw, G M; Brett, C N; Greenwood, F M; Huckabee, M L

    2016-05-01

    Cough suppression is part of the pharmacodynamic profile of opioids. We investigated the impact of clinical doses of fentanyl on suppressing the cough reflex. Thirteen volunteers received 2 μg.kg(-1) of fentanyl in a divided administration protocol. Three minutes after each administration and at 10 min intervals during washout, suppressed cough reflex testing with nebulised citric acid was performed and compared with fentanyl effect-site concentration. Mean (SD) citric acid concentration provoking cough increased from 0.5 (0.28) mol.l(-1) at baseline to 1.2 (0.50) mol.l(-1) after 2 μg.kg(-1) of fentanyl (p = 0.01). Mean (SD) fentanyl effect-site concentration after the final dose of fentanyl was 1.89 (0.05) ng.ml(-1) . A strong positive correlation was found between suppressed cough reflex thresholds and fentanyl effect-site concentrations during both fentanyl administration and washout phases of the study (r(2) = 0.79, p = 0.01). The mean (SD) length of time for return of suppressed cough response was 44.6 (18.8) min. Clinically relevant doses of fentanyl produced cough reflex suppression in healthy volunteers.

  12. No pharmacokinetic interaction between lacosamide and valproic acid in healthy volunteers.

    PubMed

    Cawello, Willi; Bonn, Rainer

    2012-11-01

    Two open-label, randomized, multiple-dose clinical studies evaluated the potential for pharmacokinetic interaction between the antiepileptic drugs lacosamide and valproic acid. The influence of lacosamide on valproic acid pharmacokinetics (trial A) and valproic acid on lacosamide pharmacokinetics (trial B) was investigated in 32 healthy male volunteers, 16 in each trial. Volunteers in trial A received valproic acid (300 mg bid) with randomization to either early or late addition of lacosamide (200 mg bid). Those in trial B received lacosamide (200 mg bid) with randomization to either early or late addition of valproic acid (300 mg bid). Area under the concentration-time curve during a 12-hour dosing interval at steady state (AUC(τ,ss)) and maximum steady-state plasma drug concentration (C(max,ss)) were measured for each drug alone and together and tested for equivalence. The point estimates (90% confidence intervals) for AUC(τ,ss) and C(max,ss) were 104% (99%-109%) and 101% (97%-107%), respectively, for valproic acid and 100% (98%-103%) and 101% (96%-107%), respectively, for lacosamide, which were within the generally accepted equivalence range of 80% to 125%. No changes in the rate or extent of absorption, terminal half-life, or time to maximum concentration were observed. These results suggest that lacosamide and valproic acid have no relevant pharmacokinetic drug-drug interaction.

  13. Bioequivalence study of 2 orodispersible formulations of zolmitriptan 5 mg in healthy volunteers.

    PubMed

    Cánovas, M; Canals, M; Polonio, F; Cabré, F

    2012-10-01

    A bioequivalence study of 2 zolmitriptan (CAS 139264-17-8) orodispersible tablet formulations was carried out in 26 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Plasma concentrations of zolmitriptan and its active metabolite (N-desmethyl-zolmitriptan) were obtained by LC/MS/MS method. Log-transformed AUCs and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80-125%. According to the European Guideline 1 it may be therefore concluded that test formulation of zolmitriptan 5 mg orodispersible tablet is bioequivalent to the reference formulation.

  14. Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers.

    PubMed

    Sandouk, P; Bouvier d'Yvoire, M; Chretien, P; Tillement, J P; Scherrmann, J M

    1994-01-01

    A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half-life (t1/2 beta) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and Cmax, as well as a slightly shorter Tmax, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters Cmax, Tmax, and AUC, suggesting that the Coltramyl tablets have an adequate in vivo dissolution profile.

  15. Effect of an acidic beverage (Coca-Cola) on the pharmacokinetics of carbamazepine in healthy volunteers.

    PubMed

    Malhotra, S; Dixit, R K; Garg, S K

    2002-01-01

    The effect of an acidic beverage (Coca-Cola) on the pharmacokinetics of a single dose of carbamazepine was studied. In a two-way cross-over design with a 1 week washout period, 10 healthy volunteers were randomized to received 200 mg carbamazepine orally with 300 ml of Coca-Cola or water. Blood samples were collected at 0, 0.5, 1, 2, 3, 6, 9, 12, 24, 48 and 72 h after drug administration. Plasma carbamazepine levels were higher with Coca-Cola as compared to water. The AUC0-infinity and Cmax of carbamazepine were significantly enhanced after Coca-Cola while tmax was achieved earlier with Coca-Cola. The results of the study indicate that concomitant administration of Coca-Cola enhances the rate and extent of absorption of carbamazepine.

  16. A comparison of the cardiovascular effects and subjective tolerability of binedaline and amitriptylene in healthy volunteers.

    PubMed

    Joubert, P H; Starke, D D; Van Reenen, O; Venter, C P

    1985-01-01

    Binedaline is a new antidepressant drug which is not a tricyclic compound. In animal investigations it showed a greater therapeutic index than imipramine and amitriptylene and a smaller ED50. It also showed less anticholinergic and antihistaminic activity. In this study the effects of 100 mg (females) and 150 mg (males) of binedaline was compared with 50 mg and 75 mg of amitriptylene and placebo in healthy volunteers. Binedaline was better tolerated than amitriptylene and produced less sedation and fewer instances of dry mouth. Binedaline was devoid of the marked postural hypotension produced by amitriptylene but caused the same degree of tachycardia as amitriptylene at rest, when subjects were tilted and when subjected to ergometry. It was concluded that binedaline causes less alpha-adrenergic blockade than amitriptylene but that the sympathomimetic effects were similar. At the doses employed no major changes in electrocardiogram or systolic time intervals occurred.

  17. Cassava Flour Substitution Modulates Glycemic Responses and Glycemic Index of Wheat Breads in Apparent Healthy Volunteers.

    PubMed

    Okafor, Ebelechukwu N; Erukainure, Ochuko L; Ozumba, Augusta U; Adewale, Chris O; Kayode, Funmi O; Asieba, Godfrey O; Adesegha, Olubukola I; Elemo, Gloria N

    2017-07-04

    Different carbohydrate foods produce different glycemic responses even with little or no difference in macronutrient composition. Cassava constitutes one of the major staples in Nigeria. Four blends of cassava-wheat bread samples with 0, 10, 15, and 20% cassava flour inclusion were fed individually to groups of healthy human volunteers. Subjects were studied on separate occasions in the morning after a 10-12-hr overnight fast. Blood glucose responses were measured at intervals of 30 min over a period of 2 hr. Glucose was used as a reference food. There were normal glucose responses to the bread samples studied. Increase in cassava incorporation led to less significant glycemic responses. The glycemic index values ranged from 91-94. Results from this study indicate that the inclusion of cassava flour in bread production might not pose a threat to blood glucose response of individuals.

  18. Single and multiple dose pharmacokinetics and tolerability of HX-1171, a novel antioxidant, in healthy volunteers

    PubMed Central

    Kim, Yo Han; Choi, Hee Youn; Lee, Shi Hyang; Lim, Hyeong-Seok; Miki, Tokutaro; Kang, Jong-Koo; Han, Kyoung-Goo; Bae, Kyun-Seop

    2015-01-01

    Background HX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a promising antioxidant with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the tolerability and pharmacokinetics of HX-1171 in healthy volunteers. Methods A randomized, single-blind, placebo-controlled, dose escalation study was conducted in 83 subjects. In the single ascending dose study, 20, 40, 80, 160, 300, 600, 1,200, 1,500 or 2,000 mg of HX-1171 was administered to 67 subjects. In the multiple ascending dose study, 500 or 1,000 mg was administered to 16 subjects for 14 days. The plasma and urine concentrations of HX-1171 were determined by using a validated liquid chromatography-mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. Results Adverse events reported in the study were all mild in intensity and resolved without any sequelae. HX-1171 was rapidly and minimally absorbed with a median time at maximal concentration of 0.63–1.50 hours and slowly eliminated with a terminal half-life of 21.12–40.96 hours. Accumulation index ranged from 2.0 to 2.2 after repeated dosing for 14 days. For both the single and multiple doses administrations, urinary concentrations indicated that less than 0.01% of the HX-1171 administered was excreted in urine. Conclusion HX-1171 was well tolerated and minimally absorbed in healthy volunteers. The pharmacokinetic profile of HX-1171 was consistent with once-a-day dosing. PMID:25848210

  19. Effect of Resveratrol Treatment on the Pharmacokinetics of Diclofenac in Healthy Human Volunteers.

    PubMed

    Bedada, Satish Kumar; Yellu, Narsimha Reddy; Neerati, Prasad

    2016-03-01

    The purpose of the present study was to assess the effect of resveratrol (RSV) treatment on the pharmacokinetics of diclofenac (DIC) in healthy human volunteers. The open-label, two period, sequential study was conducted in 12 healthy human volunteers. A single dose of RSV 500 mg was administered daily for 10 days during treatment phase. A single dose of DIC 100 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after DIC dosing and analyzed by HPLC. Treatment with RSV significantly enhanced maximum plasma concentration (Cmax) (1.73 to 2.91 µg/mL), area under the curve (AUC) (5.05 to 9.95 g h/mL), half life (T1/2) (1.12 to 1.76 h) and significantly decreased elimination rate constant (Kel ) (0.71 to 0.41 h(-1)), apparent oral clearance (CL/F) (14.58 to 6.48 L/h) of DIC as compared to control. The geometric mean ratios for Cmax, AUC, T1/2, Kel and CL/F of DIC were 1.75, 2.12, 1.65, 0.61 and 0.47, respectively were outside the limits of 0.8-1.25, which indicates clinically significant interaction between DIC and RSV. The results suggest that the altered pharmacokinetics of DIC might be attributed to RSV mediated inhibition of CYP2C9 enzyme. Therefore, combination therapy of DIC along with RSV may represent a novel approach to reduce dosage and results in reduced gastrointestinal side effects of DIC.

  20. Virtual Reality-Guided Motor Imagery Increases Corticomotor Excitability in Healthy Volunteers and Stroke Patients

    PubMed Central

    2016-01-01

    Objective To investigate the effects of using motor imagery (MI) in combination with a virtual reality (VR) program on healthy volunteers and stroke patients. In addition, this study investigated whether task variability within the VR-guided MI programs would influence corticomotor excitability. Methods The present study included 15 stroke patients and 15 healthy right-handed volunteers who were presented with four different conditions in a random order: rest, MI alone, VR-guided MI, and VR-guided MI with task variability. The corticomotor excitability of each participant was assessed before, during, and after each condition by measuring changes in the various parameters of motor-evoked potentials (MEPs) of the extensor carpi radials (ECR). Changes in intracortical inhibition (ICI) and intracortical facilitation (ICF) were calculated after each condition as percentages of inhibition (%INH) and facilitation (%FAC) at rest. Results In both groups, the increases in MEP amplitudes were greater during the two VR-guided MI conditions than during MI alone. Additionally, the reductions in ECR %INH in both groups were greater under the condition involving VR-guided MI with task variability than under that involving VR-guided MI with regular interval. Conclusion The corticomotor excitability elicited by MI using a VR avatar representation was greater than that elicited by MI with real body observations. Furthermore, the use of task variability in a VR program may enhance neural regeneration after stroke by reducing ICI. The present findings support the use of various VR programs as well as the concept of combining MI with VR programs for neurorehabilitation. PMID:27446778

  1. Alteration of the Disposition of Quinine in Healthy Volunteers After Concurrent Ciprofloxacin Administration.

    PubMed

    Adegbola, Adebanjo J; Soyinka, Julius O; Adeagbo, Babatunde A; Igbinoba, Sharon I; Nathaniel, Thomas I

    2016-01-01

    This study evaluated the effects of concurrent ciprofloxacin administration on the disposition of quinine in healthy volunteers. Quinine (600-mg single dose) was administered either alone or with the 11th dose of ciprofloxacin (500 mg every 12 hours for 7 days) to 15 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analyzed for quinine and its major metabolite, 3-hydroxquinine, using a validated high-performance liquid chromatographic method. Administration of quinine plus ciprofloxacin resulted in significant increases (P < 0.05) in the total area under the concentration-time curve, maximum plasma concentration (Cmax), and terminal elimination half-life (T1/2b) of quinine compared with values with quinine dosing alone (AUC: 27.93 ± 8.04 vs. 41.62 ± 13.98 h·mg/L; Cmax: 1.37 ± 0.24 vs. 1.64 ± 0.38 mg/L; T1/2b: 16.28 ± 2.66 vs. 21.43 ± 3.22 hours), whereas the oral plasma clearance markedly decreased (23.17 ± 6.49 vs. 16.00 ± 5.27 L/h). In the presence of ciprofloxacin, there was a pronounced decrease in the ratio of AUC (metabolite)/AUC (unchanged drug) and highly significant decreases in Cmax and AUC of the metabolite (P < 0.05). Ciprofloxacin may increase the adverse effects of concomitantly administered quinine, which can have serious consequences on the patient. Thus, a downward dosage adjustment of quinine seems to be necessary when concurrently administered with ciprofloxacin.

  2. The effect of the water-drinking test on aqueous humor dynamics in healthy volunteers.

    PubMed

    Diestelhorst, M; Krieglstein, G K

    1994-03-01

    In 19 healthy volunteers (9 men, 10 women) we studied the effect of drinking 1000 ml of water within 10 min on aqueous humor dynamics. Fluorescein was applied topically five times, 6 h before measurements. All readings were taken during the afternoon. The Wilcox-on signed-rank test was used to evaluate the statistical relevance of the data. Aqueous humor flow was measured 60 min before (F1) and 10 min (F2), 30 min (F3), 60 min (F4) and 90 min (F5) after drinking 11 of water. Flow (mean +/- SD) changed as follows: F1, 2.25 +/- 1.2 microliters/min; F2, -3.29 +/- 3.4 microliters/min (P < 0.0000); F3, 1.69 +/- 1.0 microliters/min (P = 0.007); F4, 2.39 +/- 0.9 microliters/min (P = 0.25); F5, 2.64 +/- 0.9 microliters/min (P = 0.02). Three to four days later the identical procedure was performed in each individual: F1, 2.06 +/- 1.0 microliters/min; F2, -3.12 +/- 2.4 microliters/min (P < 0.0000); F3, 1.09 +/- 0.6 microliters/min (P < 0.0001); F4, 1.76 +/- 0.6 microliters/min (P = 0.15); F5, 2.54 +/- 0.8 microliters/min (P = 0.01). The correlation coefficient for the left and night eyes (F1-F5, both days) was r = 0.85. The mean flow in the 19 healthy volunteers during the afternoon hours was 2.25 +/- 1.0 microliters/min. Water load consistently led to a reflux of unbound fluorescein into the eye about 10 min later. This is documented as a negative flow.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers.

    PubMed

    Wezenberg, Elke; Verkes, Robert Jan; Ruigt, Ge S F; Hulstijn, Wouter; Sabbe, Bernard G C

    2007-06-01

    Ampakines act as positive allosteric modulators of AMPA-type glutamate receptors and facilitate hippocampal long-term potentiation (LTP), a mechanism associated with memory storage and consolidation. The present study investigated the acute effects of farampator, 1-(benzofurazan-5-ylcarbonyl) piperidine, on memory and information processes in healthy elderly volunteers. A double-blind, placebo-controlled, randomized, cross-over study was performed in 16 healthy, elderly volunteers (eight male, eight female; mean age 66.1, SD 4.5 years). All subjects received farampator (500 mg) and placebo. Testing took place 1 h after drug intake, which was around Tmax for farampator. Subjects performed tasks assessing episodic memory (wordlist learning and picture memory), working and short-term memory (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Information processing was assessed with a tangled lines task, the symbol digit substitution test (SDST) and the continuous trail making test (CTMT). Farampator (500 mg) unequivocally improved short-term memory but appeared to impair episodic memory. Furthermore, it tended to decrease the number of switching errors in the CTMT. Drug-induced side effects (SEs) included headache, somnolence and nausea. Subjects with SEs had significantly higher plasma levels of farampator than subjects without SEs. Additional analyses revealed that in the farampator condition the group without SEs showed a significantly superior memory performance relative to the group with SEs. The positive results on short-term memory and the favorable trends in the trail making test (CTMT) are interesting in view of the development of ampakines in the treatment of Alzheimer's disease and schizophrenia.

  4. Dreaming under antidepressants: a systematic review on evidence in depressive patients and healthy volunteers.

    PubMed

    Tribl, Gotthard G; Wetter, Thomas C; Schredl, Michael

    2013-04-01

    Sleep related symptoms of depression include sleep fragmentation, early morning awakening, decreased rapid eye movement (REM) sleep latency, increased REM density, and more negative dream content. Most tricyclic antidepressants (ADs) increase total sleep time and decrease wake time after sleep onset, while many selective serotonin reuptake inhibitors (SSRIs) have an opposite effect. However, almost all ADs prolong REM sleep latency and reduce the amount of REM sleep. Case reports and research data indicate a strong effect of ADs on dream recall and dream content. We performed a systematic review (1950 to August 2010) about ADs impact on dreaming in depressive patients and healthy volunteers. Twenty-one clinical studies and 25 case reports were eligible for review and document a clear AD effect on dreaming. The major finding, both in depressed patients and in healthy volunteers, is a decrease of dream recall frequency (DRF) under ADs. This is a rather consistent effect in tricyclic ADs and phenelzine, less consistently documented also for SSRIs/serotonin norepinephrine reuptake inhibitors (SNRIs). Tricyclic ADs induce more positive dream emotions. Withdrawal from tricyclic ADs and from the monoamine oxidase inhibitors phenelzine and tranylcypromine may cause nightmares. Intake and even more withdrawal of SSRIs/SNRIs seem to intensify dreaming, which may be experienced in different ways; a potential to cause nightmares has to be taken into account. Though there are clear-cut pharmacological effects of ADs on DRF and dream content, publications have been surprisingly scarce during the past 60 years. There is evidence of a gap in neuropsychopharmacological research. AD effects on dreams should be recognized and may be used in treatment.

  5. Characterization of renal biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers

    PubMed Central

    Brott, David A; Adler, Scott H; Arani, Ramin; Lovick, Susan C; Pinches, Mark; Furlong, Stephen T

    2014-01-01

    Background Several preclinical urinary biomarkers have been qualified and accepted by the health authorities (US Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency) for detecting drug-induced kidney injury during preclinical toxicologic testing. Validated human assays for many of these biomarkers have become commercially available, and this study was designed to characterize some of the novel clinical renal biomarkers. The objective of this study was to evaluate clinical renal biomarkers in a typical Phase I healthy volunteer population to determine confidence intervals (pilot reference intervals), intersubject and intrasubject variability, effects of food intake, effect of sex, and vendor assay comparisons. Methods Spot urine samples from 20 male and 19 female healthy volunteers collected on multiple days were analyzed using single analyte and multiplex assays. The following analytes were measured: α-1-microglobulin, β-2-microglobulin, calbindin, clusterin, connective tissue growth factor, creatinine, cystatin C, glutathione S-transferase-α, kidney injury marker-1, microalbumin, N-acetyl-β-(D) glucosaminidase, neutrophil gelatinase-associated lipocalin, osteopontin, Tamm-Horsfall urinary glycoprotein, tissue inhibitor of metalloproteinase 1, trefoil factor 3, and vascular endothelial growth factor. Results Confidence intervals were determined from the single analyte and multiplex assays. Intersubject and intrasubject variability ranged from 38% to 299% and from 29% to 82% for biomarker concentration, and from 24% to 331% and from 10% to 67% for biomarker concentration normalized to creatinine, respectively. There was no major effect of food intake or sex. Single analyte and multiplex assays correlated with r2≥0.700 for five of six biomarkers when evaluating biomarker concentration, but for only two biomarkers when evaluating concentration normalized to creatinine. Conclusion Confidence intervals as well as

  6. Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers

    PubMed Central

    Qiu, Furong; Wang, Guangji; Zhao, Yanan; Sun, Hua; Mao, Guoguang; A, Jiyi; Sun, Jian

    2008-01-01

    Aims To examine the potential effect of danshen extract on the pharmacokinetics of theophylline. Methods In a sequential cross-over study with two phases, 12 volunteers took 100 mg theophylline on day 1 and day 15. From day 2 to day 15, volunteers received danshen extract tablets three times daily, four tablets each time for 14 days. On day 15, they received four danshen extract tablets with 100 mg theophylline. Plasma concentrations of theophylline were measured on days 1 and 15 periodically for 24 h. Results The 90% confidence interval of Cmax, t1/2 and CL/F of theophylline with 14-day danshen extract tablets vs. without comedication were (101.42, 121.36) (84.57, 106.72) and (88.82, 105.72), respectively. The time to peak plasma theophylline concentration was unchanged by danshen (P > 0.05). The pharmacokinetics parameter of theophylline was unaffected by danshen extract. Conclusions Danshen extract does not influence the metabolism of theophylline in healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with danshen extract tablets. What is already known about this subject Danshen extract is widely used for the treatment and prevention of coronary heart disease and other diseases of senility in Asia.Danshen extract and theophylline may be prescribed together to treat patients with asthma.In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2.In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of danshen and danshen pharmaceutical product.There may be drug interactions between danshen extract and theophylline (CYP1A2 substrate). What this study adds This study concerned drug interactions between danshen extract and theophylline in Chinese volunteers.Long-term oral intake of danshen extract does not change the basic pharmacokinetic parameters of theophylline.Dose adjustment of theophylline thus may not be necessary in patients receiving

  7. Hyperoxia Improves Hemodynamic Status During Head-up Tilt Testing in Healthy Volunteers

    PubMed Central

    Fromonot, Julien; Chaumet, Guillaume; Gavarry, Olivier; Rostain, Jean-Claude; Lucciano, Michel; Joulia, Fabrice; Brignole, Michele; Deharo, Jean-Claude; Guieu, Regis; Boussuges, Alain

    2016-01-01

    Abstract Head-up tilt test is useful for exploring neurally mediated syncope. Adenosine is an ATP derivative implicated in cardiovascular disturbances that occur during head-up tilt test. The aim of the present study was to investigate the impact of hyperoxia on adenosine plasma level and on hemodynamic changes induced by head-up tilt testing. Seventeen healthy male volunteers (mean age 35 ± 11 years) were included in the study. The experiment consisted of 2 head-up tilt tests, 1 session with subjects breathing, through a mask, medical air (FiO2 = 21%) and 1 session with administration of pure oxygen (FiO2 = 100%) in double-blind manner. Investigations included continuous monitoring of hemodynamic data and measurement of plasma adenosine levels. No presyncope or syncope was found in 15 of the 17 volunteers. In these subjects, a slight decrease in systolic blood pressure was recorded during orthostatic stress performed under medical air exposure. In contrast, hyperoxia led to increased systolic blood pressure during orthostatic stress when compared with medical air. Furthermore, mean adenosine plasma levels decreased during hyperoxic exposure before (0.31 ± 0.08 μM) and during head-up tilt test (0.33 ± 0.09 μM) when compared with baseline (0.6 ± 0.1 μM). Adenosine plasma level was unchanged during medical air exposure at rest (0.6 ± 0.1 μM), and slightly decreased during orthostatic stress. In 2 volunteers, the head-up tilt test induced a loss of consciousness when breathing air. In these subjects, adenosine plasma level increased during orthostatic stress. In contrast, during hyperoxic exposure, the head-up tilt test did not induce presyncope or syncope. In these 2 volunteers, biological study demonstrated a decrease in adenosine plasma level at both baseline and during orthostatic stress for hyperoxic exposure compared with medical air. These results suggest that hyperoxia was able to increase blood pressure during head

  8. Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers.

    PubMed

    Samuels, E R; Hou, R H; Langley, R W; Szabadi, E; Bradshaw, C M

    2006-11-01

    The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D(2)/D(3)receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus.

  9. Quantitative Magnetization Transfer Imaging of the Breast at 3.0 T: Reproducibility in Healthy Volunteers

    PubMed Central

    Arlinghaus, Lori R.; Dortch, Richard D.; Whisenant, Jennifer G.; Kang, Hakmook; Abramson, Richard G.; Yankeelov, Thomas E.

    2017-01-01

    Quantitative magnetization transfer magnetic resonance imaging provides a means for indirectly detecting changes in the macromolecular content of tissue noninvasively. A potential application is the diagnosis and assessment of treatment response in breast cancer; however, before quantitative magnetization transfer imaging can be reliably used in such settings, the technique’s reproducibility in healthy breast tissue must be established. Thus, this study aims to establish the reproducibility of the measurement of the macromolecular-to-free water proton pool size ratio (PSR) in healthy fibroglandular (FG) breast tissue. Thirteen women with no history of breast disease were scanned twice within a single scanning session, with repositioning between scans. Eleven women had appreciable FG tissue for test–retest measurements. Mean PSR values for the FG tissue ranged from 9.5% to 16.7%. The absolute value of the difference between 2 mean PSR measurements for each volunteer ranged from 0.1% to 2.1%. The 95% confidence interval for the mean difference was ±0.75%, and the repeatability value was 2.39%. These results indicate that the expected measurement variability would be ±0.75% for a cohort of a similar size and would be ±2.39% for an individual, suggesting that future studies of change in PSR in patients with breast cancer are feasible. PMID:28090588

  10. Pharmacokinetics of cinnarizine after single and multiple dosing in healthy volunteers.

    PubMed

    Castañeda-Hernández, G; Vargas-Alvarado, Y; Aguirre, F; Flores-Murrieta, F J

    1993-05-01

    Cinnarizine (CAS 298-57-7) pharmacokinetics were studied after single and repetitive dosing in healthy volunteers. Six young male healthy subjects received a 75 mg tablet and blood samples were drawn for 72 h after medication. Cinnarizine plasma levels were determined by gas chromatography. Cmax was 275 +/- 36 ng/ml, tmax 3.0 +/- 0.5 h, AUC extrapolated to infinity 4437 +/- 948 ng.h/ml and terminal half-life 23.6 +/- 3.2 h. After a 2-week washout period, 5 of these subjects received 75 mg tablets b.i.d. for 15 days. After the administration of doses 1 and 29, blood samples were drawn for 12 h and cinnarizine plasma levels were measured. Cinnarizine accumulated under these conditions. At steady state (dose 29), the observed accumulation factor was 2.79 +/- 0.23, being not significantly different from that predicted with the terminal half-life obtained from single dose data, which was 3.37 +/- 0.37. AUC0-12 for dose 29 was 5074 +/- 1021 ng.h/ml, being not significantly different from the AUC extrapolated to infinity obtained with the single dose. Results indicate that cinnarizine accumulates with repetitive dosing due to its pharmacokinetic properties.

  11. Pharmacokinetics of artesunate alone and in combination with sulfadoxine/pyrimethamine in healthy Sudanese volunteers.

    PubMed

    Matar, Kamal M; Awad, Abdelmoneim I; Elamin, Sakina B

    2014-06-01

    Artesunate (AS) in combination with sulfadoxine/pyrimethamine (SP) is the first-line therapy for management of uncomplicated Plasmodium falciparum malaria in Sudan. The objective of this study was to assess the potential impact of SP on the pharmacokinetics of AS and its active metabolite, dihydroartemisinin (DHA), in healthy adults. A single-dose, randomized, open-label, crossover study design with a washout period of three weeks was performed with 16 volunteers. After oral administration of AS alone or in combination with SP, Tmax values of AS and DHA were significantly prolonged in the combination group (P < 0.05). However, there was no significant effect on the other pharmacokinetic parameters (P > 0.05). The t1/2 values of AS and DHA were significantly higher in females than in males (P < 0.05). The present findings suggest that co-administration of SP with AS has no clinically relevant impact on the pharmacokinetics of AS or DHA in healthy persons.

  12. Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers.

    PubMed

    Sacher, Julia; Mossaheb, Nilufar; Spindelegger, Christoph; Klein, Nikolas; Geiss-Granadia, Thomas; Sauermann, Robert; Lackner, Edith; Joukhadar, Christian; Müller, Markus; Kasper, Siegfried

    2008-06-01

    Atypical antipsychotics have been linked to a higher risk for glucose intolerance, and consequentially the development of type 2 diabetes mellitus (DM2). We have therefore set out to investigate the acute effects of oral administration of olanzapine and ziprasidone on whole body insulin sensitivity in healthy subjects. Using the standardized hyperinsulinemic euglycemic clamp technique we compared whole body insulin sensitivity of 29 healthy male volunteers after oral intake of either olanzapine 10 mg/day (n = 14) or ziprasidone 80 mg/day (n = 15) for 10 days. A significant decrease (p<0.001) in whole body insulin sensitivity from 5.7 ml/h/kg ( = mean, SM = 0.4 ml/h/kg) at baseline to 4.7 ml/h/kg ( = mean, SM = 0.3 ml/h/kg) after oral intake of olanzapine (10 mg/day) for 10 days was observed. The ziprasidone (80 mg/day) group did not show any significant difference (5.2+/-0.3 ml/h/kg baseline vs 5.1+/-0.3 ml/h/kg) after 10 days of oral intake. Our main finding demonstrates that oral administration of olanzapine but not ziprasidone leads to a decrease in whole body insulin sensitivity in response to a hyperinsulinemic euglycemic challenge. Our finding is suggestive that not all atypical antipsychotics cause acute direct effects on glucose disposal and that accurate determination of side effect profile should be performed when choosing an atypical antipsychotic.

  13. Effect of St. John's wort supplementation on the pharmacokinetics of bupropion in healthy male Chinese volunteers.

    PubMed

    Lei, H-P; Yu, X-Y; Xie, H-T; Li, H-H; Fan, L; Dai, L-L; Chen, Y; Zhou, H-H

    2010-04-01

    The objective of this study was to investigate the effects of continuous St. John's wort administration on single-dose pharmacokinetics of bupropion, a substrate of cytochrome P450 (CYP) 2B6, in healthy Chinese volunteers. Eighteen unrelated healthy male subjects participated in this study. The single-dose pharmacokinetics of bupropion and hydroxybupropion were determined before (control) and after a long-term period of St. John's wort intake (325 mg, three times a day for 14 days). Plasma concentrations of bupropion and hydroxybupropion were determined before and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60 and 72 h after dosing. St. John's wort treatment decreased the area under the concentration versus time curve extrapolated to infinity of bupropion in healthy volunteers from 1.4 microg.h ml(-1) (95% confidence interval [CI] = 1.2-1.6 microg.h ml(-1)) after bupropion alone to 1.2 microg.h ml(-1) (95% CI = 1.1-1.3 microg.h ml(-1)) during St. John's wort treatment. St. John's wort treatment increased the oral clearance of bupropion from 108.3 l h(-1) (95% CI = 95.4-123.0 l h(-1)) to 130.0 l h(-1) (95% CI = 118.4-142.7 l h(-1)). No change in the time to peak concentration (t(max)) and the blood elimination half-life (t(1/2)) of bupropion was observed between the control and St. John's wort-treated phases. However, the half-life of hydroxybupropion between two phases had a significant difference by a Student's t test after logarithmic transformation. St. John's wort treatment decreased the half-life of hydroxybupropion from 26.7 h (95% CI = 23.8-29.9 h) to 24.4 h (95% CI = 21.9-27.3 h). St. John's wort decreased, to a statistically significant extent, the plasma concentrations of bupropion, probably mainly by increasing the clearance of bupropion.

  14. Altruism, personal benefit, and anxieties: a phenomenological study of healthy volunteers' experiences in a placebo‐controlled trial of duloxetine

    PubMed Central

    Kwakye, Isaac N.; Garner, Matthew; Baldwin, David S.; Bamford, Susan; Pinkney, Verity

    2016-01-01

    Objective The objective of this study was to develop an in‐depth understanding of healthy volunteers' experiences of mental health trials. Methods A qualitative study was nested within a healthy volunteer placebo‐controlled trial of duloxetine, a psychotropic drug used for treating patients with major depression and generalized anxiety disorder. Eight participants were interviewed, and data were analyzed using interpretative phenomenological analysis. Results Interviewees described volunteering for the trial because they were interested in research, wanted the monetary incentive, wanted to help researchers, and wanted to be part of something. On entering the trial, participants considered the possible risks and described feeling anxious, excited, and determined; they had some clear expectations and some loosely held hopes about what would happen. During the trial, participants were curious about whether they were taking duloxetine or placebo, self‐monitored their bodies' reactions, and guessed which treatment they received. On being un‐blinded to treatment allocation after completing the trial, some participants' guesses were confirmed, but others were surprised, and a few were disappointed. Conclusions Small changes to advertising/consent materials to reflect volunteers' motivations could improve recruitment rates to similar trials; “active” placebos might be particularly useful for maintaining blinding in healthy volunteer trials; and sensitive procedures are needed for un‐blinding participants to treatment allocation. © 2016 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd. PMID:27378326

  15. Cervical spine segmental vertebral motion in healthy volunteers feigning restriction of neck flexion and extension.

    PubMed

    Puglisi, Filadelfio; Strimpakos, Nikolaos; Papathanasiou, Matthildi; Kapreli, Eleni; Bonelli, Aurelio; Sgambetterra, Sergio; Ferrari, Robert

    2007-09-01

    The purpose of this study was to obtain comparative data concerning the percentage contribution of segmental cervical vertebral motion to the cervical range of motion (ROM) in healthy volunteers under two conditions: (1) normal, voluntary neck flexion and extension and (2) feigned restriction of neck flexion and extension. Each healthy subject's angular motion over forward cervical flexion and extension was measured first by X-ray analysis during normal, voluntary motion. Then the subjects were asked to pretend that they had a 50% restricted neck range due to pain or stiffness and thus to move in both flexion and extension only as far as about 50% of their normal range. A total of 26 healthy subjects (ten males and sixteen females, age 28.7+/-7.7 years) participated. The total angular motion from C2 to C7 was normal in the unrestricted condition and was significantly reduced in the feigned restriction condition (p<0.001). The percentage contribution of each of the functional units C2-C3 to C6-C7 to this rotation was different between the normal unrestricted and the feigned restricted conditions. In the feigned restricted neck flexion and extension, a shift occurred in the pattern of how each segment contributes to the total angular range. A greater percentage contribution was made by C2-C3 and C3-C4 than under normal conditions (P<0.01), and the percentage contribution to total rotation made by C6-C7 became much less under the feigned restricted movements than under normal, unrestricted neck range (p<0.001). Thus, simulated or feigned restricted neck ROM affects the percentage contribution of the functional units C2-C3 to C6-C7 by showing a higher percentage contribution of the upper cervical segments and less contribution to the angular rotation by the lowest cervical segment. Feigners of restricted neck range thus produce a pattern different from nonfeigning subjects.

  16. Centella asiatica Improves Physical Performance and Health-Related Quality of Life in Healthy Elderly Volunteer

    PubMed Central

    Mato, Lugkana; Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Tongun, Terdthai; Piyawatkul, Nawanant; Yimtae, Kwanchanok; Thanawirattananit, Panida; Sripanidkulchai, Bungorn

    2011-01-01

    Recently, oxidative stress has been reported to contribute an important role in the decline of physical function as age advances. Numerous antioxidants can improve both physical and psychological performances resulting in the increase of health-related quality of life (HQOL). Therefore, we hypothesized that Centella asiatica, a medicinal plant reputed for nerve tonic, strength improvement and antioxidant activity, could improve the physical performance and HQOL especially in the physical satisfaction aspect, of the healthy elderly volunteer. To test this hypothesis, a double-blind, placebo-controlled, randomized trial was performed. Eighty healthy elderly were randomly assigned to receive placebo or standardized extract of C. asiatica at doses of 250, 500 and 750 mg once daily for 90 days. The subjects were evaluated to establish baseline data of physical performance using 30-s chair stand test, hand grip test and 6-min walk test. The health-related quality of life was assessed using SF-36. These assessments were repeated every month throughout the 3-month experimental period using the aforementioned parameters. Moreover, 1 month after the cessation of C. asiatica treatment, all subjects were also evaluated using these parameters again. The results showed that after 2 months of treatment, C. asiatica at doses of 500 and 750 mg per day increased lower extremity strength assessed via the 30-s chair stand test. In addition, the higher doses of C. asiatica could improve the life satisfaction subscale within the physical function subscale. Therefore, the results from this study appear to support the traditional reputation of C. asiatica on strength improvement, especially in the lower extremities of the elderly. C. asiatica also possesses the potential to be a natural resource for vigor and strength increase, in healthy elderly persons. However, further research is essential. PMID:19880441

  17. A Natural Electromagnetic Fields Effect on Healthy Volunteers During Long-Term Experiment with Isolation

    NASA Astrophysics Data System (ADS)

    Gurfinkel, Yury I.; Mikhailov, Valery M.; Ushakov, Boris B.

    2008-06-01

    There were investigated four healthy volunteers at the age of 37, 40, 41 and 48 during the baseline 240-d isolation period starting from July 3, 1999 in the frame of SFINCSS-99 - "SIMULATION OF FLIGHT OF INTERNATIONAL CREW ON SPACE STATION". Before a starting of experiment with long-term isolation were carried out measurements of magnetic properties of module and sleeping places. With the regularity of 3 times a week each subject made records of no less then 3 video episodes with the total length of one minute minimum at the same time between 1 and 2 p.m. Applying vital non-invasive computer capillaroscopy of nailbed has allowed quantitatively estimating a capillary blood velocity (CBV). The microcirculation parameters obtained during experiment were compared to local indexes of geomagnetic activity. About 1500 episodes were recorded on laser disks and analyzed. Parameters of microcirculation were compared with other physiological parameters monitored in the experiment. CBV investigation during the most intensive magnetic storm for the period of isolation (A-index- 44) show, that CBV at all volunteers was considerably slowed down. The greatest delay of blood flow velocity revealed at the subject which the factor of shielding of a constant magnetic field at the level of the sleeping berth has made 2,0. CBV at the subject has made 498 ± 46 μm/s with (- 65,8 % from base line). Least delay of a CBV is revealed at the subject which the factor of shielding of a constant magnetic field at the level of the sleeping berth has made 3, 15 (-12 % from base line).

  18. Pharmacokinetics and bioequivalence studies of galantamine hydrobromide dispersible tablet in healthy male Chinese volunteers.

    PubMed

    Zhang, Li-jun; Fang, Xiao-ling; Li, Xue-ning; Wang, Qing-song; Han, Li-mei; Zhang, Zhi-wen; Sha, Xian-yi

    2007-03-01

    A randomized, two-way, crossover study was conducted in 18 healthy male Chinese volunteers to compare pharmacokinetics profiles of galantamine hydrobromide dispersible tablet with that of conventional tablet. A single oral dose of 10 mg galantamine was administrated to each volunteer. Plasma concentrations of galantamine were determined by a validated high-performance liquid chromatography (HPLC) method with fluorescence detection, which allowed 1 ng/mL to be assayed as the lowest quantifiable concentration. From plasma concentrations, AUC(0-->t) (the area under the plasma concentration-time curve from time 0 to the last sampling time, 32 hr), AUC(0-->infinity) (the area under the plasma concentration-time curve from time 0 to infinity), t((1/2)) (elimination of half-life of the terminal log linear phase), C(max) (maximum plasma drug concentration) and T(max) (time to reach C(max)) were evaluated through noncompartmental pharmacokinetic analysis. AUC(0-->t) and AUC(0-->infinity) were calculated by the linear-log trapezoidal rule method. C(max) and T(max) were obtained directly from the plasma concentration-time curve. Analysis of variance was carried out using logarithmically transformed AUC(0-->t), AUC(0-->infinity) and C(max). As far as AUC(0-->t), AUC(0-->infinity) and C(max) were concerned, there was no statistically significant difference between the test and reference formulations. Ninety percent confidence intervals (90% CI) for the ratio of AUC(0-->t), AUC(0-->infinity) and C(max) values for the test and reference formulations were 100.4-107.8%, 99.0-107.2% and 87.5-111.3%, respectively. As the 90% CIs of AUC(0-->t), AUC(0-->infinity) and C(max) were entirely within 80-125%, two formulations were considered bioequivalent.

  19. Amphetamine sensitisation and memory in healthy human volunteers: a functional magnetic resonance imaging study.

    PubMed

    O'Daly, Owen G; Joyce, Daniel; Tracy, Derek K; Stephan, Klaas E; Murray, Robin M; Shergill, Sukhwinder

    2014-09-01

    Amphetamine sensitisation (AS) is an established animal model of the hypersensitivity to psychostimulants seen in patients with schizophrenia. AS also models the dysregulation of mesolimbic dopamine signalling which has been implicated in the development of psychotic symptoms. Recent data suggest that the enhanced excitability of mesolimbic dopamine neurons in AS is driven by a hyperactivity of hippocampal (subiculum) neurons, consistent with a strong association between hippocampal dysfunction and schizophrenia. While AS can be modelled in human volunteers, its functional consequences on dopaminoceptive brain regions (i.e. striatum and hippocampus) remains unclear. Here we describe the effects of a sensitising dosage pattern of dextroamphetamine on the neural correlates of motor sequence learning in healthy volunteers, within a randomised, double-blind, parallel-groups design. Behaviourally, sensitisation was characterised by enhanced subjective responses to amphetamine but did not change performance (i.e. learning rate) during an explicit sequence learning task. In contrast, functional magnetic resonance imaging (fMRI) measurements showed that repeated intermittent amphetamine exposure was associated with increased blood-oxygen-level dependent (BOLD) signal within the medial temporal lobe (MTL) (subiculum/entorhinal cortex) and midbrain, in the vicinity of the substantia nigra/ventral tegmental area (SN/VTA) during sequence encoding. Importantly, MTL hyperactivity correlated with the sensitisation of amphetamine-induced attentiveness. The MTL-midbrain hyperactivity reported here mirrors observations in sensitised rodents and is consistent with contemporary models of schizophrenia and behavioural sensitisation. These findings of meso-hippocampal hyperactivity during AS thus link pathophysiological concepts of dopamine dysregulation to cognitive models of psychosis.

  20. Pharmacokinetic and bioequivalence studies of immediate release diclofenac potassium tablets (50mg) in healthy volunteers.

    PubMed

    Ali, Huma; Shoaib, Muhammad Harris; Zafar, Farya; Hanif, Muhammad; Bushra, Rabia; Naz, Asia; Khursheed, Raheela

    2016-09-01

    This study was conducted with the aim to determine the pharmacokinetic and bioequivalence of diclofenac potassium 50 mg test (F4) tablet formulation with reference product (Caflam). Present study was single dose, randomized, two phase cross over design, conducted in 12 healthy Pakistani volunteers and planned in accordance with FDA guidelines. In this study a simple, selective, sensitive and reproducible HPLC procedure was developed and validated for the estimation of diclofenac potassium in plasma. The process was validated in the range of 50 - 0.05 µg.mL-1 and used in bioequivalence trial of two products. Multiple blood samples were collected at various time points (0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 14 hr after treating volunteers with test (F4) and marketed reference brand. Plasma separation and deproteination were carried out with acetonitrile; samples (20µL) were injected using the validated HPLC method. Various pharmacokinetic parameters (compartmental and noncompartmental) were estimated using KineticaTM 4.4.1 (Thermo Electron Corp. USA). Bioequivalence among the products was established by calculating the 90% CI with log and non log transformed data for Cmaxcalc, Tmaxcalc, AUC0-∞, AUCtot and AUClast using two way ANOVA and Schirmann's Two one sided t- test. No significant difference was found between log and non-log data. The 90% confidence interval values using log transformed data for AUC0-∞ (0.997-1.024), AUCtot (1.004-1.031), AUClast (0.997 -1.024), Cmaxcalc (0.994-1.007) and Tmaxcalc (0.996-1.013) for the trial and reference products were found within the FDA acceptable limits of 0.8-1.25. Results were further verified by the Schirmann's one-sided t test. Results showed the bioequivalence of test and reference formulations. Both the products were well tolerated.

  1. Subjective, psychomotor, and physiological effects of cumulative doses of opioid mu agonists in healthy volunteers.

    PubMed

    Walker, D J; Zacny, J P

    1999-06-01

    The subjective, psychomotor, and physiological effects of three opioid mu-receptor agonists were studied in healthy volunteers using a cumulative-dosing procedure. Sixteen volunteers with no history of drug abuse received i.v. injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL was injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR: 2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological measures were recorded at various times after each injection and during recovery. MEP tended to produce the most intense effects immediately after drug injection, which dissipated rapidly. MOR produced the mildest effects but was associated with unpleasant side effects during recovery and after the session. HM's effects were stronger than MOR's, and the recovery from HM was slower than with MEP. None of the opioids produced consistent effects that are typically associated with abuse liability. Orderly dose-response functions suggested that our cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects within the same study.

  2. Isoflavone supplements stimulated the production of serum equol and decreased the serum dihydrotestosterone levels in healthy male volunteers

    PubMed Central

    Tanaka, M; Fujimoto, K; Chihara, Y; Torimoto, K; Yoneda, T; Tanaka, N; Hirayama, A; Miyanaga, N; Akaza, H; Hirao, Y

    2009-01-01

    The aim of this study was to evaluate the effect of supplementing healthy men with soy isoflavones on the serum levels of sex hormones implicated in prostate cancer development. A total of 28 Japanese healthy volunteers (18 equol producers and 10 equol non-producers) between 30 and 59 years of age were given soy isoflavones (60 mg daily) supplements for 3 months, and the changes in their sex hormone levels were investigated at the baseline and after administration. The serum and urine concentrations of daidzein, genistein, and the levels of equol in the fasting blood samples and 24-h stored urine samples were also measured. All 28 volunteers completed the 3-month supplementation with isoflavone. No changes in the serum levels of estradiol and total testosterone were detected after 3-month supplementation. The serum levels of sex hormone-binding globulin significantly increased, and the serum levels of free testosterone and dihydrotestosterone (DHT) decreased significantly after 3-month supplementation. Among the 10 equol non-producers, equol became detectable in the serum of two healthy volunteers after 3-month supplementation. This study revealed that short-term administration of soy isoflavones stimulated the production of serum equol and decreased the serum DHT level in Japanese healthy volunteers. These results suggest the possibility of converting equol non-producers to producers by prolonged and consistent soy isoflavones consumption. PMID:19597532

  3. Stopped hearts, amputated toes and NASA: contemporary legends among healthy volunteers in US phase I clinical trials.

    PubMed

    Fisher, Jill A

    2015-01-01

    The first stage of testing new pharmaceuticals in humans is referred to as a phase I clinical trial. The purpose of these studies is to test the safety of the drugs and to establish appropriate doses that can later be given to patients. Most of these studies are conducted under controlled, in-patient conditions using healthy volunteers who are paid for their participation. To explore healthy volunteers' experiences in clinical trials, an ethnographic study was conducted at six in-patient phase I clinics in the USA. In addition to the observation of clinic activities (from informed consent procedures to dosing to blood draws), 268 semi-structured interviews were conducted, 33 with clinic staff and 235 with healthy volunteers. Drawing on this dataset, this article explores healthy volunteers' exchange of contemporary legends about phase I clinical trials. In addition to potentially scaring the listener and communicating distrust in the medical community, these incredible stories help participants cope with perceived stigma and establish a gradient of risk of trial participation, creating potential boundaries to their participation in medical research. The article argues that contemporary legends play a productive role in society, shaping how people view themselves and others and influencing their decisions about risky activities.

  4. The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers

    PubMed Central

    Seaber, Emma J; Peck, Richard W; Smith, Deborah A; Allanson, John; Hefting, Nanco R; van Lier, Jan J; Sollie, Frans A E; Wemer, Johan; Jonkman, Jan H G

    1998-01-01

    Aims Zolmitriptan (Zomig (formerly 311C90)) is a novel 5-HT1B/1D receptor agonist developed for the acute oral treatment of migraine. A highly sensitive LCMS-MS assay has been developed which allows quantification of plasma concentrations of zolmitriptan and its active metabolite, 183C91, after therapeutic doses. Two studies using this assay method were conducted to investigate the pharmacokinetics, including absolute bioavailability, of 2.5 and 5 mg oral doses of zolmitriptan in men and women, the dose-proportionality of 2.5, 5 and 10 mg doses and the effect of food on the pharmacokinetics of a 5 mg oral dose. Methods Two randomized, balanced, open-label, 4-period crossover studies were conducted in a total of 32 healthy volunteers. The first study determined the absolute bioavailability of 2.5 and 5 mg doses of zolmitriptan and compared the pharmacokinetics in men and women. The second study examined the dose-proportionality in pharmacokinetics after fasting doses of 2.5, 5 and 10 mg, and the effect of food on a 5 mg dose. Blood pressure, heart rate, ECG, clinical chemistry, haematology and adverse events were also monitored. Results The mean (s.d.) absolute oral bioavailability was 0.41 (0.14 and 0.40) 0.09 after 2.5 mg and 0.48±0.14 and 0.36±0.07 after 5 mg in women and men, respectively. Without adjustment for bodyweight, plasma concentrations of zolmitriptan, but not 183C91, were higher in women than men. Mean (±s.d.) AUC was 32.7±10.1 and 60.2±26.8 ng ml−1 h after 5 mg in men and women, respectively (95% CI for ratio 0.43–0.77). After 2.5 mg mean (±s.d.) AUC was 18.4±5.4 and 23.1±9.9 ng ml−1 h in men and women, respectively (95% CI for ratio 0.61–1.09). However, these differences were of no clinical significance. Cmax and AUC of oral zolmitriptan were dose-proportional and there was a 13 and 16% fall in mean zolmitriptan Cmax and AUC, respectively, when administered after food. Adverse effects were minor, predominantly mild and transient, and

  5. The differential effects of chlorpromazine and haloperidol on latent inhibition in healthy volunteers.

    PubMed

    McCartan, D; Bell, R; Green, J F; Campbell, C; Trimble, K; Pickering, A; King, D J

    2001-06-01

    Latent inhibition (LI) is a measure of reduced learning about a stimulus to which there has been prior exposure without any consequence. It therefore requires a comparison between a pre-exposed (PE) and a non-pre-exposed (NPE) condition. Since, in animals, LI is disrupted by amphetamines and enhanced by antipsychotics, LI disruption has been proposed as a measure of the characteristic attentional deficit in schizophrenia: the inability to ignore irrelevant stimuli. The findings in humans are, however, inconsistent. In particular, a recent investigation suggested that since haloperidol disrupted LI in healthy volunteers, and LI was normal in non-medicated patients with schizophrenia, the previous findings in schizophrenic patients were entirely due to the negative effects of their medication on LI (Williams et al., 1998). We conducted two studies of antipsychotic drug effects on auditory LI using a within-subject, parallel group design in healthy volunteers. In the first of these, single doses of haloperidol (1 mg. i.v.) were compared with paroxetine (20 mg p.o.) and placebo, and in the second, chlorpromazine (100 mg p.o.) was compared with lorazepam (2 mg. p.o.) and placebo. Eye movements, neuropsychological test performance (spatial working memory (SWM), Tower of London and intra/extra dimensional shift, from the CANTAB test battery) and visual analogue rating scales, were also included as other measures of attention and frontal lobe function. Haloperidol was associated with a non-significant reduction in LI scores, and dysphoria/akathisia (Barnes Akathisia Rating Scale) in three-quarters of the subjects. The LI finding may be explained by increased distractibility which was indicated by an increase in antisaccade directional errors in this group. In contrast, LI was significantly increased by chlorpromazine but not by an equally sedative dose of lorazepam (both drugs causing marked decreases in peak saccadic velocity). Paroxetine had no effect on LI, eye

  6. Impact of humic acids on the colonic microbiome in healthy volunteers

    PubMed Central

    Swidsinski, Alexander; Dörffel, Yvonne; Loening-Baucke, Vera; Gille, Christoph; Reißhauer, Anne; Göktas, Onder; Krüger, Monika; Neuhaus, Jürgen; Schrödl, Wieland

    2017-01-01

    AIM To test the effects of humic acids on innate microbial communities of the colon. METHODS We followed the effects of oral supplementation with humic acids (Activomin®) on concentrations and composition of colonic microbiome in 14 healthy volunteers for 45 d. 3 × 800 mg Activomin® were taken orally for 10 d followed by 3 × 400 mg for 35 d. Colonic microbiota were investigated using multicolor fluorescence in situ hybridization (FISH) of Carnoy fixated and paraffin embedded stool cylinders. Two stool samples were collected a week prior to therapy and one stool sample on days 10, 31 and 45. Forty-one FISH probes representing different bacterial groups were used. RESULTS The sum concentration of colonic microbiota increased from 20% at day 10 to 30% by day 31 and remained stable until day 45 (32%) of humic acid supplementation (P < 0.001). The increase in the concentrations in each person was due to growth of preexisting groups. The individual microbial profile of the patients remained unchanged. Similarly, the bacterial diversity remained stable. Concentrations of 24 of the 35 substantial groups increased from 20% to 96%. Two bacterial groups detected with Bac303 (Bacteroides) and Myc657 (mycolic acid-containing Actinomycetes) FISH probes decreased (P > 0.05). The others remained unaffected. Bacterial groups with initially marginal concentrations (< 0.1 × 109/mL) demonstrated no response to humic acids. The concentrations of pioneer groups of Bifidobacteriaceae, Enterobacteriaceae and Clostridium difficile increased but the observed differences were statistically not significant. CONCLUSION Humic acids have a profound effect on healthy colonic microbiome and may be potentially interesting substances for the development of drugs that control the innate colonic microbiome. PMID:28223733

  7. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers.

    PubMed

    Attie, Kenneth M; Allison, Mark J; McClure, Ty; Boyd, Ingrid E; Wilson, Dawn M; Pearsall, Amelia E; Sherman, Matthew L

    2014-07-01

    ACE-536, a recombinant protein containing a modified activin receptor type IIB, is being developed for the treatment of anemias caused by ineffective erythropoiesis, such as thalassemias and myelodysplastic syndromes. ACE-536 acts through a mechanism distinct from erythropoiesis-stimulating agents to promote late-stage erythroid differentiation by binding to transforming growth factor-β superfamily ligands and inhibiting signaling through transcription factors Smad 2/3. The goal of this Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ascending dose levels of ACE-536 in healthy volunteers. Thirty-two postmenopausal women were randomized in sequential cohorts of eight subjects each to receive up to two doses of either ACE-536 (0.0625-0.25 mg/kg) or placebo (3:1 randomization) given subcutaneously every 2 weeks. Mean baseline age was 59.4 years, and hemoglobin was 13.2 g/dL. ACE-536 was well tolerated at dose levels up to 0.25 mg/kg over the 1-month treatment period. There were no serious or severe adverse events, nor clinically meaningful changes in safety laboratory measures or vital signs. Mean ACE-536 AUC0-14d and Cmax increased proportionally after first dose; mean t½ was 15-16 days. Dose-dependent increases in hemoglobin concentration were observed, beginning 7 days after initiation of treatment and maintained for several weeks following treatment. The proportion of subjects with a hemoglobin increase ≥1.0 g/dL increased in a dose-dependent manner to 83.3% of subjects in the highest dose group, 0.25 mg/kg. ACE-536 was well tolerated and resulted in sustained increases in hemoglobin levels in healthy postmenopausal women.

  8. Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers.

    PubMed

    Ruiz-Garcia, Ana; Masters, Joanna C; Mendes da Costa, Laure; LaBadie, Robert R; Liang, Yali; Ni, Grace; Ellery, Craig A; Boutros, Tanya; Goldberg, Zelanna; Bello, Carlo L

    2016-02-01

    This phase 1, open-label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI). Twenty-four male subjects received a single dacomitinib 45-mg dose under 3 different conditions separated by washout periods of ≥ 16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high-fat, high-calorie meal. Increased peak exposure of 23.7% (90% confidence interval [CI], 5.3%-45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 114.2% (90%CI, 104.7%-124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%-81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required.

  9. Antimicrobial resistance pattern and genetic correlation in Enterococcus faecium isolated from healthy volunteers.

    PubMed

    Asadian, M; Sadeghi, J; Rastegar Lari, A; Razavi, Sh; Hasannejad Bibalan, M; Talebi, M

    2016-03-01

    Enterococci are known as a cause of nosocomial infections and this aptitude is intensified by the growth of antibiotic resistance. In the present study, Enterococcus faecium isolates from healthy volunteers were considered to determine the antibiotic resistance profiles and genetic correlation. A total 91 normal flora isolates of enterococci were included in this study. Identification of Enterococcus genus and species were done by biochemical and PCR methods, respectively. Sensitivity for 10 antibiotics was determined and genetic relatedness of all isolates was assessed using Repetitive Element Palindromic PCR (REP-PCR) followed by Pulse Field Gel Electrophoresis (PFGE) on the representative patterns. None of the isolates were resistant to teicoplanin, vancomycin, quinupristin-dalfopristin, linezolid, chloramphenicol, ampicillin and high-level gentamicin. On the other hand, the resistance rate was detected in 30.7%, 23%, and 3.29% of isolates for erythromycin, tetracycline and ciprofloxacin, respectively. The results of PFGE showed 19 (61.5% of our isolates) common types (CT) and 35 (38.5%) single types (ST) amongst the isolates. This is the first study to describe antibiotic resistance pattern and genetic relationship among normal flora enterococci in Iran. This study showed no prevalence of Vancomycin Resistant Enterococci (VRE) and high degrees of diversity among normal flora isolates by genotyping using PFGE.

  10. Incidence of associated events during the performance of invasive procedures in healthy human volunteers

    NASA Technical Reports Server (NTRS)

    Highstead, R. Grant; Tipton, Kevin D.; Creson, Daniel L.; Wolfe, Robert R.; Ferrando, Arny A.

    2005-01-01

    Metabolic investigations often utilize arteriovenous sampling and muscle biopsy. These investigations represent some risk to the subject. We examined 369 studies performed in the General Clinical Research Center between January 1994 and May 2003 for events related to femoral catheterization and muscle biopsies. Incidents were further examined by age (younger: 18-59 yr, n=133; and older: 60-76 yr, n=28). There were no clinically defined major complications associated with either procedure. The incidence of femoral catheter repositioning or reinsertion was higher in the older group (25.5 vs. 9.7%). There was no difference in the incidence of premature removal of catheters, ecchymosis or hematoma, or the persistence of pain after discharge. The occurrence of all incidents did not increase with multiple catheterizations. Muscle biopsy was associated with infrequent ecchymosis or hematoma in both groups (1.1 and 3.6% in younger and older groups, respectively). Both procedures entail a small likelihood of a vagallike response (3.3% overall), resulting in nausea, dizziness, and rarely a loss of consciousness. These results indicate that, in skilled hands and a defined clinical setting, the incidents associated with femoral catheterization and muscle biopsy in healthy volunteers are reasonable and largely controllable.

  11. Bioequivalence Study of Two Orodispersible Rizatriptan Formulations of 10 mg in Healthy Volunteers

    PubMed Central

    Cánovas, Mercè; Polonio, Francisco; Cabré, Francesc

    2016-01-01

    The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions design. The test and reference formulations were administered in two treatment days, separated by a washout period of seven days. Plasma concentrations of rizatriptan were obtained by the LC/MS/MS (Liquid chromatography tandem-mass spectrometry) method. Log-transformed AUC0-t (area under the plasma concentration-time curve from zero to the last measurable concentration) and Cmax (maximum plasma concentration) values were tested for bioequivalence based on the ratios of the geometric means (test/reference). The tmax (time to reach maximum plasma concentration) was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80%–125%. According to the European Guideline, it may therefore be concluded that the test formulation of rizatriptan 10 mg orodispersible tablet is bioequivalent to the reference formulation (Maxalt® Max 10 mg oral lyophilisate). The safety profile of both formulations was consistent with the summary of the product characteristics. PMID:28117317

  12. Bioequivalence study of two oral formulations of irbesartan 300 mg in healthy volunteers.

    PubMed

    Cánovas, M; Cabré, F; Polonio, F

    2014-01-01

    A bioequivalence study of 2 irbesartan (CAS 138402-11-6) film-coated tablet formulations was carried out in 40 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Blood samples were drawn up to 96 h following drug administration. Plasma concentrations of irbesartan were obtained by a validated HPLC method using MS/MS detection. Log-transformed AUC0-t and Cmax values were tested for bioequivalence based on the ratios of the geometric LSmeans (test/reference). tmax was analysed nonparametrically. The 90% confidence intervals of the geometric LSmean values for the test/reference ratios for AUC0-t (98.06-109.48%, point estimator 103.61%) and Cmax (88.93-100.87%, point estimator 94.72%) were within the bioequivalence acceptance range of 80-125%. According to the European Guideline on the Investigation of Bioequivalence it may be therefore concluded that test formulation of irbesartan 300 mg film-coated tablet is bioequivalent to the reference formulation. Overall, it was judged that the study was conducted with a good tolerance of the subjects to both study drugs.

  13. Bioequivalence Study of Two Orodispersible Rizatriptan Formulations of 10 mg in Healthy Volunteers.

    PubMed

    Cánovas, Mercè; Polonio, Francisco; Cabré, Francesc

    2016-06-13

    The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions design. The test and reference formulations were administered in two treatment days, separated by a washout period of seven days. Plasma concentrations of rizatriptan were obtained by the LC/MS/MS (Liquid chromatography tandem-mass spectrometry) method. Log-transformed AUC0-t (area under the plasma concentration-time curve from zero to the last measurable concentration) and Cmax (maximum plasma concentration) values were tested for bioequivalence based on the ratios of the geometric means (test/reference). The tmax (time to reach maximum plasma concentration) was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80%-125%. According to the European Guideline, it may therefore be concluded that the test formulation of rizatriptan 10 mg orodispersible tablet is bioequivalent to the reference formulation (Maxalt(®) Max 10 mg oral lyophilisate). The safety profile of both formulations was consistent with the summary of the product characteristics.

  14. Scintigraphic evaluation of colon targeting pectin-HPMC tablets in healthy volunteers.

    PubMed

    Hodges, L A; Connolly, S M; Band, J; O'Mahony, B; Ugurlu, T; Turkoglu, M; Wilson, C G; Stevens, H N E

    2009-03-31

    The in vivo evaluation of colon-targeting tablets was conducted in six healthy male volunteers. A pectin-hydroxypropyl methylcellulose coating was compressed onto core tablets labelled with 4MBq (99m)Tc-DTPA. The tablets released in the colon in all subjects; three in the ascending colon (AC) and three in the transverse colon (TC). Tablets that released in the TC had reached the AC before or just after food (Group A). The other three tablets released immediately upon AC entry at least 1.5h post-meal (Group B). Release onset for Group B was earlier than Group A (343min vs 448min). Group B tablets exhibited a clear residence period at the ileocaecal junction (ICJ) which was not observed in Group A. Prolonged residence at the ICJ is assumed to have increased hydration of the hydrogel layer surrounding the core tablet. Forces applied as the tablets progressed through the ICJ may have disrupted the hydrogel layer sufficiently to initiate radiolabel release. Conversely, Group A tablets moved rapidly through the AC to the TC, possibly minimising contact times with water pockets. Inadequate prior hydration of the hydrogel layer preventing access of pectinolytic enzymes and reduced fluid availability in the TC may have retarded tablet disintegration and radiolabel diffusion.

  15. Comparison of the effects of binodaline and amitriptyline on peripheral autonomic functions in healthy volunteers.

    PubMed Central

    Longmore, J; Szabadi, E; Bradshaw, C M

    1985-01-01

    Twelve healthy male volunteers participated in five experimental sessions separated by weekly intervals. At the beginning of each session the subjects received one single oral dose of the following drugs, according to a double-blind, balanced cross-over design: binodaline hydrochloride (50 mg or 100 mg); amitriptyline hydrochloride (50 mg or 100 mg); lactose placebo. Salivation and resting pupil diameter were assessed before and 2 h after the ingestion of the drugs; baseline sweating, carbachol- or phenylephrine-evoked sweating were measured 2 h following drug taking. Binodaline, like placebo, had little effect on salivary output, whereas amitriptyline caused a dose-dependent decrease in salivation. None of the drugs caused any significant change in resting pupil diameter or in baseline sweating. Carbachol-evoked sweating did not differ significantly following the ingestion of binodaline or placebo; on the other hand responses to carbachol were significantly reduced following amitriptyline. Phenylephrine-evoked sweating was reduced by both binodaline and amitriptyline. The lack of effect of binodaline on salivation, resting pupil diameter, baseline and carbachol-evoked sweating is in agreement with the results of animal experiments indicating the lack of an interaction of this drug with cholinergic mechanisms. The reduction in phenylephrine-evoked sweating would be indicative of an alpha-adrenoceptor blocking property of this drug. PMID:3986084

  16. Hydroxyl-platelet-activating factor exists in blood of healthy volunteers and periodontal patients.

    PubMed Central

    Antonopoulou, Smaragdi; Tsoupras, Alexandros; Baltas, George; Kotsifaki, Helen; Mantzavinos, Zacharias; Demopoulos, Constantinos A

    2003-01-01

    Periodontal diseases are localized chronic inflammatory conditions of the gingival and underlying bone and connective tissue. Platelet-activating factor (PAF), a potent inflammatory phospholipid mediator that has been previously detected in elevated levels in inflamed gingival tissues, in gingival crevicular fluid and in saliva, is implicated in periodontal disease. Our results from previous studies showed that the biologically active phospholipid detected in gingival crevicular fluid is a hydroxyl-PAF analogue. In this study, hydroxyl-PAF analogue was detected for the first time in human blood derived from patients with chronic periodontitis as well as from periodontally healthy volunteers. The hydroxyl-PAF analogue was purified by high-performance liquid chromatography, detected by biological assays and identified by electrospray analysis. In addition, the quantitative determination of PAF and hydroxyl-PAF analogue (expressed as PAF-like activity) showed a statistically significant increase in the ratio of hydroxyl-PAF analogue levels to PAF levels in periodontal patients, suggesting that this bioactive lipid may play a role in oral inflammation. PMID:14514473

  17. A pharmacoscintigraphic study of three time-delayed capsule formulations in healthy male volunteers.

    PubMed

    McConville, Jason T; Hodges, Lee-Ann; Jones, Tamara; Band, Janet P; O'Mahony, Bridget; Lindsay, Blythe; Ross, Alistair C; Florence, Alastair J; Stanley, Adrian J; Humphrey, Michael J; Wilson, Clive G; Stevens, Howard N E

    2009-11-01

    Three time-delayed capsule (TDC) formulations were investigated in a pharmacoscintigraphic study, using a three-way crossover design in eight healthy male volunteers. Additionally, the pulsed release of a TDC was investigated with time-lapse photography, using a nondisintegrating riboflavin tablet. The photographic study indicated how the release characteristics of the TDC relied on the erosion of a tablet containing hypromellose (HPMC). Each TDC was duel radio labelled with indium-111 and technetium-99 m DTPA complexes, to observe drug release scintigraphically (theophylline was a marker compound). Three formulations, having in vitro dissolution release times of 1.8, 2.9 or 4.0 h were shown to compare favourably with mean in vivo scintigraphic release times of 2.7, 3.0 and 4.0 h for each formulation containing 20, 24 or 35% (w/w) HPMC concentrations respectively. An increase in HPMC concentration was associated with a delayed technetium release time, and followed the same rank order as the in vitro dissolution study. Observed radiolabel dispersion always occurred in the small intestine. In conclusion, the study established that the TDC performs and demonstrates an in vitro-in vivo correlation. Additionally, time and site of release were accurately visualized by gamma scintigraphy, and confirmed with determination of theophylline absorption.

  18. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.

    PubMed

    Dooley, K E; Bliven-Sizemore, E E; Weiner, M; Lu, Y; Nuermberger, E L; Hubbard, W C; Fuchs, E J; Melia, M T; Burman, W J; Dorman, S E

    2012-05-01

    Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AU C0–24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.

  19. Safety and Pharmacokinetics of Escalating Daily Doses of the Antituberculosis Drug Rifapentine in Healthy Volunteers

    PubMed Central

    Dooley, KE; Bliven-Sizemore, EE; Weiner, M; Lu, Y; Nuermberger, EL; Hubbard, WC; Fuchs, EJ; Melia, MT; Burman, WJ; Dorman, SE

    2013-01-01

    Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high as a prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RPT concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AUC0–24) and maximum concentration (Cmax) were similar in the 15- and 20-mg/kg cohorts. Although RPT pharmacokinetics (PK) appeared to be time-dependent, accumulation occurred with daily dosing. The mean AUC0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01). Changes in the oral clearance of MDZ did not vary by RPT dose. In conclusion, RPT was tolerated at doses as high as 20 mg/kg/day, its PK were less than dose-proportional, and its CYP3A induction was robust. PMID:22472995

  20. The effect of 5-hydroxytryptophan on cholecystokinin-4-induced panic attacks in healthy volunteers.

    PubMed

    Maron, Eduard; Tõru, Innar; Vasar, Veiko; Shlik, Jakov

    2004-06-01

    Previous studies suggest a modulatory role of serotonin (5-HT) in experimentally-induced panic attacks. In the current study, we investigated the acute effects of 5-HT precursor l-5-hydroxytryptophan (5-HTP) on the response to panicogenic challenge with cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. Thirty-two subjects were randomized to receive either 200 mg of 5-HTP or placebo with the CCK-4 challenge following in 90 min in a double-blind, parallel-group design. The results showed a nonsignificant difference between the groups in panic rate (19% after 5-HTP and 44% after placebo, p = 0.13) with a trend for lower intensity of symptoms after 5-HTP (p = 0.08). Further analysis by gender revealed that females in the 5-HTP group had a significantly lower panic rate and intensity of cognitive symptoms whereas, in males, the effect of 5-HTP was limited to lowering the intensity of somatic panic symptoms. Thus, an increased availability of 5-HT may have a gender-dependent protective effect in CCK-4-induced panic.

  1. A Pharmacometabonomic Approach To Predicting Metabolic Phenotypes and Pharmacokinetic Parameters of Atorvastatin in Healthy Volunteers.

    PubMed

    Huang, Qing; Aa, Jiye; Jia, Huning; Xin, Xiaoqing; Tao, Chunlei; Liu, Linsheng; Zou, Bingjie; Song, Qinxin; Shi, Jian; Cao, Bei; Yong, Yonghong; Wang, Guangji; Zhou, Guohua

    2015-09-04

    Genetic polymorphism and environment each influence individual variability in drug metabolism and disposition. It is preferable to predict such variability, which may affect drug efficacy and toxicity, before drug administration. We examined individual differences in the pharmacokinetics of atorvastatin by applying gas chromatography-mass spectrometry-based metabolic profiling to predose plasma samples from 48 healthy volunteers. We determined the level of atorvastatin in plasma using liquid chromatography-tandem mass spectrometry. With the endogenous molecules, which showed a good correlation with pharmacokinetic parameters, a refined partial least-squares model was calculated based on predose data from a training set of 36 individuals and exhibited good predictive capability for the other 12 individuals in the prediction set. In addition, the model was successfully used to predictively classify individual pharmacokinetic responses into subgroups. Metabolites such as tryptophan, alanine, arachidonic acid, 2-hydroxybutyric acid, cholesterol, and isoleucine were indicated as candidate markers for predicting by showing better predictive capability for explaining individual differences than a conventional physiological index. These results suggest that a pharmacometabonomic approach offers the potential to predict individual differences in pharmacokinetics and therefore to facilitate individualized drug therapy.

  2. Subjective, Psychomotor, and Physiological Effects of Pregabalin Alone and in Combination With Oxycodone in Healthy Volunteers

    PubMed Central

    Zacny, James P.; Paice, Judith A.; Coalson, Dennis W.

    2011-01-01

    Pregabalin is an anticonvulsant drug indicated for neuropathic disorders and fibromyalgia. Some chronic pain patients suffering from these disorders take both this drug and an opioid for pain relief. Pregabalin is a scheduled drug under the Controlled Substance Act. The subjective effects of this drug have not been well-characterized, and the extent to which it alters the subjective effects of opioids has not been studied to the best of our knowledge. Using a double-blind, randomized, crossover design, 16 healthy volunteers were administered (in separate sessions) capsules containing placebo, 75 mg pregabalin, 150 mg pregabalin, 10 mg oxycodone, and 75 mg pregabalin combined with 10 mg oxycodone. Subjective, psychomotor, and physiological measures were assessed during each of the five sessions. Pregabalin produced dose-related increases in some subjective effects and decreased respiration rate, but did not impact on psychomotor performance. Abuse liability-related subjective effects such as drug liking and desire to take the drug again were not increased by either pregabalin dose. Oxycodone produced increases in several subjective effects, including ratings of drug liking. When 75 mg pregabalin was combined with oxycodone some subjective effects were altered relative to placebo, in contrast to when each drug was tested alone. Liking of oxycodone was not increased by 75 mg pregabalin. However, recent studies have suggested that this drug is abused, and we would recommend that further psychopharmacological studies with pregabalin are warranted, including a study assessing its abuse liability across a range of doses in sedative abusers. PMID:22085697

  3. The brain signature of paracetamol in healthy volunteers: a double-blind randomized trial

    PubMed Central

    Pickering, Gisèle; Kastler, Adrian; Macian, Nicolas; Pereira, Bruno; Valabrègue, Romain; Lehericy, Stéphane; Boyer, Louis; Dubray, Claude; Jean, Betty

    2015-01-01

    Background Paracetamol’s (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans. Methods and results This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter. Conclusion These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain. PMID:26229445

  4. Comparative bioavailability and tolerability study of two intramuscular formulations of thiocolchicoside in healthy volunteers.

    PubMed

    Ferrari, M P; Gatti, G; Fattore, C; Fedele, G; Novellini, R

    2001-01-01

    The comparative bioavailability and tolerability of two intramuscular fomulations of thiocolchicoside (test, Thiocolchicoside, 4 mg ampoules, Dompé S.p.A.; reference, Muscoril, 4 mg ampoules, Inverni della Beffa S.p.A.) were investigated in twelve healthy volunteers according to a single dose (4 mg), cross-over, randomized design. Plasma thiocolchicoside concentrations were determined by using a validated specific HPLC/MS assay and local tolerability was investigated by assessing subjective pain intensity on a visual analogue scale (VAS), reddening at the injection site, and plasma creatinine phosphokinase (CPK) levels. Pharmacokinetic parameters after administration of the test formulation were similar to those observed after administration of the reference (Tmax 0.50 (0.25-1.00) vs 0.50 (0.25-1.00), median and range; Cmax 115.5 +/- 26.6 vs 113.2 +/- 40.4 ng/ml; AUC 291.6 +/- 77.7 vs 283.3 +/- 98.9 ng.h/ml, means +/- SD). Relative bioavailability (F) was 1.05 +/- 0.13. Statistical comparison of pain intensity, CPK levels and occurrence of redness at the injection site did not show statistically significant differences between formulations. It is concluded that the investigated test formulation is bioequivalent and equally well tolerated as the marketed reference formulation.

  5. Functional biomarkers for the acute effects of alcohol on the central nervous system in healthy volunteers

    PubMed Central

    Zoethout, Remco W M; Delgado, Wilson L; Ippel, Annelies E; Dahan, Albert; van Gerven, Joop M A

    2011-01-01

    The central nervous system (CNS) effects of acute alcohol administration have been frequently assessed. Such studies often use a wide range of methods to study each of these effects. Unfortunately, the sensitivity of these tests has not completely been ascertained. A literature search was performed to recognize the most useful tests (or biomarkers) for identifying the acute CNS effects of alcohol in healthy volunteers. All tests were grouped in clusters and functional domains. Afterwards, the effect of alcohol administration on these tests was scored as improvement, impairment or as no effect. Furthermore, dose–response relationships were established. A total number of 218 studies, describing 342 different tests (or test variants) were evaluated. Alcohol affected a wide range of CNS domains. Divided attention, focused attention, visuo-motor control and scales of feeling high and of subjective drug effects were identified as the most sensitive functional biomarkers for the acute CNS effects of alcohol. The large number of CNS tests that are used to determine the effects of alcohol interferes with the identification of the most sensitive ones and of drug–response relationships. Our results may be helpful in selecting rational biomarkers for studies investigating the acute CNS effects of alcohol or for future alcohol- interaction studies. PMID:21284693

  6. The effects of exercise and body armor on cognitive function in healthy volunteers.

    PubMed

    Roberts, Aaron P J; Cole, Jon C

    2013-05-01

    Police officers routinely wear body armor to protect themselves against the threat posed by firearms and edged weapons, yet little is known of the cognitive effects of doing so. Two studies investigated the effects of exercise and body armor on working memory function in healthy volunteers. In study 1, male undergraduates were assigned to one of four groups: (i) brief exercise, (ii) brief exercise wearing body armor, (iii) extended exercise, and (iv) extended exercise wearing body armor. In study 2, university gym members were assigned to one of two groups: (i) wearing body armor and (ii) not wearing body armor. In both studies, heart rate and oral temperature were measured before, immediately after, and 5 minutes after exercise. The phonemic verbal fluency task and digits backward test were administered at the same time points. In both studies, a mixed analysis of variance revealed statistically significant changes to the cognitive functioning of participants. A change in cognitive strategy was observed, reflected by a decrease in executive function (switches) and an increase in nonexecutive function (cluster size). These data suggest that the cognitive effects of exercise and body armor may have profound implications for police officers' ability to make tactical decisions.

  7. Subjective, psychomotor, and physiological effects of pregabalin alone and in combination with oxycodone in healthy volunteers.

    PubMed

    Zacny, James P; Paice, Judith A; Coalson, Dennis W

    2012-01-01

    Pregabalin is an anticonvulsant drug indicated for neuropathic disorders and fibromyalgia. Some chronic pain patients suffering from these disorders take both this drug and an opioid for pain relief. Pregabalin is a scheduled drug under the Controlled Substances Act. The subjective effects of this drug have not been well-characterized, and the extent to which it alters the subjective effects of opioids has not been studied to the best of our knowledge. Using a double-blind, randomized, crossover design, 16 healthy volunteers were administered (in separate sessions) capsules containing placebo, 75 mg pregabalin, 150 mg pregabalin, 10 mg oxycodone, and 75 mg pregabalin combined with 10 mg oxycodone. Subjective, psychomotor, and physiological measures were assessed during each of the five sessions. Pregabalin produced dose-related increases in some subjective effects and decreased respiration rate, but did not impact on psychomotor performance. Abuse liability-related subjective effects such as drug liking and desire to take the drug again were not increased by either pregabalin dose. Oxycodone produced increases in several subjective effects, including ratings of drug liking. When 75 mg pregabalin was combined with oxycodone some subjective effects were altered relative to placebo, in contrast to when each drug was tested alone. Liking of oxycodone was not increased by 75 mg pregabalin. However, recent studies have suggested that this drug is abused, and we would recommend that further psychopharmacological studies with pregabalin are warranted, including a study assessing its abuse liability across a range of doses in sedative abusers.

  8. Pharmacokinetics, metabolism, and excretion of nefopam, a dual reuptake inhibitor in healthy male volunteers.

    PubMed

    Sanga, Madhu; Banach, John; Ledvina, Aaron; Modi, Nishit B; Mittur, Aravind

    2016-11-01

    1. The disposition of nefopam, a serotonin-norepinephrine reuptake inhibitor, was characterized in eight healthy male volunteers following a single oral dose of 75 mg [(14)C]-nefopam (100 μCi). Blood, urine, and feces were sampled for 168 h post-dose. 2. Mean (± SD) maximum blood and plasma radioactivity concentrations were 359 ± 34.2 and 638 ± 64.7 ngEq free base/g, respectively, at 2 h post-dose. Recovery of radioactive dose was complete (mean 92.6%); a mean of 79.3% and 13.4% of the dose was recovered in urine and feces, respectively. 3. Three main radioactive peaks were observed in plasma (metabolites M2 A-D, M61, and M63). Intact [(14)C]-nefopam was less than 5% of the total radioactivity in plasma. In urine, the major metabolites were M63, M2 A-D, and M51 which accounted for 22.9%, 9.8%, and 8.1% of the dose, respectively. An unknown entity, M55, was the major metabolite in feces (4.6% of dose). Excretion of unchanged [(14)C]-nefopam was minimal.

  9. Cardiac metabolism during exercise in healthy volunteers measured by 31P magnetic resonance spectroscopy

    PubMed Central

    Conway, Michael A; Bristow, J David; Blackledge, Martin J; Rajagopalan, Bheeshma; Radda, George K

    1991-01-01

    A technique was devised for individuals to exercise prone in a magnet during magnetic resonance spectroscopy of the heart and phosphorus-31 magnetic resonance spectra of the heart were obtained by the phase modulated rotating frame imaging technique in six healthy volunteers during steady state dynamic quadriceps exercise. During prone exercise heart rate, blood pressure, and total body oxygen consumption were measured at increasing loads and the results were compared with those during Bruce protocol treadmill exercise. During prone exercise with a 5 kg load the heart rate was similar and the systolic and diastolic blood pressures were higher than those during stage 1 of the Bruce protocol. The rate-pressure products were similar but the total body oxygen consumption was lower during prone exercise. There was no difference in the ratio of phosphocreatine to adenosine triphosphate during rest and exercise. Thus during exercise that produced a local cardiac stress equal to or greater than that during stage 1 of the Bruce protocol treadmill exercise, the energy requirements of the normal human myocardium were adequately supplied by oxidative phosphorylation. PMID:1993127

  10. Influence of smoking on caffeine elimination in healthy volunteers and in patients with alcoholic liver cirrhosis.

    PubMed

    Joeres, R; Klinker, H; Heusler, H; Epping, J; Zilly, W; Richter, E

    1988-01-01

    The effect of smoking on caffeine elimination was measured in 7 healthy volunteers and in 18 smoking and in 30 nonsmoking patients with alcoholic liver cirrhosis following oral application of 366 mg caffeine. In an intraindividual experiment in smoking health probands, caffeine clearance decreased from 118 +/- 33 to 77 +/- 22 ml per min (p less than 0.05) after abstaining cigarette smoking for 3 weeks. In a control group without liver disease (8 smokers, 15 nonsmokers), we found a caffeine clearance of 114 +/- 40 ml per min in smokers and 64 +/- 20 in nonsmokers (p less than 0.05). Smoking and nonsmoking patients with alcoholic liver cirrhosis did not differ with respect to clinical and laboratory data and hexobarbitone elimination. However, caffeine clearance was 63 +/- 63 ml per min in smoking patients compared to 34 +/- 49 ml per min in nonsmokers (p less than 0.05). Fasting plasma concentrations of caffeine were higher in nonsmokers (5.1 +/- 6.2 micrograms per ml) than in smokers (2.1 +/- 4.5 micrograms per ml, p less than 0.05). We conclude that smoking habits have to be taken into account if caffeine is used as a model compound for measuring quantitative liver function.

  11. First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers.

    PubMed

    Stevens, Misty W; Henry, Ralph L; Owens, S Michael; Schutz, Ralph; Gentry, W Brooks

    2014-01-01

    This first-in-human study examined the safety and pharmacokinetics of ch-mAb7F9, an anti-methamphetamine monoclonal antibody, in healthy volunteers. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20 mg/kg were administered to 42 subjects who were followed for 147 d. Safety was measured by physical examinations, adverse events, vital signs, electrocardiograms, and clinical laboratory testing. Serum ch-mAb7F9 concentration and immunogenicity analyses were performed. There were no serious adverse reactions or discontinuations from the study due to adverse events. No trends emerged in the frequency, relatedness, or severity of adverse events with increased dose or between active and placebo treated subjects. Ch-mAb7F9 displayed expected IgG pharmacokinetic parameters, including a half-life of 17-19 d in the 3 highest dose groups and volume of distribution of 5-6 L, suggesting the antibody is confined primarily to the vascular compartment. Four (12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study; however, this response did not appear to be dose related. Overall, no apparent safety or tolerability concerns were identified; a maximum tolerated dose was not reached in this Phase 1 study. Ch-mAb7F9 therefore appears safe for human administration.

  12. Validation of the simplified UVB model to assess the pharmacodynamics of analgesics in healthy human volunteers.

    PubMed

    Ing Lorenzini, Kuntheavy; Besson, Marie; Daali, Youssef; Salomon, Denis; Dayer, Pierre; Desmeules, Jules

    2012-01-01

    A pharmacokinetic/pharmacodynamic, randomized, crossover, placebo-controlled study was conducted in healthy human volunteers with the primary objective of exploring the existence of a positive interaction between paracetamol 1 g and ketorolac 20 mg intravenously on experimental pain models. Further, the simplified UVB model was validated as a screening tool for analgesics or a combination of analgesics in clinical drug development. It was observed that the UVB irradiation induced primary hyperalgesia, evidenced by significant decreases of the heat pain threshold from (mean ± SD) 46.9 ± 1.1 °C to 40.1 ± 1.7 °C (p <0.001) and of the mechanical pain threshold (62% decrease). A small intra- and inter-individual variability was observed as well as consistent intra-day stability for the heat pain threshold. The UVB irradiation also resulted in the development of an area of secondary hyperalgesia of 21.3 ± 11.3 cm(2). The mechanical pain threshold and area of secondary hyperalgesia showed small intra-individual variability and consistent intra-day stability. However, a greater variability was observed between subjects, which suggests that a crossover design would allow limiting the number of subjects.

  13. Emotional processing in women with anorexia nervosa and in healthy volunteers.

    PubMed

    Jänsch, Claire; Harmer, Catherine; Cooper, Myra J

    2009-08-01

    Emotional processing was investigated in patients with anorexia nervosa (AN) and in healthy volunteers (HVs) using self report questionnaires and information processing tasks. Compared to the HVs, patients with AN had lower levels of self reported emotional awareness and expression. They also responded more slowly to, correctly identified fewer emotions and misclassified more emotions in a facial recognition task, and responded more slowly to, and recalled fewer, self-referent emotion words. There were no key differences between the two groups on non-emotional control tasks, suggesting that their deficits are specific to emotional information and not a general feature of the illness. Analysis indicated that some, but not all, of the differences found remained when depressive symptoms were taken into account. Exploratory analysis of sub-groups (medicated vs. unmedicated patients) indicated that those who were on medication may perform very differently from those who were not on medication, including when level of depression is controlled, although it is important to emphasise that these findings are preliminary. The implications of a deficit in emotional processing in those with AN, including discussion of the specific differences found between medicated and unmedicated, are discussed in relation to previous findings in the area. A number of implications for future research, theory and therapy with those with AN are discussed.

  14. Acute neuropsychological effects of MDMA and ethanol (co-)administration in healthy volunteers

    PubMed Central

    Wezenberg, E.; Valkenberg, M. M. G. J.; de Jong, C. A. J.; Buitelaar, J. K.; van Gerven, J. M. A.; Verkes, R. J.

    2008-01-01

    Rationale In Western societies, a considerable percentage of young people expose themselves to 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”). Commonly, ecstasy is used in combination with other substances, in particular alcohol (ethanol). MDMA induces both arousing as well as hallucinogenic effects, whereas ethanol is a general central nervous system depressant. Objective The aim of the present study is to assess the acute effects of single and co-administration of MDMA and ethanol on executive, memory, psychomotor, visuomotor, visuospatial and attention function, as well as on subjective experience. Materials and methods We performed a four-way, double-blind, randomised, crossover, placebo-controlled study in 16 healthy volunteers (nine male, seven female) between the ages of 18–29. MDMA was given orally (100 mg) and blood alcohol concentration was maintained at 0.6‰ by an ethanol infusion regime. Results Co-administration of MDMA and ethanol was well tolerated and did not show greater impairment of performance compared to the single-drug conditions. Impaired memory function was consistently observed after all drug conditions, whereas impairment of psychomotor function and attention was less consistent across drug conditions. Conclusions Co-administration of MDMA and ethanol did not exacerbate the effects of either drug alone. Although the impairment of performance by all drug conditions was relatively moderate, all induced significant impairment of cognitive function. PMID:18305926

  15. The effect of the M1-selective telenzepine on esophageal acid exposure in healthy volunteers.

    PubMed

    Stockbrügger, R W; Armbrecht, U; Reul, W

    1988-06-01

    In order to study the effect of the new M1-selective antimuscarinic compound telenzepine on physiological esophageal acid exposure, ten healthy volunteers underwent a 24-hour esophageal pH-monitoring during a one week treatment with either tablets containing telenzepine 3 mg nightly or placebo in a double-blind cross-over trial. Side-effects were recorded, and stimulated salivary output was assessed. Using a cut-off pH less than 4, under telenzepine a significant reduction of reflux time and of maximum reflux duration was observed in supine position. Using a cut-off pH less than 2, reflux time was reduced during and after meals, number of refluxes was decreased during meals, and esophageal clearance was improved with telenzepine in supine position. Telenzepine reduced salivary output significantly on day 4 and on day 7. From the results it can be concluded that the drug is not contraindicated in peptic ulcer patients with heartburn. As telenzepine reduces gastroesophageal reflux time during and after meals and in supine position it may be tried as adjuvant treatment in esophageal reflux disease.

  16. Lack of bioequivalence of gatifloxacin when coadministered with calcium-fortified orange juice in healthy volunteers.

    PubMed

    Wallace, Allison W; Victory, Jennifer M; Amsden, Guy W

    2003-01-01

    Previous work has demonstrated that the chelation interaction seen with ciprofloxacin when it is coadministered with antacids also happens when it is coadministered with calcium-fortified foods. This study was conducted to study whether this was a drug-specific finding or whether the interaction occurs with other members of the fluoroquinolone class of drugs. Sixteen healthy volunteers received single 400-mg oral doses of gatifloxacin with 12 ounces each of water, nonfortified orange juice, and calcium-fortified orange juice and had plasma samples drawn for assay over the subsequent 48 hours. Results demonstrated significant increases in total oral clearance (15%) and volume of distribution (13%) along with a matching significant decrease (12%) in exposure (AUC) when gatifloxacin was taken with the fortified juice. Although not statistically significant, peak concentrations decreased by 15% and were reached (tmax) approximately 38% later when gatifloxacin was coadministered with the calcium-fortified juice. Bioavailability testing indicated that although the 90% confidence intervals (CIs) for the ratio of the geometric means of the calcium-fortified juice and water arms' AUC stayed within the range of 80% to 125%, those for Cmax did not. This study demonstrated a chelation or adsorption interaction between the fortified juice and gatifloxacin that reached regulatory significance. As a result, clinicians may wish to instruct patients to take gatifloxacin either with nonfortified foods or on an empty stomach.

  17. Absolute bioavailability and absorption characteristics of divalproex sodium extended-release tablets in healthy volunteers.

    PubMed

    Dutta, Sandeep; Reed, Ronald C; Cavanaugh, John H

    2004-07-01

    Conventional delayed-release, enteric-coated divalproex sodium tablet has an absolute bioavailability of approximately 100%. Divalproex sodium extended-release (ER) tablet is a novel formulation of valproic acid (VPA) designed to release the drug slowly at a constant zero-order rate. The purpose of this study was to evaluate the absolute bioavailability and absorption characteristics of divalproex ER. Healthy adult volunteers (n = 16) received divalproex ER and intravenous VPA in crossover fashion. Absolute bioavailability was calculated as the divalproex ER/intravenous VPA ratio of area under the curve extrapolated to infinity. The duration and rate of absorption of VPA from divalproex ER tablets were determined by deconvolution analysis. The geometric mean absolute bioavailability of divalproex ER was 0.896. The mean (coefficient of variation) duration of drug absorption from divalproex ER was 21.8 (17%) hours, and the zero-order absorption rate was 21.6 (24%) mg/h for a 500-mg tablet. Divalproex ER has a lower absolute bioavailability than conventional divalproex tablets but exhibits good extended-release characteristics without any dose dumping.

  18. Bioequivalence Study of Modified-Release Gliclazide Tablets in Healthy Volunteers

    PubMed Central

    Rojanasthien, Noppamas; Autsavakitipong, Thatree; Kumsorn, Boonyium; Manorot, Maleeya; Teekachunhatean, Supanimit

    2012-01-01

    This study was aimed to investigate bioequivalence of modified-release 30 mg gliclazide tablets in 18 healthy Thai volunteers. A test product, Glycon MR (Siam Bheasach, TH), was compared with a reference product, Diamicron MR (Servier, France). The study was performed under a single-dose, two-treatment, two-period, and two-sequence crossover design in fasted and fed conditions with a washout period of 2 weeks. Blood samples were collected for 72 h after drug administration. Drug plasma concentrations were determined by HPLC with a UV detector. Analysis of pharmacokinetic characteristics was based on a non-compartmental model. The logarithmically transformed data of Cmax and AUCs were analyzed for 90% confidence intervals using ANOVA. The test product gave slightly higher Cmax in both conditions and shorter Tmax in the fed condition. However, there is no significant difference in pharmacokinetic characteristics between both products under fasted and fed conditions. Effect of food was not significantly observed. The 90% confidence intervals were within the acceptance criteria of 0.80–1.25 regardless of the food effect, indicating bioequivalence between the two products on the rate and extent of gliclazide MR absorption without regard to meals. PMID:23029622

  19. Pharmacokinetic/pharmacodynamic modeling of psychomotor impairment induced by oral clonazepam in healthy volunteers.

    PubMed

    dos Santos, Fábio Monteiro; Gonçalves, José Carlos Saraiva; Caminha, Ricardo; da Silveira, Gabriel Estolano; Neves, Claúdia Silvana de Miranda; Gram, Karla Regina da Silva; Ferreira, Carla Teixeira; Jacqmin, Philippe; Noël, François

    2009-10-01

    This study was undertaken to model the relationship between clonazepam plasma concentrations and a central nervous system adverse effect (impairment of the psychomotor performance) following the oral administration of immediate-release tablets of clonazepam in healthy volunteers. Such a (P)pharmacokinetic/(P)pharmacodynamic (PK/PD) study is important to interpret properly the consequences of determined levels of plasma concentrations of psychoactive therapeutic drugs reported to be involved in road-traffic accidents. Twenty-three male subjects received a single oral dose of 4 mg clonazepam. Plasma concentration, determined by on-line solid phase extraction coupled with high-performance liquid chromatography tandem mass spectrometry, and psychomotor performance, quantified through the Digit Symbol Substitution Test, were monitored for 72 hours. A 2-compartment open model with first order absorption and lag-time better fitted the plasma clonazepam concentrations. Clonazepam decreased the psychomotor performance by 72 +/- 3.7% (observed maximum effect), 1.5 to 4 hours (25th-75th percentile) after drug administration. A simultaneous population PK/PD model based on a sigmoid Emax model with time-dependent tolerance described well the time course of effect. Such acute tolerance could minimize the risk of accident as a result of impairment of motor skill after a single dose of clonazepam. However, an individual analysis of the data revealed a great interindividual variation in the relationship between clonazepam effect and plasma concentration, indicating that the phenomenon of acute tolerance can be predicted at a population, but not individual, level.

  20. Emission rates of selected volatile organic compounds from skin of healthy volunteers.

    PubMed

    Mochalski, Paweł; King, Julian; Unterkofler, Karl; Hinterhuber, Hartmann; Amann, Anton

    2014-05-15

    Gas chromatography with mass spectrometric detection (GC-MS) coupled with solid phase micro-extraction as pre-concentration method (SPME) was applied to identify and quantify volatile organic compounds (VOCs) emitted by human skin. A total of 64 C4-C10 compounds were quantified in skin emanation of 31 healthy volunteers. Amongst them aldehydes and hydrocarbons were the predominant chemical families with eighteen and seventeen species, respectively. Apart from these, there were eight ketones, six heterocyclic compounds, six terpenes, four esters, two alcohols, two volatile sulphur compounds, and one nitrile. The observed median emission rates ranged from 0.55 to 4,790 fmol cm(-2)min(-1). Within this set of analytes three volatiles; acetone, 6-methyl-5-hepten-2-one, and acetaldehyde exhibited especially high emission rates exceeding 100 fmol cm(-2)min(-1). Thirty-three volatiles were highly present in skin emanation with incidence rates over 80%. These species can be considered as potential markers of human presence, which could be used for early location of entrapped victims during Urban Search and Rescue Operations (USaR).

  1. Effect of valdecoxib pretreatment on pain and secondary hyperalgesia: a randomized controlled trial in healthy volunteers [ISRCTN05282752, NCT00260325

    PubMed Central

    Burns, David; Hill, Lindsay; Essandoh, Michael; Jarzembowski, Tomasz M; Schuler, H Gregg; Janicki, Piotr K

    2006-01-01

    Background Induction of the COX-2 isoenzyme appears to play a major role in the genesis of central sensitization after nociceptive stimulation. This study aimed to investigate the efficacy of a single, oral dose of the specific COX-2 inhibitor-valdecoxib in attenuating the central sensitization – induced secondary hyperalgesia in a heat/capsaicin pain model in healthy volunteers. Methods The study was a randomized, double blind, placebo controlled, crossover, single dose efficacy trial using 20 healthy volunteers. Two hours following placebo or 40 mg, PO valdecoxib, participants underwent skin sensitization with heat/capsaicin, as well as supra-threshold pain and re-kindling measurements according to an established, validated pain model. Subjects rated pain intensity and unpleasantness on a visual analog scale and the area of secondary hyperalgesia was serially mapped. Results The area of secondary hyperalgesia produced after 40 mg of valdecoxib was no different than that after placebo. Furthermore, there were no significantly relevant differences when volunteers were treated with valdecoxib or placebo in relation to either cold- or hot pain threshold or the intensity of pain after supra-threshold, thermal pain stimulation. Conclusion We demonstrated that a single, oral dose of valdecoxib when does not attenuate secondary hyperalgesia induced by heat/capsaicin in a cutaneous sensitization pain model in healthy volunteers. PMID:16529650

  2. Cutaneous Respirometry as Novel Technique to Monitor Mitochondrial Function: A Feasibility Study in Healthy Volunteers

    PubMed Central

    Stolker, Robert Jan; Mik, Egbert

    2016-01-01

    Background The protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT) is proposed as a potential clinical non-invasive tool to monitor mitochondrial function. This technique has been evaluated in several animal studies. Mitochondrial respirometry allows measurement in vivo of mitochondrial oxygen tension (mitoPO2) and mitochondrial oxygen consumption (mitoVO2) in skin. This study describes the first use of a clinical prototype in skin of humans. Methods The clinical prototype was tested in 30 healthy volunteers. A self-adhesive patch containing 2 mg 5-aminolevulinic acid (ALA) was applied on the skin of the anterior chest wall (sternal) for induction of mitochondrial protoporphyrin IX and was protected from light for 5 h. MitoPO2 was measured by means of oxygen-dependent delayed fluorescence of protoporphyrin IX. MitoVO2 was determined by dynamic mitoPO2 measurements on the primed skin, while locally blocking oxygen supply by applying local pressure with the measurement probe. MitoPO2 was recorded before and during a 60-s period of compression of the microcirculation, at an interval of 1 Hz. Oxygen consumption (i.e. the local oxygen disappearance rate) was calculated from the decay of the mitoPO2 slope. Results Oxygen-dependent delayed fluorescence measurements were successfully performed in the skin of 27 volunteers. The average value (± SD) of mitoPO2 was 44 ± 17 mmHg and mean mitoVO2 values were 5.8 ± 2.3 and 6.1 ± 1.6 mmHg s-1 at a skin temperature of 34°C and 40°C, respectively. No major discomfort during measurement and no long-term dermatological abnormalities were reported in a survey performed 1 month after measurements. Conclusion These results show that the clinical prototype allows measurement of mitochondrial oxygenation and oxygen consumption in humans. The development of this clinically applicable device offers opportunities for further evaluation of the technique in humans and the start of first clinical studies. PMID:27455073

  3. Safety, Tolerability, and Pharmacokinetics of Intravenous Nemonoxacin in Healthy Chinese Volunteers

    PubMed Central

    Cao, Guo-ying; Zhang, Ying-yuan; Guo, Bei-ning; Yu, Ji-cheng; Wu, Xiao-jie; Chen, Yuan-cheng; Wu, Ju-Fang; Shi, Yao-guo

    2014-01-01

    Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (Cmax) values were 4.826 μg/ml, 7.152 μg/ml, and 11.029 μg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC0–72 h) were 17.05 μg · h/ml, 39.30 μg · h/ml, and 61.98 μg · h/ml. The mean elimination half-life (t1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC0–72 h and AUC0–∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.) PMID:25092690

  4. The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age

    PubMed Central

    Al-Salameh, Abdallah; Croixmarie, Vincent; Masson, Perrine; Corruble, Emmanuelle; Fève, Bruno; Colle, Romain; Ripoll, Laurent; Walther, Bernard; Boursier-Neyret, Claire; Werner, Erwan; Becquemont, Laurent; Chanson, Philippe

    2017-01-01

    Metabolomic approaches are increasingly used to identify new disease biomarkers, yet normal values of many plasma metabolites remain poorly defined. The aim of this study was to define the “normal” metabolome in healthy volunteers. We included 800 French volunteers aged between 18 and 86, equally distributed according to sex, free of any medication and considered healthy on the basis of their medical history, clinical examination and standard laboratory tests. We quantified 185 plasma metabolites, including amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, sphingomyelins and hexose, using tandem mass spectrometry with the Biocrates AbsoluteIDQ p180 kit. Principal components analysis was applied to identify the main factors responsible for metabolome variability and orthogonal projection to latent structures analysis was employed to confirm the observed patterns and identify pattern-related metabolites. We established a plasma metabolite reference dataset for 144/185 metabolites. Total blood cholesterol, gender and age were identified as the principal factors explaining metabolome variability. High total blood cholesterol levels were associated with higher plasma sphingomyelins and phosphatidylcholines concentrations. Compared to women, men had higher concentrations of creatinine, branched-chain amino acids and lysophosphatidylcholines, and lower concentrations of sphingomyelins and phosphatidylcholines. Elderly healthy subjects had higher sphingomyelins and phosphatidylcholines plasma levels than young subjects. We established reference human metabolome values in a large and well-defined population of French healthy volunteers. This study provides an essential baseline for defining the “normal” metabolome and its main sources of variation. PMID:28278231

  5. Safety and Tolerability of Panax ginseng Root Extract: A Randomized, Placebo-Controlled, Clinical Trial in Healthy Korean Volunteers

    PubMed Central

    Lee, Nam-Hun; Yoo, Sa-Ra; Kim, Hyeong-Geug; Cho, Jung-Hyo

    2012-01-01

    Abstract Objectives Panax ginseng has been extensively used as an adaptogen and is among the top 10 selling herbal supplements in the United States over the past decade. However, there have been few reports about the toxicity of P. ginseng in human studies. Given the lack of toxicological studies in human, this study investigated whether P. ginseng administration causes any noticeable toxic effects in healthy volunteers. Methods This study was designed as a randomized, double-blind, placebo-controlled, and parallel group trial in healthy volunteers. The subjects were required to be healthy, free from any significant disease, as assessed at screening by physical examination, medical history, and laboratory (hematological and biochemical) tests. Eligible subjects received P. ginseng extract (1 g/day or 2 g/day) or placebo over a 4-week period. Results Although mild adverse events, such as dyspepsia, hot flash, insomnia, and constipation, were reported in both P. ginseng and placebo group, no serious untoward reactions were reported following P. ginseng administration. Nonsignificant changes were observed in hematological and biochemical tests. Conclusions P. ginseng administration for 4 weeks was shown to be safe, tolerable, and free of any untoward toxic effect in healthy male and female volunteers. Future results from ongoing multicenter collaborative efforts to evaluate short- and long-term effects of P. ginseng may contribute to our current understanding of safety and tolerability of this herbal product. PMID:22909282

  6. The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age.

    PubMed

    Trabado, Séverine; Al-Salameh, Abdallah; Croixmarie, Vincent; Masson, Perrine; Corruble, Emmanuelle; Fève, Bruno; Colle, Romain; Ripoll, Laurent; Walther, Bernard; Boursier-Neyret, Claire; Werner, Erwan; Becquemont, Laurent; Chanson, Philippe

    2017-01-01

    Metabolomic approaches are increasingly used to identify new disease biomarkers, yet normal values of many plasma metabolites remain poorly defined. The aim of this study was to define the "normal" metabolome in healthy volunteers. We included 800 French volunteers aged between 18 and 86, equally distributed according to sex, free of any medication and considered healthy on the basis of their medical history, clinical examination and standard laboratory tests. We quantified 185 plasma metabolites, including amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, sphingomyelins and hexose, using tandem mass spectrometry with the Biocrates AbsoluteIDQ p180 kit. Principal components analysis was applied to identify the main factors responsible for metabolome variability and orthogonal projection to latent structures analysis was employed to confirm the observed patterns and identify pattern-related metabolites. We established a plasma metabolite reference dataset for 144/185 metabolites. Total blood cholesterol, gender and age were identified as the principal factors explaining metabolome variability. High total blood cholesterol levels were associated with higher plasma sphingomyelins and phosphatidylcholines concentrations. Compared to women, men had higher concentrations of creatinine, branched-chain amino acids and lysophosphatidylcholines, and lower concentrations of sphingomyelins and phosphatidylcholines. Elderly healthy subjects had higher sphingomyelins and phosphatidylcholines plasma levels than young subjects. We established reference human metabolome values in a large and well-defined population of French healthy volunteers. This study provides an essential baseline for defining the "normal" metabolome and its main sources of variation.

  7. Transcutaneous immunization of healthy volunteers with an attenuated Listeria monocytogenes vaccine strain and cholera toxin adjuvant☆☆☆

    PubMed Central

    Eypper, Elizabeth H.; Johnson, Paul V.; Purro, Eva I.; Hohmann, Elizabeth L.

    2013-01-01

    Background Attenuated Listeria monocytogenes vaccine strains have been administered intravenously (Le et al. [1], Maciag et al. [2]) and orally (Angelakopoulos et al. [3], Johnson et al. [4]) to humans. Here, one was given transcutaneously with cholera toxin adjuvant. Methods Eight healthy volunteers were studied (5 active, 3 placebo). Safety was assessed by physical exam and labs. Systemic immunological responses were measured by ELISA and IFN-gamma ELISpot. Results 4/5 active volunteers had cellular responses to listerial antigens. 5/5 active volunteers showed humoral responses to cholera toxin. Conclusions An attenuated L. monocytogenes vector was safely administered transcutaneously. Topical administration appeared at least as immunogenic as previously studied oral delivery. PMID:23707162

  8. Using “Clinical Trial Diaries” to Track Patterns of Participation for Serial Healthy Volunteers in U.S. Phase I Studies

    PubMed Central

    Edelblute, Heather B.; Fisher, Jill A.

    2015-01-01

    Phase I testing of investigational drugs relies on healthy volunteers as research participants. Many U.S. healthy volunteers enroll repeatedly in clinical trials for the financial compensation. Serial participants are incentivized to ignore restrictions on their participation, and no centralized clinical trial registry prevents dual enrollment. Little is currently known about how healthy volunteers participate in studies over time, hampering the development of policies to protect this group. We detail a methodology developed as part of a longitudinal study to track in real-time healthy volunteers’ Phase I participation. Illustrating these data through three case studies, we document how healthy volunteers use strategies, such as qualifying for studies at more than one clinic and traveling significant distances, to maximize their participation. Our findings suggest that “clinical trial diaries” can generate critical information about serial research participation and point to ethical issues unique to healthy volunteers’ involvement in Phase I clinical trials. PMID:25742668

  9. Effect of ginkgo biloba on the pharmacokinetics of raltegravir in healthy volunteers.

    PubMed

    Blonk, Maren; Colbers, Angela; Poirters, Anne; Schouwenberg, Bas; Burger, David

    2012-10-01

    Medicinal herbs may cause clinically relevant drug interactions with antiretroviral agents. Ginkgo biloba extract is a popular herbal product among HIV-infected patients because of its positive effects on cognitive function. Raltegravir, an HIV integrase inhibitor, is increasingly being used as part of combined antiretroviral therapy. Clinical data on the potential inhibitory or inductive effect of ginkgo biloba on the pharmacokinetics of raltegravir were lacking, and concomitant use was not recommended. We studied the effect of ginkgo biloba extract on the pharmacokinetics of raltegravir in an open-label, randomized, two-period, crossover phase I trial in 18 healthy volunteers. Subjects were randomly assigned to a regimen of 120 mg of ginkgo biloba twice daily for 15 days plus a single dose of raltegravir (400 mg) on day 15, a washout period, and 400 mg of raltegravir on day 36 or the test and reference treatments in reverse order. Pharmacokinetic sampling of raltegravir was performed up to 12 h after intake on an empty stomach. All subjects (9 male) completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence intervals) of the area under the plasma concentration-time curve from dosing to infinity (AUC(0-∞)) and the maximum plasma concentration (C(max)) of raltegravir with ginkgo biloba versus raltegravir alone were 1.21 (0.93 to 1.58) and 1.44 (1.03 to 2.02). Ginkgo biloba did not reduce raltegravir exposure. The potential increase in the C(max) of raltegravir is probably of minor importance, given the large intersubject variability of raltegravir pharmacokinetics and its reported safety profile.

  10. Pharmacokinetics of iron(III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers.

    PubMed

    Danielson, B G; Salmonson, T; Derendorf, H; Geisser, P

    1996-06-01

    The pharmacokinetics of iron were investigated after intravenous administration to 12 healthy volunteers of iron(III)-hydroxide sucrose complex (Venofer) as a single i.v. dose containing 100 mg Fe. The average predose concentration was 35.7 +/- 12.5 mumol/l. There was no statistically significant difference between the serum iron level before injection (0 h) and the level at 24 h after the injection. The compartment model used includes a Michaelis-Menten term and is in excellent agreement with the observed exchange of iron to transferrin and with the daily iron turnover by transferrin. The intravenously injected iron(III)-hydroxide sucrose complex led rapidly to high serum iron levels. Maximum measured levels averaged 538 mumol/l (30.0 mg/l) at 10 min after the injection. The terminal half-life of the injected iron was calculated to be 5.3 h. Mean total area under the curve (AUC) was 1491 mumol/l h, the mean residence time (MRT) was 5.5 h. The total body clearance was 20.5 ml/min. The volume of distribution of the central compartment (Vc) was 3.21, hence close to the volume of the serum; the volume of distribution at steady state (Vdss) was 7.31; and the volume of distribution during elimination (Vdarea) was 9.21. The calculated amount of iron transported by transferrin was 31.0 +/- 6.6 mg Fe/ 24h. In summary, the data show that the injected iron(III)-hydroxide sucrose complex is quickly cleared from the serum with a terminal half-life of approximately 5-6 h. Renal elimination of iron contributed very little to the overall elimination (in average < 5%). Renal elimination of sucrose averaged about 68 +/- 10% and 75 +/- 11% of the administered dose after 4 h and 24 h, respectively.

  11. Cerebral venous blood oxygenation monitoring during hyperventilation in healthy volunteers with a novel optoacoustic system

    NASA Astrophysics Data System (ADS)

    Petrov, Andrey; Prough, Donald S.; Petrov, Irene Y.; Petrov, Yuriy; Deyo, Donald J.; Henkel, Sheryl N.; Seeton, Roger; Esenaliev, Rinat O.

    2013-03-01

    Monitoring of cerebral venous oxygenation is useful to facilitate management of patients with severe or moderate traumatic brain injury (TBI). Prompt recognition of low cerebral venous oxygenation is a key to avoiding secondary brain injury associated with brain hypoxia. In specialized clinical research centers, jugular venous bulb catheters have been used for cerebral venous oxygenation monitoring and have demonstrated that oxygen saturation < 50% (normal range is 55-75%) correlates with poor clinical outcome. We developed an optoacoustic technique for noninvasive monitoring of cerebral venous oxygenation. Recently, we designed and built a novel, medical grade optoacoustic system operating in the near-infrared spectral range for continuous, real-time oxygenation monitoring in the superior sagittal sinus (SSS), a large central cerebral vein. In this work, we designed and built a novel SSS optoacoustic probe and developed a new algorithm for SSS oxygenation measurement. The SSS signals were measured in healthy volunteers during voluntary hyperventilation, which induced changes in SSS oxygenation. Simultaneously, we measured exhaled carbon dioxide concentration (EtCO2) using capnography. Good temporal correlation between decreases in optoacoustically measured SSS oxygenation and decreases in EtCO2 was obtained. Decreases in EtCO2 from normal values (35-45 mmHg) to 20-25 mmHg resulted in SSS oxygenation decreases by 3-10%. Intersubject variability of the responses may relate to nonspecific brain activation associated with voluntary hyperventilation. The obtained data demonstrate the capability of the optoacoustic system to detect in real time minor changes in the SSS blood oxygenation.

  12. Flosequinan does not affect systemic and regional vascular responses to simulated orthostatic stress in healthy volunteers.

    PubMed Central

    Duranteau, J; Pussard, E; Edouard, A; Samii, K; Berdeaux, A; Giudicelli, J F

    1992-01-01

    1. The effects of a single oral dose (100 mg) of flosequinan on systemic and regional (forearm, splanchnic and renal) vascular responses to simulated orthostatic stress (lower body negative pressure, LBNP) were investigated in nine healthy male volunteers, in a double-blind, placebo-controlled crossover study. 2. Forty-five minutes after its administration and before LBNP, flosequinan induced a significant decrease in total peripheral and in forearm vascular resistances without any concomitant change in arterial pressure, in heart rate and in the investigated biological parameters (plasma catecholamines, arginine vasopressin and renin activity). 3. After flosequinan and placebo, LBNP induced similar decreases in central venous pressure at all levels of LBNP (-10, -20 and -40 mm Hg) and in pulse pressure at LBNP -40 mm Hg. LBNP-induced increase in forearm vascular resistance was significantly more marked after flosequinan than after placebo at all levels of LBNP, and this was also true for splanchnic vascular resistance but at LBNP -40 mm Hg only. However, inasmuch as the basal values of these two parameters before LBNP were lower after flosequinan than after placebo, their final values after LBNP -40 mm Hg were similar. Finally, LBNP-induced changes in renal vascular resistance, glomerular filtration rate and filtration fraction as well as in plasma catecholamines, arginine vasopressin and renin activity were similar after flosequinan and placebo at all levels of LBNP. 4. Flosequinan affected neither reflex control of heart rate (phenylephrine test) nor non-specific vasoconstrictor responses (cold pressor test). (ABSTRACT TRUNCATED AT 250 WORDS) PMID:1389945

  13. Methylnaltrexone: Its Pharmacological Effects Alone and Effects on Morphine in Healthy Volunteers

    PubMed Central

    Zacny, James P.; Wroblewski, Kristen; Coalson, Dennis W.

    2014-01-01

    Rationale Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans, and have suggested based on their results that these other effects are altered by peripheral opioid actions. Objective The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally-mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine. Methods In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed. Results Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis. Conclusions We present indirect evidence that MTNX crosses the blood-brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question. PMID:24871705

  14. Glycine Transporter Type 1 Occupancy by Bitopertin: a Positron Emission Tomography Study in Healthy Volunteers

    PubMed Central

    Martin-Facklam, Meret; Pizzagalli, Flavia; Zhou, Yun; Ostrowitzki, Susanne; Raymont, Vanessa; Brašić, James R; Parkar, Nikhat; Umbricht, Daniel; Dannals, Robert F; Goldwater, Ron; Wong, Dean F

    2013-01-01

    Deficient N-methyl-D-aspartate (NMDA) receptor transmission is thought to underlie schizophrenia. An approach for normalizing glutamate neurotransmission by enhancing NMDA receptor transmission is to increase glycine availability by inhibiting the glycine transporter type 1 (GlyT1). This study investigated the relationship between the plasma concentration of the glycine reuptake inhibitor bitopertin (RG1678) and brain GlyT1 occupancy. Healthy male volunteers received up to 175 mg bitopertin once daily, for 10–12 days. Three positron emission tomography scans, preceded by a single intravenous infusion of ∼30 mCi [11C]RO5013853, were performed: at baseline, on the last day of bitopertin treatment, and 2 days after drug discontinuation. Eighteen subjects were enrolled. At baseline, regional volume of distribution (VT) values were highest in the pons, thalamus, and cerebellum (1.7–2.7 ml/cm3) and lowest in cortical areas (∼0.8 ml/cm3). VT values were reduced to a homogeneous level following administration of 175 mg bitopertin. Occupancy values derived by a two-tissue five-parameter (2T5P) model, a simplified reference tissue model (SRTM), and a pseudoreference tissue model (PRTM) were overall comparable. At steady state, the relationship between bitopertin plasma concentration and GlyT1 occupancy derived by the 2T5P model, SRTM, and PRTM exhibited an EC50 of ∼190, ∼200, and ∼130 ng/ml, respectively. Emax was ∼92% independently of the model used. Bitopertin plasma concentration was a reliable predictor of occupancy because the concentration–occupancy relationship was superimposable at steady state and 2 days after drug discontinuation. These data allow understanding of the concentration–occupancy–efficacy relationship of bitopertin and support dose selection of future molecules. PMID:23132267

  15. Bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers

    PubMed Central

    Parikh, Neha; Kramer, William G; Khurana, Varun; Cognata Smith, Christina; Vetticaden, Santosh

    2016-01-01

    Background Dronabinol, a pharmaceutical Δ-9-tetrahydrocannabinol, was originally developed as an oral capsule. This study evaluated the bioavailability of a new formulation, dronabinol oral solution, versus a dronabinol capsule formulation. Methods In an open-label, four-period, single-dose, crossover study, healthy volunteers were randomly assigned to one of two treatment sequences (T-R-T-R and R-T-R-T; T = dronabinol 4.25 mg oral solution and R = dronabinol 5 mg capsule) under fasted conditions, with a minimum 7-day washout period between doses. Analyses were performed on venous blood samples drawn 15 minutes to 48 hours postdose, and dronabinol concentrations were assayed by liquid chromatography–tandem mass spectrometry. Results Fifty-one of 52 individuals had pharmacokinetic data for analysis. The 90% confidence interval of the geometric mean ratio (oral solution/capsule) for dronabinol was within the 80%–125% bioequivalence range for area under the plasma concentration–time curve (AUC) from time zero to last measurable concentration (AUC0–t) and AUC from time zero to infinity (AUC0–∞). Maximum plasma concentration was also bioequivalent for the two dronabinol formulations. Intraindividual variability in AUC0–∞ was >60% lower for dronabinol oral solution 4.25 mg versus dronabinol capsule 5 mg. Plasma dronabinol concentrations were detected within 15 minutes postdose in 100% of patients when receiving oral solution and in <25% of patients when receiving capsules. Conclusion Single-dose dronabinol oral solution 4.25 mg was bioequivalent to dronabinol capsule 5 mg under fasted conditions. Dronabinol oral solution formulation may provide an easy-to-swallow administration option with lower intraindividual variability as well as more rapid absorption versus dronabinol capsules. PMID:27785111

  16. Pharmacokinetics of cefetamet pivoxil (Ro 15-8075) with ascending oral doses in normal healthy volunteers.

    PubMed Central

    Tam, Y K; Kneer, J; Dubach, U C; Stoeckel, K

    1989-01-01

    The pharmacokinetics of cefetamet pivoxil during administration of ascending oral doses were studied in 16 male normal healthy volunteers (age, 24.5 +/- 2.1 years; weight, 73.5 +/- 8.5 kg). The subjects were randomly assigned to four oral treatments of 500, 1,000, 1,500, and 2,000 mg of cefetamet pivoxil according to a four-by-four Latin square design. After an overnight fast, the drug was administered 10 min after a standard breakfast. It was found that both the rate and extent of prodrug absorption, measured as cefetamet adsorption, were reduced with increasing doses. The time to maximum concentration of cefetamet in serum was delayed from 4.00 +/- 0.81 to 4.88 +/- 0.96 h (P less than 0.05) when the dose of cefetamet pivoxil was increased from 500 to 2,000 mg. The dose-normalized values of area under the curve from 0 h to infinity for cefetamet and fraction of dose excreted as cefetamet were reduced by averages of 10.3 and 12.5%, respectively, over the dose range studied (P less than 0.05). The changes in rate and extent of prodrug absorption are thought to be the main factors contributing to the nonlinear relationship between maximum concentration in serum and dose. The change in absorption characteristics of cefetamet pivoxil with dose is, however, expected to have few clinical consequences because the magnitudes of these changes are comparable with their respective intragroup variations. PMID:2764545

  17. Effect of meal timing and glycaemic index on glucose control and insulin secretion in healthy volunteers.

    PubMed

    Morgan, Linda M; Shi, Jiang-Wen; Hampton, Shelagh M; Frost, Gary

    2012-10-01

    Shiftworkers have a higher risk of CHD and type 2 diabetes. They consume a large proportion of their daily energy and carbohydrate intake in the late evening or night-time, a factor which could be linked to their increase in disease risk. We compared the metabolic effects of varying both dietary glycaemic index (GI) and the time at which most daily energy intake was consumed. We hypothesised that glucose control would be optimal with a low-GI diet, consumed predominantly early in the day. A total of six healthy lean volunteers consumed isoenergetic meals on four occasions, comprising either high- or low-GI foods, with 60 % energy consumed predominantly early (breakfast) or late (supper). Interstitial glucose was measured continuously for 20 h. Insulin, TAG and non-esterified fatty acids were measured for 2 h following every meal. Highest glucose values were observed when large 5021 kJ (1200 kcal) high-GI suppers were consumed. Glucose levels were also significantly higher in predominantly late high- v. low-GI meals (P<0·01). Using an estimate of postprandial insulin sensitivity throughout the day, we demonstrate that this follows the same trend, with insulin sensitivity being significantly worse in high energy consumed in the evening meal pattern. Both meal timing and GI affected glucose tolerance and insulin secretion. Avoidance of large, high-GI meals in the evening may be particularly beneficial in improving postprandial glucose profiles and may play a role in reducing the risk of type 2 diabetes; however, longer-term studies are needed to confirm this.

  18. Methylene blue MMX tablets for chromoendoscopy. Safety tolerability and bioavailability in healthy volunteers.

    PubMed

    Repici, A; Di Stefano, A F D; Radicioni, M M; Jas, V; Moro, L; Danese, S

    2012-03-01

    Methylene blue-MMX tablets are proposed as colonic diagnostic staining. Methylene blue taken prior to colonoscopy is expected to provide an effective staining of colonic and rectal mucosa leaving unstained the dysplastic or polypoid areas. The present single dose, open-label study investigated the safety of methylene blue after single oral doses of 200 and 400mg in healthy volunteers. The absolute bioavailability was also investigated after the intake of 2L of bowel cleansing preparation in 2h and by comparing the dose of 200mg with a single iv dose of 100mg in the same subjects. Only non-serious adverse events occurred. Related events occurred to 8/22 subjects. Most of the events were mild and transient. Abnormal transaminases, gastrointestinal disorders and dysuria frequency were 13.6%. After intake of the laxative and the oral dose of 200mg, systemic exposure to methylene blue was shown in all subjects with concentrations increasing for 12h. The peak was reached in a median of 16 h. Peak blood concentration did not increase proportionally with the dose. AUC(0-t) was 32.94 μg/mL × h after 200mg and 38.08 μg/mL × h after 400mg. Half life ranged between 14 and 27 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative excretion was about 40% of the injected dose, 39.67% after 200mg and 23.48% after 400mg. Absolute bioavailability of methylene blue calculated as ratio between AUC(0-t) oral/iv corrected for the dose was on average F(abs)=139.19 ± 52.00%.

  19. Effect of fosamprenavir/ritonavir on the pharmacokinetics of single-dose olanzapine in healthy volunteers.

    PubMed

    Jacobs, Birgit S; Colbers, Angela P H; Velthoven-Graafland, Kirsten; Schouwenberg, Bas J J W; Burger, David M

    2014-08-01

    Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.

  20. Oscillatory lower body negative pressure impairs task related functional hyperemia in healthy volunteers.

    PubMed

    Stewart, Julian M; Balakrishnan, Keshawadhana; Visintainer, Paul; Del Pozzi, Andrew T; Messer, Zachary R; Terilli, Courtney; Medow, Marvin S

    2016-03-15

    Neurovascular coupling refers to the link between an increase in neural activity in response to a task and an increase in cerebral blood flow denoted "functional hyperemia." Recent work on postural tachycardia syndrome indicated that increased oscillatory cerebral blood flow velocity (CBFv) was associated with reduced functional hyperemia. We hypothesized that a reduction in functional hyperemia could be causally produced in healthy volunteers by using oscillations in lower body negative pressure (OLBNP) to force oscillations in CBFv. CBFv was measured by transcranial Doppler ultrasound of the left middle cerebral artery. We used passive arm flexion applied during eight periodic 60-s flexion/60-s relaxation epochs to produce 120-s periodic changes in functional hyperemia (at 0.0083 Hz). We used -30 mmHg of OLBNP at 0.03, 0.05, and 0.10 Hz, the range for cerebral autoregulation, and measured spectral power of CBFv at all frequencies. Arm flexion power performed without OLBNP was compared with arm flexion power during OLBNP. OLBNP power performed in isolation was compared with power during OLBNP plus arm flexion. Cerebral flow velocity oscillations at 0.05 Hz reduced and at 0.10 Hz eliminated functional hyperemia, while 0.03 Hz did not reach significance. In contrast, arm flexion reduced OLBNP-induced oscillatory power at all frequencies. The interactions between OLBNP-driven CBFv oscillations and arm flexion-driven CBFv oscillations are reciprocal. Thus induced cerebral blood flow oscillations suppress functional hyperemia, and functional hyperemia suppresses cerebral blood flow oscillations. We conclude that oscillatory cerebral blood flow produces a causal reduction of functional hyperemia.

  1. Pharmacokinetic study of Growth Hormone-Releasing Peptide 6 (GHRP-6) in nine male healthy volunteers.

    PubMed

    Cabrales, Ania; Gil, Jeovanis; Fernández, Eduardo; Valenzuela, Carmen; Hernández, Francisco; García, Idrián; Hernández, Ariadna; Besada, Vladimir; Reyes, Osvaldo; Padrón, Gabriel; Berlanga, Jorge; Guillén, Gerardo; González, Luis Javier

    2013-01-23

    GHRP-6 is a growth hormone secretagogue that also enhances tissue viability in different organs. In the present work, we studied the pharmacokinetics of this short therapeutic hexapeptide (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH(2,) MW=872.44 Da) in nine male healthy volunteers after a single intravenous bolus administration of 100, 200 and 400 μg/kg of body weight. GHRP-6 was quantified in human plasma by a specific LC-MS method, previously developed and validated following FDA guidelines, using (13)C(3)Ala-GHRP-6 as internal standard (Gil et al., 2012, J. Pharm. Biomed. Anal. 60, 19-25). The Lower Limit of Quantification (5 ng/mL) was reached in all subjects at 12h post-administration, which was sufficient for modeling a pharmacokinetic profile including over 85% of the Area under the Curve (AUC). Disposition of GHRP-6 best fitted a bi-exponential function with R(2) higher than 0.99, according to a mathematic modeling and confirmed by an Akaike index (AIC) lower than that of the corresponding one-compartment model for all subjects. Averaging all three dose levels, the distribution and elimination half-life of GHRP-6 were 7.6 ± 1.9 min and 2.5 ± 1.1h, respectively. These values are coherent with existing data for other drugs whose disposition also fits this model. Dose dependence analysis revealed a noticeable trend for AUC to increase proportionally with administered dose. Atypical GHRP-6 concentration spikes were observed during the elimination phase in four out of the nine subjects studied.

  2. Lack of influence of sulglycotide on naproxen bioavailability in healthy volunteers.

    PubMed

    Berté, F; Feletti, F; di Valserra, M B; Nazzari, M; Cenedese, A; Cornelli, U

    1988-03-01

    We explored the bioavailability and kinetics of naproxen (N) in 12 healthy volunteers treated orally with single doses of 500 mg and retreated after a washout period with the same dose of N plus sulglycotide (S) 200 mg. Naproxen blood levels were measured by high-performance liquid chromatography (HPLC) in samples collected at 0.5, 1, 2, 4, 8, 12, and 24 h of dosing with N or with N + S. No statistically significant difference in terms of naproxen blood levels emerged as the product was administered alone or concurrently with sulglycotide. Peak plasma concentrations and AUC values were 71 +/- 3.16 micrograms/ml and 685 +/- 27 micrograms/ml/h, respectively for N alone, and 72.5 +/- 2.85 micrograms/ml and 651 +/- 28 micrograms/ml/h, respectively for N + S. The difference was not significant. Similarly, the kinetic behavior of naproxen was not modified by the simultaneous presence of sulglycotide, as shown by the t1/2 beta-values obtained with N alone (8.39 +/- 0.31 h) and with N + S (7.93 +/- 0.30 h), and likewise by the distribution volumes at equilibrium (7.63 +/- 0.42 and 7.9 +/- 0.38, respectively), Cmax (63.3 +/- 2.86 and 60.4 +/- 2.9 micrograms/ml, respectively) and tmax (0.95 +/- 0.06 and 1.10 +/- 0.10 h, respectively). From these findings it seems legitimate to claim that sulglycotide can be administered concurrently with naproxen to prevent possible gastric injury by the anti-inflammatory agent thanks to its wellknown antiulcer and cytoprotective activity on the gastric mucosa, without any undue interference with the absorption (hence effectiveness) of naproxen.

  3. Emotional traits predict individual differences in amphetamine-induced positive mood in healthy volunteers

    PubMed Central

    Kirkpatrick, Matthew G.; Goldenson, Nicholas I.; Kapadia, Nahel; Kahler, Christopher W.; de Wit, Harriet; Swift, Robert M.; McGeary, John E.; Sussman, Steve; Leventhal, Adam M.

    2015-01-01

    BACKGROUND Previous research on emotional correlates of individual differences in subjective responses to d-amphetamine has focused on relatively broad personality traits. Yet, emotional functioning is best characterized by several narrow subcomponents, each of which may contribute uniquely to amphetamine response. Here, we examine several specific subdomains of emotional functioning in relation to acute amphetamine response. METHOD At a baseline session, healthy stimulant-naïve volunteers (N=97) completed measures of several subdomains of baseline trait emotional functioning, and then completed two counterbalanced experimental sessions during which they received a single dose of 20-mg oral d-amphetamine or placebo. Acute subjective drug response measures were completed at repeated intervals before and after drug administration. Data from subjective measures that were significantly modulated by amphetamine were reduced using principal components analysis (amphetamine – placebo) into three higher-order factors of “Positive Mood,” “Arousal,” and “Drug High.” Amphetamine did not significantly alter any “negative” subjective states. Separate multiple regression analyses were conducted regressing these three drug factors on baseline trait emotional functioning scales. RESULTS The combined set of trait emotional functioning indicators accounted for approximately 22% of the variance in acute amphetamine-induced positive mood changes. Greater anticipatory pleasure and greater anxious distress each uniquely predicted greater amphetamine-induced Positive Mood. Trait emotional functioning did not significantly predict amphetamine-induced changes in Arousal or Drug High. DISCUSSION Emotional traits appear to moderate drug-induced positive mood but not other dimensions of amphetamine effects. Different facets of emotional functioning may differentially modulate amphetamine's subjective effect profile. PMID:26429791

  4. Pharmacodynamic interactions of a solid formulation of sodium oxybate and ethanol in healthy volunteers

    PubMed Central

    Pross, Nathalie; Patat, Alain; Vivet, Philippe; Bidaut, Michelle; Fauchoux, Nicolas

    2015-01-01

    Aim The pharmacologic effects of sodium oxybate (SO) have a number of similarities with those of alcohol. This study evaluated the pharmacodynamic interaction of SMO.IR (a solid immediate release formulation of SO) and alcohol (0.7 (males) or 0.57 (females) g kg–1 alcohol using 40% vodka). Methods In a randomized, double-blind, double-dummy, crossover trial, 24 healthy volunteers received randomly a) 2.25 g SMO.IR and placebo alcohol preparation, b) 2.25 g f SMO.IR and alcohol, c) 2.25 g SMO.IR matching placebo and alcohol and d) 2.25 g of SMO.IR matching placebo and placebo alcohol preparation. Objective and subjective cognitive parameters, adverse events and vital signs were assessed before, 15 and 165 min after treatment administration. Results Alcohol produced the expected cognitive impairment and the expected subjective sedation rapidly after intake (from 15 min). The objective effects of SMO.IR were much less pronounced than those of alcohol. The reverse was observed for subjective complaints, which were related to lesser stimulation and greater sedation. Nevertheless, 165 min after administration this sedation feeling was less with SMO.IR than with alcohol. There was a significant interaction between SMO.IR and alcohol at 15 min (i.e. increase in alertness and stimulation and decrease in sedation). In addition, an isolated mild decrease in digit vigilance accuracy occurred at 165 min post-dose after the combination. The co-administration of SMO.IR and alcohol was safe and well-tolerated. Conclusion SMO.IR and alcohol have distinct adverse effect profiles. The objective effects of SMO.IR are much less marked than those of alcohol. No deleterious interaction was observed. PMID:25782469

  5. Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers.

    PubMed

    Deloose, Eveline; Janssen, Pieter; Corsetti, Maura; Biesiekierski, Jessica; Masuy, Imke; Rotondo, Alessandra; Van Oudenhove, Lukas; Depoortere, Inge; Tack, Jan

    2017-03-01

    Background: Denatonium benzoate (DB) has been shown to influence ongoing ingestive behavior and gut peptide secretion.Objective: We studied how the intragastric administration of DB affects interdigestive motility, motilin and ghrelin plasma concentrations, hunger and satiety ratings, and food intake in healthy volunteers.Design: Lingual bitter taste sensitivity was tested with the use of 6 concentrations of DB in 65 subjects. A placebo or 1 μmol DB/kg was given intragastrically to assess its effect on fasting gastrointestinal motility and hunger ratings, motilin and ghrelin plasma concentrations, satiety, and caloric intake.Results: Women (n = 39) were more sensitive toward a lingual bitter stimulus (P = 0.005) than men (n = 26). In women (n = 10), intragastric DB switched the origin of phase III contractions from the stomach to the duodenum (P = 0.001) and decreased hunger ratings (P = 0.04). These effects were not observed in men (n = 10). In women (n = 12), motilin (P = 0.04) plasma concentrations decreased after intragastric DB administration, whereas total and octanoylated ghrelin were not affected. The intragastric administration of DB decreased hunger (P = 0.008) and increased satiety ratings (P = 0.01) after a meal (500 kcal) in 13 women without affecting gastric emptying in 6 women. Caloric intake tended to decrease after DB administration compared with the placebo (mean ± SEM: 720 ± 58 compared with 796 ± 45 kcal; P = 0.08) in 20 women.Conclusions: Intragastric DB administration decreases both antral motility and hunger ratings during the fasting state, possibly because of a decrease in motilin release. Moreover, DB decreases hunger and increases satiety ratings after a meal and shows potential for decreasing caloric intake. This trial was registered at clinicaltrials.gov as NCT02759926.

  6. Pharmacokinetic, partial pharmacodynamic and initial safety analysis of (−)-Epicatechin in healthy volunteers

    PubMed Central

    Barnett, Christopher F.; Moreno-Ulloa, Aldo; Shiva, Sruti; Ramirez-Sanchez, Israel; Taub, Pam R.; Su, Yongxuan; Ceballos, Guillermo; Dugar, Sundeep; Schreiner, George; Villarreal, Francisco

    2015-01-01

    (−)-Epicatechin ((−)-EPI), a naturally occurring flavanol has emerged as a likely candidate for cocoa-based product reported reductions in cardiometabolic risk. The present study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of purified (−)-EPI administered to healthy volunteers. In this phase I, open-label, two-part single- and multiple-dose study subjects received either a single dose (n=9) of 50, 100 or 200 mg or multiple doses (n=8) of 50 mg daily (q.d.) or twice daily (b.i.d) for 5 days. Blood was collected at 0, 0.5, 1, 2, 4 and 6 hrs after (−)-EPI administration in the single and multiple dose groups (blood collection repeated in day 5). Samples were analyzed by HPLC-HR-ESI-MS for EPI and metabolites quantification. In the q.d. and b.i.d. groups, blood samples were analyzed for NO surrogates, follistatin, platelet mitochondrial complex I, V and citrate synthase level determinations. (−)-EPI was well tolerated and readily absorbed with further phase 2 metabolism. On day 5, in the q.d. and b.i.d. groups, there were significant increases in plasma nitrite of 30 % and 17 %, respectively. In the q.d. group on day 5 vs. day 1, platelet mitochondria complexes I, IV and citrate synthase activities demonstrated a significant increase of ~ 92, 62 and 8 %, respectively. Average day 5 follistatin AUC levels were ~2.5 fold higher vs. day 1 AUC levels in the b.i.d. group. (−)-EPI was safe with no observed adverse effects and our findings suggest that increases in NO metabolites, mitochondrial enzyme function and plasma follistatin levels may underlie some of the beneficial effects of cocoa products or (−)-EPI as reported in other studies. PMID:25598082

  7. Pharmacokinetics and bioequivalence studies of cefteram pivoxil in healthy Chinese volunteers.

    PubMed

    Wei, Fangmi; Zhu, Rong; Zhao, Wenhui; Yang, Jing; Cai, Zheng; Hu, Qin

    2009-01-01

    A simple, sensitive and specific method has been developed for the determination of cefteram in human plasma. Sample preparation was accomplished through protein precipitation with 20% trichloroacetic acid (v/v) and chromatographic separation was performed on a C18 column at 25 degrees C. The mobile phase consisted of methanol-aqueous 20 mM ammonium acetate (18:82, v/v) at flow rate of 1.0 mL/min. Wavelength was set at 235 nm. The lower limit of quantification was 0.04 microg/mL and the assay exhibited a linear range of 0.04-3.2 microg/mL (r=0.9996). The relative recoveries of cefteram from human plasma at three different concentrations were more than 90%. The method was successfully applied to investigate the bioequivalence between two kinds of cefteram pivoxil preparations (test vs reference) in 24 healthy Chinese volunteers. After a single 100 mg dose for the test and reference product, the resulting means of major pharmacokinetic parameters such as AUC(0-t), AUC(0-infinity), Cmax and Tmax of cefteram pivoxil were 4.75 +/- 1.35 vs 4.76 +/- 1.29 microg h/mL, 4.89 +/- 1.36 vs 4.91 +/- 1.29 microg h/mL, 1.65 +/- 0.45 vs 1.73 +/- 0.45 microg/mL and 1.48 +/- 0.59 vs 1.73 +/- 0.45 h, respectively, indicating that these two kinds of preparations were bioequivalent.

  8. Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials.

    PubMed

    Molina, I; Salvador, F; Sánchez-Montalvá, A; Artaza, M A; Moreno, R; Perin, L; Esquisabel, A; Pinto, L; Pedraz, J L

    2017-04-01

    Despite its toxicity and low efficacy in the chronic phase, benznidazole is the drug of choice in Chagas disease. Scarce information about pharmacokinetics and pharmacodynamics of benznidazole has been published. We performed a phase I, open-label, nonrandomized pharmacokinetic study of benznidazole (Abarax) conducted with 8 healthy adult volunteers at the Infectious Diseases Department of the Vall d'Hebron University Hospital (Barcelona, Spain). The separation and detection of benznidazole were performed on a Waters Acquity ultraperformance liquid chromatography system (UPLC) coupled with a Waters Xevo TQ MS triple quadrupole mass spectrometer. The pharmacokinetic parameters were calculated based on a noncompartmental body model using Phoenix WinNonlin version 6.3 software. Furthermore, computational simulations were calculated for the multiple-dose administration at two dose regimens: 100 mg of benznidazole administered every 8 h and 150 mg of benznidazole administered every 12 h. After benznidazole administration, the median area under the concentration-time curve from time zero to time t (AUC0-t ) and extrapolated to infinity (AUC0-∞) were about 46.4 μg · h/ml and 48.4 μg · h/ml, respectively. Plasma benznidazole concentrations peaked at 3.5 h, with maximal concentrations of 2.2 μg/ml, and benznidazole exhibited a terminal half-life of 12.1 h. The median maximum concentration (Cmax) of benznidazole was lower in men than in women (1.6 versus 2.9 μg/ml), and median volume of distribution (V) as a function of bioavailability (F) was higher in men than in women (125.9 versus 88.6 liters). In conclusion, dose regimens (150 mg/12 h or 100 mg/8 h) reached a steady-state range concentration above of the minimum experimental therapeutic dose. Sex differences in the benznidazole pharmacokinetics were observed; mainly, men had lower Cmax and higher V/F than women.

  9. Pharmacokinetics of pholcodine in healthy volunteers: single and chronic dosing studies.

    PubMed Central

    Chen, Z R; Bochner, F; Somogyi, A

    1988-01-01

    1. The pharmacokinetics of pholcodine after two single doses and after chronic administration were studied in healthy human volunteers. 2. Six subjects received single oral doses of 20 and 60 mg of pholcodine according to a balanced cross-over design with an interval of 3 weeks between the two treatments. Blood and saliva samples and all urine were collected over 168 h after each dosage administration. Subsequently, the same subjects received 20 mg pholcodine 8 hourly orally for 10 days. Blood and saliva samples and all urine were collected during an 8 h dosing interval after the last dose on day 11. 3. Plasma, saliva and urine concentrations of pholcodine were determined by a high performance liquid chromatographic assay. 4. After the single doses, pholcodine was absorbed rapidly (tmax = 1.6 +/- 1.2 h) and eliminated slowly with a mean half-life of 50.1 +/- 4.1 h. The renal clearance of pholcodine was 137 +/- 34 ml min-1 and was inversely correlated with urine pH (r = 0.60) but not with urine flow rate. 26.2 +/- 3.3% of the dose was excreted as unchanged pholcodine after both doses. The concentration of pholcodine in saliva was 3.6 times higher than in plasma. 5. After chronic administration, the pharmacokinetics of pholcodine were not statistically different from the single dose parameters. 6. Pholcodine did not appear to undergo conjugation. The plasma protein binding was 23.5%. Morphine, in unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine administration. PMID:3190994

  10. Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

    PubMed Central

    Qiu, Furong; Wang, Guangji; Zhang, Rong; Sun, Jianguo; Jiang, Jian; Ma, Yueming

    2010-01-01

    AIMS To assess the effect of danshen extract on CYP3A4 activity using midazolam as an in vivo probe. METHODS A sequential, open-label, two-period pharmacokinetic interaction study design was used to compare midazolam pharmacokinetic parameters before and after 14 days of administration of danshen tablets. Twelve healthy volunteers received a single oral dose (15 mg) of midazolam followed by danshen tablets (four tablets orally, three times a day) for 14 days. On the last day of the study they received four danshen tablets with a 15 mg midazolam tablet and plasma concentrations of midazolam and its corresponding metabolite 1–hydroxylmidazolam were measured prior to and after the administration of danshen tablets periodically for 12 h. RESULTS The 90% confidence intervals of Cmax,t1/2, CL/F and AUC(0,∞) of midazolam before and after administration of danshen tablets were (0.559, 0.849), (0.908, 1.142), (1.086, 1.688) and (0.592, 0.921), respectively; and those of Cmax, t1/2 and AUC(0,∞) of 1-hydroxylmidazolam after vs. before administration of danshen tablets were (0.633, 0.923), (0.801, 1.210) and (0.573, 0.980), respectively. Ratios of geometric LS means of Cmax(1OHMid) : Cmax(Mid) and AUCmax(1OHMid) : AUCmax(Mid) (after vs. before 14-day danshen) were 1.072 and 1.035, respectively. CONCLUSIONS Our findings suggest that multiple dose administration of danshen tablets may induce CYP3A4 in the gut. Accordingly, caution should be taken when danshen products are used in combination with therapeutic drugs metabolized by CYP3A. PMID:20565457

  11. Full Spectrum of LPS Activation in Alveolar Macrophages of Healthy Volunteers by Whole Transcriptomic Profiling

    PubMed Central

    Zhao, Yutong; Zhao, Jing; Donahoe, Michael P.; Barge, Suchitra; Horne, William T.; Kolls, Jay K.; McVerry, Bryan J.; Birukova, Anastasiya; Tighe, Robert M.; Foster, W. Michael; Hollingsworth, John; Ray, Anuradha; Mallampalli, Rama; Ray, Prabir; Lee, Janet S.

    2016-01-01

    Despite recent advances in understanding macrophage activation, little is known regarding how human alveolar macrophages in health calibrate its transcriptional response to canonical TLR4 activation. In this study, we examined the full spectrum of LPS activation and determined whether the transcriptomic profile of human alveolar macrophages is distinguished by a TIR-domain-containing adapter-inducing interferon-β (TRIF)-dominant type I interferon signature. Bronchoalveolar lavage macrophages were obtained from healthy volunteers, stimulated in the presence or absence of ultrapure LPS in vitro, and whole transcriptomic profiling was performed by RNA sequencing (RNA-Seq). LPS induced a robust type I interferon transcriptional response and Ingenuity Pathway Analysis predicted interferon regulatory factor (IRF)7 as the top upstream regulator of 89 known gene targets. Ubiquitin-specific peptidase (USP)-18, a negative regulator of interferon α/β responses, was among the top up-regulated genes in addition to IL10 and USP41, a novel gene with no known biological function but with high sequence homology to USP18. We determined whether IRF-7 and USP-18 can influence downstream macrophage effector cytokine production such as IL-10. We show that IRF-7 siRNA knockdown enhanced LPS-induced IL-10 production in human monocyte-derived macrophages, and USP-18 overexpression attenuated LPS-induced production of IL-10 in RAW264.7 cells. Quantitative PCR confirmed upregulation of USP18, USP41, IL10, and IRF7. An independent cohort confirmed LPS induction of USP41 and IL10 genes. These results suggest that IRF-7 and predicted downstream target USP18, both elements of a type I interferon gene signature identified by RNA-Seq, may serve to fine-tune early cytokine response by calibrating IL-10 production in human alveolar macrophages. PMID:27434537

  12. Microbiome Changes in Healthy Volunteers Treated with GSK1322322, a Novel Antibiotic Targeting Bacterial Peptide Deformylase

    PubMed Central

    Arat, Seda; Spivak, Aaron; Van Horn, Stephanie; Thomas, Elizabeth; Traini, Christopher; Sathe, Ganesh; Livi, George P.; Ingraham, Karen; Jones, Lori; Aubart, Kelly; Holmes, David J.; Naderer, Odin

    2014-01-01

    GSK1322322 is a novel antibacterial agent under development, and it has known antibacterial activities against multidrug-resistant respiratory and skin pathogens through its inhibition of the bacterial peptide deformylase. Here, we used next-generation sequencing (NGS) of the bacterial 16S rRNA genes from stool samples collected from 61 healthy volunteers at the predosing and end-of-study time points to determine the effects of GSK1322322 on the gastrointestinal (GI) microbiota in a phase I, randomized, double-blind, and placebo-controlled study. GSK1322322 was administered either intravenously (i.v.) only or in an oral-i.v. combination in single- and repeat-dose-escalation infusions. Analysis of the 16S rRNA sequence data found no significant changes in the relative abundances of GI operational taxonomic units (OTUs) between the prestudy and end-of-study samples for either the placebo- or i.v.-only-treated subjects. However, oral-i.v. treatment resulted in significant decreases in some bacterial taxa, the Firmicutes and Bacteroidales, and increases in others, the Betaproteobacteria, Gammaproteobacteria, and Bifidobacteriaceae. Microbiome diversity plots clearly differentiated the end-of-study oral-i.v.-dosed samples from all others collected. The changes in genome function as inferred from species composition suggest an increase in bacterial transporter and xenobiotic metabolism pathways in these samples. A phylogenetic analysis of the peptide deformylase protein sequences collected from the published genomes of clinical isolates previously tested for GSK1322322 in vitro susceptibility and GI bacterial reference genomes suggests that antibiotic target homology is one of several factors that influences the response of GI microbiota to this antibiotic. Our study shows that dosing regimen and target class are important factors when considering the impact of antibiotic usage on GI microbiota. (This clinical trial was registered at the GlaxoSmithKline Clinical Study

  13. Breathing guidance in radiation oncology and radiology: A systematic review of patient and healthy volunteer studies

    SciTech Connect

    Pollock, Sean Keall, Paul; Keall, Robyn

    2015-09-15

    Purpose: The advent of image-guided radiation therapy has led to dramatic improvements in the accuracy of treatment delivery in radiotherapy. Such advancements have highlighted the deleterious impact tumor motion can have on both image quality and radiation treatment delivery. One approach to reducing tumor motion irregularities is the use of breathing guidance systems during imaging and treatment. These systems aim to facilitate regular respiratory motion which in turn improves image quality and radiation treatment accuracy. A review of such research has yet to be performed; it was therefore their aim to perform a systematic review of breathing guidance interventions within the fields of radiation oncology and radiology. Methods: From August 1–14, 2014, the following online databases were searched: Medline, Embase, PubMed, and Web of Science. Results of these searches were filtered in accordance to a set of eligibility criteria. The search, filtration, and analysis of articles were conducted in accordance with preferred reporting items for systematic reviews and meta-analyses. Reference lists of included articles, and repeat authors of included articles, were hand-searched. Results: The systematic search yielded a total of 480 articles, which were filtered down to 27 relevant articles in accordance to the eligibility criteria. These 27 articles detailed the intervention of breathing guidance strategies in controlled studies assessing its impact on such outcomes as breathing regularity, image quality, target coverage, and treatment margins, recruiting either healthy adult volunteers or patients with thoracic or abdominal lesions. In 21/27 studies, significant (p < 0.05) improvements from the use of breathing guidance were observed. Conclusions: There is a trend toward the number of breathing guidance studies increasing with time, indicating a growing clinical interest. The results found here indicate that further clinical studies are warranted that quantify the

  14. Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers

    PubMed Central

    Brealey, Noushin; Gupta, Ashutosh; Renaux, Jessica; Mehta, Rashmi; Allen, Ann; Henderson, Alex

    2015-01-01

    Objective: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. Methods: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPTA® dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 μg, FF/UMEC 400/500 μg, UMEC/VI 500/100 μg, or FF/VI 400/100 μg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 μg or 400/250/100 μg, FF/VI 400/100 μg, or UMEC/VI 250/100 μg. PK and PD parameters and safety were assessed. Results: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. Conclusions: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies. PMID:26227101

  15. Effects of acute hypoventilation and hyperventilation on exhaled carbon monoxide measurement in healthy volunteers

    PubMed Central

    2009-01-01

    Background High levels of exhaled carbon monoxide (eCO) are a marker of airway or lung inflammation. We investigated whether hypo- or hyperventilation can affect measured values. Methods Ten healthy volunteers were trained to achieve sustained end-tidal CO2 (etCO2) concentrations of 30 (hyperventilation), 40 (normoventilation), and 50 mmHg (hypoventilation). As soon as target etCO2 values were achieved for 120 sec, exhaled breath was analyzed for eCO with a photoacoustic spectrometer. At etCO2 values of 30 and 40 mmHg exhaled breath was sampled both after a deep inspiration and after a normal one. All measurements were performed in two different environmental conditions: A) ambient CO concentration = 0.8 ppm and B) ambient CO concentration = 1.7 ppm. Results During normoventilation, eCO mean (standard deviation) was 11.5 (0.8) ppm; it decreased to 10.3 (0.8) ppm during hyperventilation (p < 0.01) and increased to 11.9 (0.8) ppm during hypoventilation (p < 0.01). eCO changes were less pronounced than the correspondent etCO2 changes (hyperventilation: 10% Vs 25% decrease; hypoventilation 3% Vs 25% increase). Taking a deep inspiration before breath sampling was associated with lower eCO values (p < 0.01), while environmental CO levels did not affect eCO measurement. Conclusions eCO measurements should not be performed during marked acute hyperventilation, like that induced in this study, but the influence of less pronounced hyperventilation or of hypoventilation is probably negligible in clinical practice PMID:20030802

  16. Comparison of diphenhydramine and modafinil on arousal and autonomic functions in healthy volunteers.

    PubMed

    Hou, R H; Langley, R W; Szabadi, E; Bradshaw, C M

    2007-08-01

    Arousal is regulated by the interplay between wakefulness- and sleep-promoting nuclei. Major wakefulness-promoting nuclei are the histaminergic tuberomamillary nucleus (TMN) of the hypothalamus and the noradrenergic locus coeruleus (LC) of the pons, which also play a role in autonomic regulation. First generation antihistamines, such as diphenhydramine, are likely to cause sedation by blocking excitatory H1 histamine receptors in the cerebral cortex, and the anti-narcolepsy drug modafinil may promote wakefulness by activating the locus coeruleus. We compared the effects of single doses of diphenhydramine (75 mg) and modafinil (200 mg) on arousal and autonomic functions in 16 healthy male volunteers, using a placebo-controlled, balanced, double-blind design. Arousal was assessed by critical flicker fusion frequency (CFFF), visual analogue scales (VAS) and pupillary fatigue waves (Pupillographic Sleepiness Test (PST)). Autonomic functions measured included resting pupil diameter, light and darkness reflex responses, blood pressure, heart rate and salivation. Data were analysed with ANOVA, with multiple comparisons. Diphenhydramine had sedative effects as shown by reductions in CFFF, VAS alertness ratings and increases of the indices of pupillary fatigue. Modafinil had alerting effects as indicated by reductions in the measures of pupillary fatigue. Comparison of pre-post medication changes in pupil diameter showed a decrease after diphenhydramine and an increase after modafinil. Diphenhydramine reduced salivation, and modafinil increased systolic blood pressure. In conclusion, diphenhydramine and modafinil evoked opposite effects on arousal and sympathetic functions, which are likely to reflect their interaction with the central histaminergic and noradrenergic systems. Hyposalivation by diphenhydramine is likely to be due to its additional anticholinergic property.

  17. Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

    PubMed

    Jung, J A; Kim, N; Yang, J-S; Kim, T-e; Kim, J-R; Song, G-S; Kim, H; Ko, J W; Huh, W

    2014-12-01

    Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 μg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 μg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · μg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.

  18. Short term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers

    PubMed Central

    Baudouin, C.; de Lunardo, C.

    1998-01-01

    AIM—A crossover, randomised double blind study was undertaken in 30 healthy volunteers, in order to compare the tolerance of 2% carteolol with and without preservative in short term use.
METHODS—Complete ophthalmic examinations were performed before and 30, 60, and 180 minutes after instillation of one drop of the solution, and after 3 days of preservative treatment. After a 5 day washout, the same examinations were done with the second drug.
RESULTS—Results showed good general tolerance for both formulations. No significant difference in subjective tolerance, corneal aesthesiometry, punctuate keratitis, Schirmer's test, intraocular pressure (IOP) decrease (about 25% in the two groups at 3 hours, 10% after 3 days of treatment), resting cardiac frequency, or blood pressure was observed. However, break up time was significantly reduced from baseline by preserved carteolol both at 3 hours (10.40 (5.9) seconds to 6.15 (3.9) seconds, p=0.001) and after 3 days (7.72 (5.5) seconds, p=0.04). Preservative free carteolol did not significantly change the break up time (baseline 9.08 (5.7) seconds; 3 hours = 7.88 (5.5) seconds, not significant; day 3 = 8.35 (5.8), non-significant).
CONCLUSIONS—These results confirm that carteolol is well tolerated, either with or without preservative. The preservative free group showed better stability of the tear film, without loss of effect on IOP. This difference, although mild in the healthy young subjects in the present study could be much more relevant in those patients treated long term, older patients, and/or those suffering from ocular surface disorders. In such instances, preservative free drugs could be of potential benefit to protect the lacrimal fluid integrity and corneoconjunctival surface.

 Keywords: glaucoma; carteolol; benzalkonium; preservatives; β blockers PMID:9536878

  19. Pramipexole Increases Go Timeouts but Not No-go Errors in Healthy Volunteers.

    PubMed

    Yang, Xue Qing; Glizer, Daniel; Vo, Andrew; Seergobin, Ken N; MacDonald, Penny A

    2016-01-01

    Parkinson's disease (PD) is characterized by motor symptoms, such as resting tremor, bradykinesia and rigidity, but also features non-motor complications. PD patients taking dopaminergic therapy, such as levodopa but especially dopamine agonists (DAs), evidence an increase in impulse control disorders (ICDs), suggesting a link between dopaminergic therapy and impulsive pursuit of pleasurable activities. However, impulsivity is a multifaceted construct. Motor impulsivity refers to the inability to overcome automatic responses or cancel pre-potent responses. Previous research has suggested that PD patients, on dopaminergic medications, have decreased motor impulsivity. Whether effects on impulsivity are main effects of dopaminergic therapies or are specific to PD is unclear. Using a Go No-go task, we investigated the effect of a single dose of the DA pramipexole on motor impulsivity in healthy participants. The Go No-go task consisted of Go trials, for which keystroke responses were made as quickly as possible, and lesser frequency No-go trials, on which motor responses were to be inhibited. We hypothesized that pramipexole would decrease motor impulsivity. This would manifest as: (a) fewer No-go errors (i.e., fewer responses on trials in which a response ought to have been inhibited); and (b) more timed-out Go trials (i.e., more trials on which the deadline elapsed before a decision to make a keystroke occurred). Healthy volunteers were treated with either 0.5 mg of pramipexole or a standard placebo (randomly determined). During the 2-h wait period, they completed demographic, cognitive, physiological and affective measures. The pramipexole group had significantly more Go timeouts (p < 0.05) compared to the placebo group though they did not differ in percent of No-go errors. In contrast to its effect on pursuit of pleasurable activities, pramipexole did not increase motor impulsivity. In fact, in line with findings in PD and addiction, dopaminergic therapy might

  20. Pramipexole Increases Go Timeouts but Not No-go Errors in Healthy Volunteers

    PubMed Central

    Yang, Xue Qing; Glizer, Daniel; Vo, Andrew; Seergobin, Ken N.; MacDonald, Penny A.

    2016-01-01

    Parkinson’s disease (PD) is characterized by motor symptoms, such as resting tremor, bradykinesia and rigidity, but also features non-motor complications. PD patients taking dopaminergic therapy, such as levodopa but especially dopamine agonists (DAs), evidence an increase in impulse control disorders (ICDs), suggesting a link between dopaminergic therapy and impulsive pursuit of pleasurable activities. However, impulsivity is a multifaceted construct. Motor impulsivity refers to the inability to overcome automatic responses or cancel pre-potent responses. Previous research has suggested that PD patients, on dopaminergic medications, have decreased motor impulsivity. Whether effects on impulsivity are main effects of dopaminergic therapies or are specific to PD is unclear. Using a Go No-go task, we investigated the effect of a single dose of the DA pramipexole on motor impulsivity in healthy participants. The Go No-go task consisted of Go trials, for which keystroke responses were made as quickly as possible, and lesser frequency No-go trials, on which motor responses were to be inhibited. We hypothesized that pramipexole would decrease motor impulsivity. This would manifest as: (a) fewer No-go errors (i.e., fewer responses on trials in which a response ought to have been inhibited); and (b) more timed-out Go trials (i.e., more trials on which the deadline elapsed before a decision to make a keystroke occurred). Healthy volunteers were treated with either 0.5 mg of pramipexole or a standard placebo (randomly determined). During the 2-h wait period, they completed demographic, cognitive, physiological and affective measures. The pramipexole group had significantly more Go timeouts (p < 0.05) compared to the placebo group though they did not differ in percent of No-go errors. In contrast to its effect on pursuit of pleasurable activities, pramipexole did not increase motor impulsivity. In fact, in line with findings in PD and addiction, dopaminergic therapy might

  1. Esophageal solid bolus transit: studies using combined multichannel intraluminal impedance and manometry in healthy volunteers.

    PubMed

    Chen, C L; Yi, C H; Chou, A S B; Liu, T T

    2013-01-01

    The purpose of this study is to apply combined multichannel intraluminal impedance and esophageal manometry (MII-EM) to test esophageal function during solid swallowing in a normal healthy population. We determined whether combined MII-EM with solid bolus is more sensitive than that with viscous bolus in the detection of motility abnormality. Eighteen healthy volunteers (11 men and 7 women; mean age 22 years, range 20-26 years) underwent combined MII-EM with a catheter containing four impedance-measuring segments and five solid-state pressure transducers. Each subject received 10 viscous and 10 solid materials. Tracings were analyzed manually for bolus presence time, total bolus transit time, contraction amplitude, duration, and onset velocity. Three hundred and sixty swallows including viscous and solid materials were analyzed. Contraction amplitude for the viscous swallows was higher at 20 cm above the lower esophageal sphincter (LES) (P= 0.049) but lower at 15 cm above the LES (P < 0.001). Duration of contractions for the solid swallows was longer at 15 cm (P= 0.002) and 10 cm above the LES (P= 0.011) compared with viscous swallows. The total bolus transit time for solid was significantly shorter than that for viscous boluses (6.8 vs. 7.7 seconds, P < 0.001). Bolus presence time appeared to be similar between viscous and solid boluses (except in the proximal esophagus). The percentage of swallows with ineffective peristalsis by manometry, as well as those with incomplete bolus transit by impedance, did not differ between viscous and solid swallows. The proportion of manometrically ineffective solid swallows with incomplete bolus transit was greater than that of viscous swallows (62.1% vs. 34.8%, P= 0.05). Application of solid boluses may potentially enhance diagnostic capability of esophageal function testing. Solid boluses can be regarded as a valuable complement to viscous boluses in the detection of esophageal motility abnormalities when applied with

  2. Effects of Sulpiride on True and False Memories of Thematically Related Pictures and Associated Words in Healthy Volunteers

    PubMed Central

    Guarnieri, Regina V.; Ribeiro, Rafaela L.; de Souza, Altay A. Lino; Galduróz, José Carlos F.; Covolan, Luciene; Bueno, Orlando F. A.

    2016-01-01

    Episodic memory, working memory, emotional memory, and attention are subject to dopaminergic modulation. However, the potential role of dopamine on the generation of false memories is unknown. This study defined the role of the dopamine D2 receptor on true and false recognition memories. Twenty-four young, healthy volunteers ingested a single dose of placebo or 400 mg oral sulpiride, a dopamine D2-receptor antagonist, just before starting the recognition memory task in a randomized, double-blind, and placebo-controlled trial. The sulpiride group presented more false recognitions during visual and verbal processing than the placebo group, although both groups had the same indices of true memory. These findings demonstrate that dopamine D2 receptors blockade in healthy volunteers can specifically increase the rate of false recognitions. The findings fit well the two-process view of causes of false memories, the activation/monitoring failures model. PMID:27047394

  3. Effects of Sulpiride on True and False Memories of Thematically Related Pictures and Associated Words in Healthy Volunteers.

    PubMed

    Guarnieri, Regina V; Ribeiro, Rafaela L; de Souza, Altay A Lino; Galduróz, José Carlos F; Covolan, Luciene; Bueno, Orlando F A

    2016-01-01

    Episodic memory, working memory, emotional memory, and attention are subject to dopaminergic modulation. However, the potential role of dopamine on the generation of false memories is unknown. This study defined the role of the dopamine D2 receptor on true and false recognition memories. Twenty-four young, healthy volunteers ingested a single dose of placebo or 400 mg oral sulpiride, a dopamine D2-receptor antagonist, just before starting the recognition memory task in a randomized, double-blind, and placebo-controlled trial. The sulpiride group presented more false recognitions during visual and verbal processing than the placebo group, although both groups had the same indices of true memory. These findings demonstrate that dopamine D2 receptors blockade in healthy volunteers can specifically increase the rate of false recognitions. The findings fit well the two-process view of causes of false memories, the activation/monitoring failures model.

  4. The pharmacokinetic characters of simvastatin after co-administration with Shexiang Baoxin Pill in healthy volunteers' plasma.

    PubMed

    Tao, Jianfei; Jiang, Peng; Peng, Chengcheng; Li, Min; Liu, Runhui; Zhang, Weidong

    2016-07-15

    To investigate the effect of Shexiang Baoxin Pill (SBP), a tranditional Chinese medicine, on the pharmacokinetic (PK) parameters of simvastatin in healthy volunteers' plasma, a quantitative method was developed using an Agilent G6410A rapid performance liquid chromatography (RPLC) coupled with triple quadrupole mass spectrometry system. The established method was rapid with high extraction recovery and successfully applied for the determination of simvastatin in plasma of 16 healthy volunteers. The results demonstrated that the MRT(0-∞), T1/2 and Tmax value of simvastatin were significantly decreased, while the AUC(0-t) and Cmax values of smivastatin were increased by SBP. The pharmacokinetic study demonstrated that the metabolism parameters of simvastatin could be affected by SBP and the potential drug-drug interaction should be noted in the future clinical practice.

  5. Nasal PMN response to repeated challenge with endotoxin in healthy volunteers**

    EPA Science Inventory

    Abstract Rationale: We have employed nasal challenge with Iipopolysaccharid (lPS) followed by nasal lavage (NU to experimentally induce and examine upper airway inflammation in human volunteers.It is unclear however whether adaptation within individuals occurs following repeated ...

  6. Modafinil Increases the Latency of Response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial

    PubMed Central

    Mohamed, Ahmed Dahir; Lewis, Chris Roberts

    2014-01-01

    Background Modafinil is a medication licensed for the treatment of narcolepsy. However, it has been reported that healthy individuals without wakefulness disorders are using modafinil off-label to enhance cognitive functioning. Although some studies have reported that modafinil improves cognitive task performance in healthy volunteers, numerous other studies have failed to detect cognitive enhancing effects of modafinil on several well-established neuropsychological tasks. Interestingly, several clinical and preclinical studies have found that improved cognitive task performance by modafinil is accompanied by slower response times. This observation raises the question as to whether this slowing of response time in healthy volunteers is a necessary and sufficient condition for cognitive enhancement with modafinil. The aim of the current experiment was to explore this question by investigating the effects of modafinil on the Hayling Sentence Completion Test (HSCT). Methodology Sixty-four healthy volunteers received either a single dose (200 mg) of modafinil (n = 32) or placebo (n = 32) in a randomized, double-blind, placebo-controlled, parallel group study in which the principal outcome measures were response latencies on the response initiation and response inhibition sections of the HSCT. Principal Findings Participants dosed with modafinil had significantly longer mean response latencies on the HSCT for both the response initiation and response inhibition compared to participants dosed with placebo. However, participants in both groups made a similar number of errors on each of these measures, indicating that modafinil did not enhance the accuracy of performance of the task relative to placebo. Conclusions This study demonstrated that administration of single 200 mg doses of modafinil to healthy individuals increased the latency of responses in the performance of the HSCT, a task that is highly sensitive to prefrontal executive function, without enhancing

  7. Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers.

    PubMed

    Wu, Xiao-jie; Zhang, Jing; Guo, Bei-ning; Zhang, Ying-yuan; Yu, Ji-cheng; Cao, Guo-ying; Chen, Yuan-cheng; Zhu, De-mei; Ye, Xin-yu; Wu, Ju-fang; Shi, Yao-guo; Chang, Li-wen; Chang, Yu-ting; Tsai, Cheng-yuan

    2015-03-01

    This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 μg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 μg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 μg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 μg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

  8. Diesel exhaust modulates ozone-induced lung function decrements in healthy human volunteers

    PubMed Central

    2014-01-01

    The potential effects of combinations of dilute whole diesel exhaust (DE) and ozone (O3), each a common component of ambient airborne pollutant mixtures, on lung function were examined. Healthy young human volunteers were exposed for 2 hr to pollutants while exercising (~50 L/min) intermittently on two consecutive days. Day 1 exposures were either to filtered air, DE (300 μg/m3), O3 (0.300 ppm), or the combination of both pollutants. On Day 2 all exposures were to O3 (0.300 ppm), and Day 3 served as a followup observation day. Lung function was assessed by spirometry just prior to, immediately after, and up to 4 hr post-exposure on each exposure day. Functional pulmonary responses to the pollutants were also characterized based on stratification by glutathione S-transferase mu 1 (GSTM1) genotype. On Day 1, exposure to air or DE did not change FEV1 or FVC in the subject population (n = 15). The co-exposure to O3 and DE decreased FEV1 (17.6%) to a greater extent than O3 alone (9.9%). To test for synergistic exposure effects, i.e., in a greater than additive fashion, FEV1 changes post individual O3 and DE exposures were summed together and compared to the combined DE and O3 exposure; the p value was 0.057. On Day 2, subjects who received DE exposure on Day 1 had a larger FEV1 decrement (14.7%) immediately after the O3 exposure than the individuals’ matched response following a Day 1 air exposure (10.9%). GSTM1 genotype did not affect the magnitude of lung function changes in a significant fashion. These data suggest that altered respiratory responses to the combination of O3 and DE exposure can be observed showing a greater than additive manner. In addition, O3-induced lung function decrements are greater with a prior exposure to DE compared to a prior exposure to filtered air. Based on the joint occurrence of these pollutants in the ambient environment, the potential exists for interactions in more than an additive fashion affecting lung physiological

  9. Pharmacodynamic and safety results of PEG-Hirudin in healthy volunteers.

    PubMed

    Esslinger, H U; Haas, S; Maurer, R; Lassmann, A; Dübbers, K; Müller-Peltzer, H

    1997-05-01

    PEG-Hirudin, a chemically defined conjugate of recombinant hirudin and two molecules of polyethylene glycol (PEG)-5000 is a highly selective direct thrombin inhibitor with a significantly longer duration of action than non-conjugated recombinant hirudin permitting once daily subcutaneous administration. A series of placebo-controlled, randomized, Phase I clinical trials were conducted in 75 healthy volunteers to investigate the anticoagulant effects, safety and pharmacodynamics of PEG-Hirudin when administered intravenously as a bolus injection, infusion, and subcutaneously. After single i.v. injections of various doses of PEG-Hirudin (0.03-0.3 mg/kg) dose-dependent increases in anti-IIa activity and APTT were observed. Four hours after injection of 0.3 mg/kg, mean plasma concentration expressed in terms of anti-IIa activity was still 0.89 micrograms/ml, corresponding to a 1.8-fold prolongation of APTT. Continuous intravenous infusions of 0.01 and 0.02 mg/kg/h PEG-Hirudin resulted in maximum anti-IIa activities of 0.42 micrograms/ml and 0.77 micrograms/ml, respectively, at the end of a six-hour infusion period without having reached steady state at this time. After termination of the infusion, anticoagulant activity displayed an immediate exponential decrease. The anticoagulant activities of single subcutaneous doses of 0.05 to 0.6 mg/kg were studied in a further series of investigations and slow increases and prolonged durations of anti-IIa activity and APTT prolongation were found. Repeated, once daily subcutaneous administrations of 0.2 to 0.4 mg/kg for five days resulted in dose-dependent prolongations of APTT and increases in anti-IIa activity without completely reaching steady state conditions. In a further study, 0.3 mg/kg of PEG-Hirudin was given as an i.v. bolus injection followed by three repeated single daily s.c. injections. In this trial, the APTT was shorter than expected from previous studies; therefore, a direct comparison of various APTT reagents

  10. Effect of royal jelly ingestion for six months on healthy volunteers

    PubMed Central

    2012-01-01

    Background Royal jelly is a widely ingested supplement for health, but its effects on humans are not well known. The objective was to evaluate the effects of long-term royal jelly ingestion on humans. Methods We conducted a randomized placebo-controlled, double-blind trial. A total of 61 healthy volunteers aged 42-83 years were enrolled and were randomly divided into a royal jelly group (n = 31) and a control group (n = 30). Three thousand mg of royal jelly (RJ) or a placebo in 100 ml liquid/day were ingested for 6 months. The primary outcomes were changes in anthropometric measurements and biochemical indexes from baseline to 6 months after intervention. Results Thirty subjects in the RJ group and 26 in the control group were included in the analysis of endpoints. In an adjusted mean change of the variables from the baseline, significant differences between the two groups could be found in red blood cell counts (+0.16x106 /μL for the RJ group vs. -0.01x106 /μL for the control group, P = 0.0134), hematocrit (+0.9% vs. -0.8%, P = 0.0251), log (fasting plasma glucose) (+0.01 ± 0.01 log mg/dL vs. +0.05 ± 0.01 log mg/dL, P = 0.0297), log (insulinogenic index) (+0.25 vs. -0.13, P = 0.0319), log dehydroepiandrosterone sulfate (DHEA-S) (+0.08 log μg/dL vs. +0.20 log μg/dL, P = 0.0483), log testosterone (T) (+0.12 ± 0.04 log ng/mL vs. -0.02 ± 0.05 log ng/mL, P = 0.0416), log T/DHEA-S ratio (+0.05 ± 0.05 vs. -0.23 ± 0.59, P = 0.0015), and in one of the SF-36 subscale scores, mental health (MH) (+4 vs. -7, P = 0.0276). Conclusions Six-month ingestion of RJ in humans improved erythropoiesis, glucose tolerance and mental health. Acceleration of conversion from DHEA-S to T by RJ may have been observed among these favorable effects. PMID:22995464

  11. Bioavailability and safety study of resveratrol 500 mg tablets in healthy male and female volunteers

    PubMed Central

    SERGIDES, CHRISTAKIS; CHIRILĂ, MARINELA; SILVESTRO, LUIGI; PITTA, DAPHNE; PITTAS, ANDREAS

    2016-01-01

    Over the past few decades, trans-resveratrol has received widespread attention as a preventive agent for numerous diseases. Several studies have demonstrated that it has significant biological and pharmacological properties. Trans-resveratrol has been reported to possess anti-oxidant, anti-inflammatory, anticarcinogenic, antidiabetic, anti-aging, cardioprotective and neuroprotective properties, which can be relevant in chronic diseases and longevity in humans. The aim of the present study was to investigate the rate and extend of absorption, and also the safety of resveratrol following a single 500 mg oral dose. This was an open label, single dose, one period, bioavailability study in 15 healthy volunteers under fasting conditions. Blood samples were collected at predefined time points up to 24 h after resveratrol administration, and plasma concentrations of resveratrol and its conjugated (glucuronated and sulphated) metabolites were determined using a validated high performance liquid chromatography/tandem mass spectrometry method. Pharmacokinetic parameters, including Cmax, AUC0-t, AUC0-inf, Tmax, T1/2 and MRT, were determined from plasma concentration-time profiles and found to be in good agreement with previously reported data. Cmax and AUC0-inf were lower for resveratrol when compared with the values for its glucuronated and sulphated metabolites. Cmax for resveratrol, glucuronated resveratrol and sulphated resveratrol were 71.2±42.4 ng/ml, 4,083.9±1,704.4 ng/ml and 1,516.0±639.0 ng/ml, respectively, while the AUC0-inf values were 179.1±79.1 ng/ml, 39,732.4±16,145.6 ng/ml and 14,441.7±7,593.2 ng/ml, respectively. No adverse reactions associated with resveratrol were reported during the study. The plasma concentrations of resveratrol (free and conjugated) were in agreement with those mentioned in the literature, and were adequate to promote the pharmacological activities of resveratrol. In conclusion, resveratrol 500 mg tablets were well-tolerated by all

  12. Stopped hearts, amputated toes and NASA: contemporary legends among healthy volunteers in US phase I clinical trials

    PubMed Central

    Fisher, Jill A.

    2015-01-01

    The first stage of testing new pharmaceuticals in humans is referred to as a phase I clinical trial. The purpose of these studies is to test the safety of the drugs and to establish appropriate doses that can later be given to patients. Most of these studies are conducted under controlled, in-patient conditions using healthy volunteers who are paid for their participation. To explore healthy volunteers’ experiences in clinical trials, an ethnographic study was conducted at six in-patient phase I clinics in the USA. In addition to the observation of clinic activities (from informed consent procedures to dosing to blood draws), 268 semi-structured interviews were conducted, 33 with clinic staff and 235 with healthy volunteers. Drawing on this dataset, this article explores healthy volunteers’ exchange of contemporary legends about phase I clinical trials. In addition to potentially scaring the listener and communicating distrust in the medical community, these incredible stories help participants cope with perceived stigma and establish a gradient of risk of trial participation, creating potential boundaries to their participation in medical research. The article argues that contemporary legends play a productive role in society, shaping how people view themselves and others and influencing their decisions about risky activities. PMID:25601069

  13. Bioavailability of a new generic formulation of mycophenolate mofetil MMF 500 versus CellCept in healthy adult volunteers.

    PubMed

    Masri, M A; Rizk, S; Attia, M L E; Barbouch, H; Rost, M

    2007-05-01

    Several studies have revealed a decreased incidence of early graft rejection with the use of mycophenate mofetil (MMF). The cost of the drug is, however, prohibitive especially in developing countries with limited resources. We compared the pharmacokinetic profile of a new MMF generic formulation (MMF 500 batch number: 06T3001; Medis Tunis) with those of Cellcept, (batch number: M1427; Hoffmann La Roche, Switzerland) in healthy volunteers. The study was double-blinded to investigator and volunteers. It had a balanced randomized, two-treatment, two-period, two-sequence, single-dose, crossover, comparative oral bioavailability design in adult healthy human volunteers. The study was designed, performed, and monitored by CRO Transmedical s.a.l International (Beirut, Lebanon) in accordance with the Basic Principals defined in the US 21 CFR Part 312.20, and the principals enunciated in the World Medical Association Declaration of Helsinki. We included nonsmoking healthy volunteers between the ages of 22 and 45 years. The subjects were admitted to the hospital one night prior to blood sampling. After volunteers received the same dinner, they were fasted overnight and for 2 hours postdosing. At 8 am each person received a single oral dose of 500 mg of either formulation. Blood samples were collected to construct the pharmacokinetic profiles as follows: 0, 0.15, 0.30, 0.45 minutes and 1, 1.15, 1.30, 2, 4, 6, 10, 12, and 24 hours. Water and food intake were the same for all volunteers during the whole study period. Following an 8-day washout period, the subjects were crossed over. Plasma mycophenolic acid concentrations were determined using a high-performance liquid chromatography validated enzyme-linked immunosorbent assay-based method (TransMedical, Beirut Lebanon). Physical examinations, hematology, urinanalysis, serum chemistry tests, and liver enzymes were performed at screening and at the end of each period. Subjects were monitored for safety and adverse events

  14. Effectiveness of Topical Chia Seed Oil on Pruritus of End-stage Renal Disease (ESRD) Patients and Healthy Volunteers

    PubMed Central

    Jeong, Se Kyoo; Park, Hyun Jung; Park, Byeong Deog

    2010-01-01

    Background Several studies have been performed to evaluate the efficacy of dietary n-3 fatty acid for patients with renal dysfunction. While about 40% to 80% of patients with end-stage renal disease (ESRD) complain about pruritus and xerosis, there are few reports on the effects of topical n-3 fatty acid on these symptoms. Objective In order to investigate the possible beneficial effects of topical n-3 fatty acid, oils extracted from chia (Salvia hispanica) seed were formulated into topical products, the effects of which were measured. Methods Five healthy volunteers having xerotic pruritus symptoms and 5 patients with pruritus caused by either ESRD or diabetes were involved in this study. A topical formulation containing 4% chia seed oils were applied for an 8-week duration. Subjective itching symptoms were assessed on a 6-point scale, as were other skin functions, namely transepidermal water loss and skin capacitance. Results After the 8 weeks of application, significant improvements in skin hydration, lichen simplex chronicus, and prurigo nodularis were observed in all patients. A similar improvement was also observed among healthy volunteers with xerotic pruritus. Improvement of epidermal permeability barrier function and skin hydration, represented by trans-epidermal water loss and skin capacitance, respectively, were also observed. No adverse effects were observed in all the tested patients and volunteers. Conclusion Chia seed oil can be used as an adjuvant moisturizing agent for pruritic skin, including that of ESRD patients. PMID:20548903

  15. The Vaccine Candidate Vibrio cholerae 638 Is Protective against Cholera in Healthy Volunteers

    PubMed Central

    García, Luis; Jidy, Manuel Díaz; García, Hilda; Rodríguez, Boris L.; Fernández, Roberto; Año, Gemma; Cedré, Bárbara; Valmaseda, Tania; Suzarte, Edith; Ramírez, Margarita; Pino, Yadira; Campos, Javier; Menéndez, Jorge; Valera, Rodrigo; González, Daniel; González, Irma; Pérez, Oliver; Serrano, Teresita; Lastre, Miriam; Miralles, Fernando; del Campo, Judith; Maestre, Jorge Luis; Pérez, José Luis; Talavera, Arturo; Pérez, Antonio; Marrero, Karen; Ledón, Talena; Fando, Rafael

    2005-01-01

    Vibrio cholerae 638 is a living candidate cholera vaccine strain attenuated by deletion of the CTXΦ prophage from C7258 (O1, El Tor Ogawa) and by insertion of the Clostridium thermocellum endoglucanase A gene into the hemagglutinin/protease coding sequence. This vaccine candidate was previously found to be well tolerated and immunogenic in volunteers. This article reports a randomized, double-blind, placebo-controlled trial conducted to test short-term protection conferred by 638 against subsequent V. cholerae infection and disease in volunteers in Cuba. A total of 45 subjects were enrolled and assigned to receive vaccine or placebo. The vaccine contained 109 CFU of freshly harvested 638 buffered with 1.3% NaHCO3, while the placebo was buffer alone. After vaccine but not after placebo intake, 96% of volunteers had at least a fourfold increase in vibriocidal antibody titers, and 50% showed a doubling of at least the lipopolysaccharide-specific immunoglobulin A titers in serum. At 1 month after vaccination, five volunteers from the vaccine group and five from the placebo group underwent an exploratory challenge study with 109 CFU of ΔCTXΦ attenuated mutant strain V. cholerae 81. Only two volunteers from the vaccine group shed strain 81 in their feces, but none of them experienced diarrhea; in the placebo group, all volunteers excreted the challenge strain, and three had reactogenic diarrhea. An additional 12 vaccinees and 9 placebo recipients underwent challenge with 7 × 105 CFU of virulent strain V. cholerae 3008 freshly harvested from a brain heart infusion agar plate and buffered with 1.3% NaHCO3. Three volunteers (25%) from the vaccine group and all from the placebo group shed the challenge agent in their feces. None of the 12 vaccinees but 7 volunteers from the placebo group had diarrhea, and 2 of the latter exhibited severe cholera (>5,000 g of diarrheal stool). These results indicate that at 1 month after ingestion of a single oral dose (109 CFU) of strain

  16. Static Subjective Visual Vertical in Healthy Volunteers: The Effects of Different Preset Angle Deviations and Test-Retest Variability

    PubMed Central

    Venhovens, J.; Meulstee, J.; Verhagen, W. I. M.

    2016-01-01

    ABSTRACT The static subjective visual vertical (SVV) was assessed in 24 healthy volunteers with different preset angles (i.e., 10, 20, and 30 degrees), and in 20 other volunteers, the static SVV was tested and retested 1 week later. The static SVV results are influenced by the side of the preset angle (Wilcoxon test, p ≤ 0.001), but not by the preset angle deviation. The test-retest static SVV outcomes are stable at a group level; however, they show statistically relevant variability at an individual level (−0.240 ≤ intraclass correlation coefficient [ICC] ≤ 0.508). A robust static SVV protocol is described in this paper. PMID:27928394

  17. The effects of levetiracetam on objective and subjective sleep parameters in healthy volunteers and patients with partial epilepsy.

    PubMed

    Bell, Caroline; Vanderlinden, Hilde; Hiersemenzel, Reinhard; Otoul, Christian; Nutt, David; Wilson, Sue

    2002-09-01

    Levetiracetam is a novel antiepileptic drug which has recently been released as an adjunctive treatment for partial epilepsy. In the two studies reported here we examined the objective and subjective effects of levetiracetam on sleep in 12 healthy volunteers and 17 patients [16 who could be evaluated for electroencephalogram (EEG) recordings] with a history of partial epilepsy on stable carbamazepine monotherapy. The studies were of a similar double-blind crossover placebo-controlled design with subjects' sleep being recorded in their own homes. The results from the two studies showed considerable similarities. In both, levetiracetam produced an increase in the time spent in stage 2 sleep, which in the patient study was accompanied by a decrease in the time spent in stage 4 sleep and in the volunteer study an increase in rapid eye movement (REM) latency. The subjective changes included reports that sleep was of a better quality with fewer awakenings and patients also reported that their sleep was more restful. Volunteers and patients did, however, feel less alert on waking in the morning. Therefore, both groups reported a decrease in awakenings after levetiracetam despite the finding from the EEG of no change in the actual number of awakenings. It may be concluded from both studies that levetiracetam does affect some indicators of subjective sleep perception, but does not influence objective sleep measures of sleep continuity. The results from the patient study during placebo add-on treatment also showed that patients on carbamazepine had a marked increase in SWS, an increase in stage 2 sleep and an increase in REM latency compared with healthy volunteers. Interestingly, levetiracetam also reduced bilateral epileptiform EEG activity, particularly in patients with more discharges.

  18. A validation of the 7.5% CO2 model of GAD using paroxetine and lorazepam in healthy volunteers.

    PubMed

    Bailey, Jayne E; Kendrick, Adrian; Diaper, Alison; Potokar, John P; Nutt, David J

    2007-01-01

    The inhalation of 7.5% carbon dioxide (CO2) in healthy subjects produces an increase in blood pressure and heart rate, and increased feelings of anxiety, fear and tension (Bailey et al. 2005). As this state is similar to that of general anxiety rather than panic, we further validated this by examining the effects of anxiolytic medication. Two separate studies in healthy volunteers are described; study one is a double-blind, placebo-controlled study of a single dose of 2 mg lorazepam and study two describes the effects of 21 days of treatment with paroxetine. Gas challenges were air and 7.5% CO2 inhaled for 20 minutes, delivered on day 0 (before treatment) and day 21 (after treatment) in the paroxetine study. Subjective effects were measured using visual analogue scales and questionnaires. When compared with placebo, lorazepam 2 mg significantly reduced peak CO2-induced subjective fear, feelings of wanting to leave, tension and worry. In the paroxetine study, when compared with day 0, day 21 showed a significantly attenuated peak CO2-induced nervousness and a trend for reduced ratings of anxiety, fear, feel like leaving, tense and worried. In these studies we have shown that this CO2 model of anxiety is sensitive to lorazepam and to a lesser extent paroxetine. This gives support to its utility as an experimental model of general anxiety disorder in healthy volunteers.

  19. Noninvasive Assessment of the Effect of Position and Exercise on Pulse Arrival to Peripheral Vascular Beds in Healthy Volunteers

    PubMed Central

    Obata, Yurie; Ong, Qi J.; Magruder, J. T.; Grichkevitch, Helen; Berkowitz, Dan E.; Nyhan, Daniel; Steppan, Jochen; Barodka, Viachaslau

    2017-01-01

    Background: The effects of position and exercise on pulse wave distribution across a healthy, compliant arterial tree are not fully understood. We studied the effects of exercise and position on the pattern of pulse arrival times (PATs) in healthy volunteers. Moreover, we compared the pulse arrival time ratios to the respective distance ratios between different locations. Methods: Thirteen young healthy volunteers were studied, using an electrocardiogram and plethysmograph to simultaneously record pulse wave arrival at the ear lobe, index finger and big toe. We compared the differences in PAT between each location at rest and post-exercise in the supine, sitting, and standing position. We also compared the PAT ratio (toe/ear, toe/finger, and finger/ear) to the corresponding pulse path distance ratios. Results: PAT was shortest at the ear then finger and longest at the toe regardless of position or exercise status. PATs were shorter post-exercise compared to rest. When transitioning from a standing to sitting or supine position, PAT to the ear decreased, while the PAT to the toe increased, and PAT to the finger didn't significantly change. PAT ratios were significantly smaller than predicted by the path distance ratios regardless of position or exercise status. Conclusions: Exercise makes PATs shorter. Standing position decrease PAT to the toe and increase to the ear. We conclude that PAT and PAT ratio represent the arterial vascular tree properties as surely as pulse transit time and pulse wave velocity. PMID:28220077

  20. Bioequivalence study of generic tablet formulations containing ethinylestradiol and chlormadinone acetate in healthy female volunteers.

    PubMed

    Bonn, Michael; Eydeler, Urte; Barkworth, Martin; Rovati, Lucio C

    2009-01-01

    The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol (CAS 57-63-6) and chlormadinone acetate (CAS 302-22-7) (Bellissima as test and the respective preparation from the originator as reference) were investigated in 20 healthy female volunteers after oral single-dose administration. The study was performed according to a single-center, randomised, single-dose, 2-way cross-over design with a wash-out phase of 28 days. Blood samples for pharmacokinetic profiling were taken up to 168 h post-dose, and ethinylestradiol and chlormadinone acetate plasma concentrations were determined with a validated LC-MS/MS method. The observed mean maximum plasma concentrations (Cmax) of ethinylestradiol were 124.96 pg/ml (test) and 129.12 pg/ml (reference). In the case of chlormadinone acetate, Cmax averaged 6.9566 ng/ml (test) and 6.6663 ng/m (reference). The geometric means of area under the plasma concentration-time curve (AUC(0-infinity)) of ethinylestradiol were 1292.35 pg/ml x h (test) and 1380.49 pg/ml x h (reference). For chlormadinone acetate, geometric means of AUC(0-infinity) were 53.322 ng/ml x h (test) and 58.111 ng/ml x h (reference). The median of tmax of ethinylestradiol was 1.5 h for both test and reference and the median of tmax of chlormadinone acetate 1.0 h (test) and 1.5 h (reference). Plasma elimination half-lives (t1/2) of ethinylestradiol were 14.96 h (test) and 15.41 h (reference) and of chlormadinone acetate 56.63 h (test) and 56.17 h (reference), respectively. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA). The point estimator and the 90% confidence intervals for the AUC(0-infinity) ratio (test/reference: 93.72% [86.62%-101.39%]) indicate high similarity of both formulations with respect to the extent of ethinylestradiol exposure. A high degree of similarity was also observed for Cmax of ethinylestradiol, as the point estimator and the 90

  1. Influence of a Nigerian honey on CYP3A4 biotransformation of quinine in healthy volunteers

    PubMed Central

    Igbinoba, S. I.; Akanmu, M. A.; Onyeji, C. O.; Soyinka, J. O.; Owolabi, A. R.; Nathaniel, T. I.; Pullela, S. V.; Cook, J. M.

    2016-01-01

    What is known and objectives Some studies, howbeit with conflicting reports have suggested that consumption of honey has a potential to modulate drug metabolising enzymes which may result in a honey - drug interaction. Numerous studies have established that honey varies in composition, influenced by the dominant floral, processing and environmental factors. Thus, variation in honey composition may be a contributing factor to the controversial results obtained. No previous drug interaction study has been done with any honey from Africa. CYP 3A4 is an important enzyme in drug metabolism studies as it is involved in the metabolism of over 50 % of drugs in clinical use and quinine remains very relevant in malaria treatment in the tropics, we therefore determined whether there is potential drug interaction between a Nigeria honey and quinine, a drug whose metabolism to 3 –hydroxyquinine is mediated majorly by CYP3A4. Methods In a three phase randomized cross-over study with a wash out period of two weeks between each treatment phase, ten (10) healthy volunteers received quinine sulphate tablet (600 mg single dose) alone (phase 1) or after administration of 10 ml of honey (Phase 2) and 20 ml of honey (Phase 3) twice daily for seven (7) days. Blood samples were collected at the 16th hour post quinine administration in each phase and quinine and its major metabolite, 3-hydroxyquinine were analyzed using a validated HPLC method. Results After scheduled doses of honey, the mean metabolic ratios of quinine (3-hydroxyquinine/quinine) increased by 24.4 % (with 10 ml of honey) and reduced by 23.9 % (with 20 ml of honey) when compared to baseline. These magnitudes of alteration in the mean metabolic ratios were not significant (p > 0.05; Friedman-test). The geometric mean (95 % CI) for the metabolic ratio of quinine before and after honey intake at the two dose levels studied were 0.82 (0.54, 1.23) and 1.29 (0.96, 1.72) respectively and were also not significant (P = 0.296 and

  2. Healthy Connections. A Training Program for Volunteers Working with At-Risk Pregnant Women. Leader's Manual.

    ERIC Educational Resources Information Center

    Harris, Carolyn DeMeyer; McKinney, David D., Ed.

    This leader's manual, keyed to an accompanying videotape, contains step-by-step instructions for conducting a training session for volunteers who are preparing to work with young unmarried pregnant women. The manual, which includes transparency masters of handouts, is laid out with the outside column of each page containing instructions to the…

  3. Seniors Serving Seniors: Volunteers Promoting Healthy Aging Project. Feasibility Study Report.

    ERIC Educational Resources Information Center

    Ellis, Cathy

    A research study assessed whether health-related agencies and organizations in Regina, Saskatchewan, Canada, were willing to use trained older adults as volunteer health promoters, mentors, and tutors working with other seniors, despite the fact that no other programs in the Regina Health District specifically used older adults in these roles. A…

  4. Pharmacokinetics of an extended release formulation of alprazolam (Xanax XR) in healthy normal adolescent and adult volunteers.

    PubMed

    Glue, Paul; Fang, Annie; Gandelman, Kuan; Klee, Brian

    2006-01-01

    The purpose of this study was to estimate pharmacokinetics, safety, and tolerability of single doses of an extended release formulation of alprazolam (Xanax XR) in adolescent and adult healthy volunteers. This was a randomized, open-label, single-dose, 2-period crossover study. Twelve adolescent healthy volunteers (13-17 years) and 12 adult healthy volunteers (20-45 years) received single doses of Xanax XR 1 mg or 3 mg tablets. Blood samples were obtained predose and for 48 hours postdose. Plasma samples were assayed for alprazolam and its two active metabolites alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam using a validated LC-MS/MS method. Safety assessments included clinical laboratory tests, vital signs, and adverse event monitoring. At both dose levels, mean plasma concentration-time profiles of alprazolam, alpha-hydroxy-alprazolam, and 4-hydroxy-alprazolam were similar in adolescent and adult subjects. The ratios of estimated geometric means for AUC(0-infinity) and Cmax between adolescents and adults for both dose levels were 115% (95% CI: [93, 143]) and 111% (95% CI: [95, 129]), respectively. An assessment of dose proportionality between the 3 mg and 1 mg alprazolam doses within both age groups indicated that the AUC(0-infinity) and Cmax were both within 80-125% equivalence limits. Parent-metabolite ratios were similar in both age groups and were consistent with those previously reported. Alprazolam was well tolerated by both age groups. The most common adverse event was somnolence, which occurred in a dose-related manner. Based on the similar pharmacokinetic profiles, dosing of Xanax XR should be similar in adolescents and adults.

  5. A pilot study on the effect of acute tai chi practice on peripheral blood cytokine expression in healthy volunteers.

    PubMed

    Li, Hongtao; Howk, Cherie; Geib, Roy W

    2012-01-01

    Tai chi (TC) is a unique form of exercise having both mind and body components – focused mindfulness and physical movement. It is perhaps best known for its ability to prevent falls in elderly people. It is also thought to improve vitality, longevity, mental and physical health. Recent studies have demonstrated its effectiveness as an intervention for chronic diseases associated with the inflammatory process, such as arthritis, heart disease, diabetes, and obesity. The objective of this study was to explore the modulatory effect of acute TC practice on anti-inflammatory cytokine levels in healthy volunteers.

  6. LDL cholesterol-lowering effects of grape extract used as a dietary supplement on healthy volunteers.

    PubMed

    Yubero, Noemí; Sanz-Buenhombre, Marisa; Guadarrama, Alberto; Villanueva, Sonia; Carrión, Juan M; Larrarte, Eider; Moro, Carlos

    2013-06-01

    The aim of this study was to evaluate the effects of Eminol®, the polyphenol-rich grape extract supplement (700 mg), on cardiovascular risk and oxidant stress indicators in a sample of volunteers. A randomized, double-blind, placebo-controlled clinical trial was performed over 56 days and included 60 volunteers. Thirty volunteers took 700 mg of the grape extract, Eminol® (E), and 30 took the placebo (P). On comparison of the results, a decrease in total cholesterol (E: 213.77 ± 4.1 mg/dl and P: 245.57 ± 4.1 mg/dl; p = 0.01) and LDL cholesterol (E: 142.17 ± 3.1 mg/dl and P: 165.13 ± 3.1 mg/dl; p = 0.02) levels as well as an increase in antioxidant capacity (E: 65.63 ± 5.8 μmol TE/mg and P: 57.80 ± 7.7 μmol TE/mg; p < 0.01) and vitamin E (E: 11.46 ± 0.5 μg/ml and P: 9.06 ± 0.5 μg/ml; p = 0.018) was observed. This result indicates that the grape extract Eminol® modulated the lipid profile in terms of cardiovascular risk indicators, lowering total blood cholesterol and LDL cholesterol levels.

  7. Pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam in healthy volunteers: an interethnic comparative study between Japanese and European volunteers.

    PubMed

    van Gerven, J M; Uchida, E; Uchida, N; Pieters, M S; Meinders, A J; Schoemaker, R C; Nanhekhan, L V; Kroon, J M; de Visser, S J; Altorf, B; Yasuda, K; Yasuhara, H; Cohen, A F

    1998-12-01

    Potential interethnic differences in drug disposition and effects between Japanese and white subjects hamper the registration in Japan of medications already used in Western countries. This double-blind, placebo-controlled, crossover study was conducted to compare the pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam (5 mg) in age- and sex-matched Japanese (n = 8) and white (n = 8) healthy volunteers. The study was performed in centers in Japan and the Netherlands using the same methods and study design. Subjects were individually matched for gender, age, and body stature. Drug effects were measured by means of saccadic and smooth pursuit eye movements and visual analog lines obtained from the scales of Bond and Lader. There were no pharmacokinetic differences between the Japanese and white subjects. Clearance of nitrazepam was 0.91 +/- 0.165 mL/min/kg and 1.17 +/- 0.492 mL/min/kg, and half-life (t1/2) was 22.1 +/- 4.96 hours and 21.5 +/- 7.51 hours for the Japanese and European groups, respectively. Pharmacokinetic parameters showed no significant correlation with age, height, or weight. The average time-effect curves for the different parameters were comparable between groups. Compared with placebo, both groups showed similar significant reductions in average peak velocity and increases in saccadic inaccuracy and reaction time. Visual analog scores showed clear sedation in the white subjects, but insignificant effects in the Japanese subjects. Smooth pursuit did not change significantly in either group. Slope and intercept of the concentration-effect relationships for saccadic peak velocity showed considerable intersubject variability, but no clear differences between groups. The pharmacokinetics and pharmacodynamics of nitrazepam were similar in matched healthy Japanese and white subjects. Interethnic comparative studies are feasible, and provide meaningful information about potential racial differences in disposition and action of drugs

  8. Disassociation of static and dynamic cerebral autoregulatory performance in healthy volunteers after lipopolysaccharide infusion and in patients with sepsis.

    PubMed

    Berg, Ronan M G; Plovsing, Ronni R; Ronit, Andreas; Bailey, Damian M; Holstein-Rathlou, Niels-Henrik; Møller, Kirsten

    2012-12-01

    Sepsis is frequently complicated by brain dysfunction, which may be associated with disturbances in cerebral autoregulation, rendering the brain susceptible to hypoperfusion and hyperperfusion. The purpose of the present study was to assess static and dynamic cerebral autoregulation 1) in a human experimental model of the systemic inflammatory response during early sepsis and 2) in patients with advanced sepsis. Cerebral autoregulation was tested using transcranial Doppler ultrasound in healthy volunteers (n = 9) before and after LPS infusion and in patients with sepsis (n = 16). Static autoregulation was tested by norepinephrine infusion and dynamic autoregulation by transfer function analysis (TFA) of spontaneous oscillations between mean arterial blood pressure and middle cerebral artery blood flow velocity in the low frequency range (0.07-0.20 Hz). Static autoregulatory performance after LPS infusion and in patients with sepsis was similar to values in healthy volunteers at baseline. In contrast, TFA showed decreased gain and an increased phase difference between blood pressure and middle cerebral artery blood flow velocity after LPS (both P < 0.01 vs. baseline); patients exhibited similar gain but lower phase difference values (P < 0.01 vs. baseline and LPS), indicating a slower dynamic autoregulatory response. Our findings imply that static and dynamic cerebral autoregulatory performance may disassociate in sepsis; thus static autoregulation was maintained both after LPS and in patients with sepsis, whereas dynamic autoregulation was enhanced after LPS and impaired with a prolonged response time in patients. Hence, acute surges in blood pressure may adversely affect cerebral perfusion in patients with sepsis.

  9. The effects of acute tryptophan depletion on brain activation during cognition and emotional processing in healthy volunteers.

    PubMed

    Evers, E A T; Sambeth, A; Ramaekers, J G; Riedel, W J; van der Veen, F M

    2010-01-01

    Acute tryptophan depletion (ATD), a method to temporarily lower central serotonin levels, has been used to study the functioning of the serotonergic system. Relatively recent studies that examined the effects of ATD on brain activation associated with cognitive and emotional processing in healthy volunteers are reviewed. An overview of the findings in healthy volunteers is important for the interpretation of the effect of ATD on brain activation in patients with an affective disorder, such as major depression. These studies show that during response control and negative feedback processing ATD modulates the BOLD response in the inferior/orbitofrontal cortex, the anterior cingulate cortex and the dorsomedial prefrontal cortex. During emotional processing, it is consistently found that ATD modulates the BOLD response in the amygdala. These brain regions also show abnormal activation in depressed patients. However, at the moment it remains unclear if the changes induced by ATD are related to decreased basal serotonin (5-HT) release or the result of other biochemical changes that are mediated by ATD. Future studies should implement methodological improvements, explore the possibilities of new promising imaging techniques and expand investigations into the effects of ATD on basal 5-HT release and other biochemical mechanisms that might be modulated by ATD.

  10. Sphenopalatine Ganglion Acupuncture Improves Nasal Ventilation and Modulates Autonomic Nervous Activity in Healthy Volunteers: A Randomized Controlled Study

    PubMed Central

    Wang, Kuiji; Chen, Luquan; Wang, Yang; Wang, Chengshuo; Zhang, Luo

    2016-01-01

    The study aimed to assess the effects of Sphenopalatine ganglion (SPG) acupuncture on nasal ventilation function and autonomic nervous system in health volunteers. 39 healthy subjects were randomly assigned to either active SPG acupuncture group (AA group) or sham-SPG acupuncture group (SA group). All subjects were assessed for self-reported nasal ventilation, nasal patency (nasal airway resistance (NAR) and nasal cavity volume (NCV), exhaled nasal nitric oxide (nNO), and neuropeptides (substance P(SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY)) in nasal secretions at baseline, 30 minutes, 2 hours, and 24 hours after acupuncture. Significantly more subjects in AA group reported improvements in nasal ventilation at all time points after acupuncture, compared to SA group. NAR and NCV were also significantly lower in AA group than SA group. The level of nNO in AA group was significantly decreased after 24 hours compared to SA group. The level of NPY was significantly increased in AA group at 30 minutes and 2 hours compared to baseline and SA group. The levels of SP and VIP were not significantly different in the two groups. We concluded that SPG acupuncture could help to improve nasal ventilation by increasing sympathetic nerve excitability in healthy volunteers. PMID:27425415

  11. Preliminary study of relationships between hypnotic susceptibility and personality disorder functioning styles in healthy volunteers and personality disorder patients

    PubMed Central

    2011-01-01

    Background Hypnotic susceptibility is one of the stable characteristics of individuals, but not closely related to the personality traits such as those measured by the five-factor model in the general population. Whether it is related to the personality disorder functioning styles remains unanswered. Methods In 77 patients with personality disorders and 154 healthy volunteers, we administered the Stanford Hypnotic Susceptibility Scale: Form C (SHSSC) and the Parker Personality Measure (PERM) tests. Results Patients with personality disorders showed higher passing rates on SHSSC Dream and Posthypnotic Amnesia items. No significant correlation was found in healthy volunteers. In the patients however, SHSSC Taste hallucination (β = 0.26) and Anosmia to Ammonia (β = -0.23) were significantly correlated with the PERM Borderline style; SHSSC Posthypnotic Amnesia was correlated with the PERM Schizoid style (β = 0.25) but negatively the PERM Narcissistic style (β = -0.23). Conclusions Our results provide limited evidence that could help to understand the abnormal cognitions in personality disorders, such as their hallucination and memory distortions. PMID:21801440

  12. Anxiolytic effects of vestipitant in a sub-group of healthy volunteers known to be sensitive to CO2 challenge.

    PubMed

    Poma, Stefano Zanone; Merlo-Pich, Emilio; Bettica, Paolo; Bani, Massimo; Fina, Paolo; Ziviani, Luigi; Milleri, Stefano

    2014-05-01

    The pharmacological properties of two NK1 antagonists were studied in comparison with a benzodiazepine during a 7% CO2 challenge in a population of healthy volunteers selected for a high sensitivity to the challenge. In total, 19 healthy subjects, pre-screened for their responsiveness to the 7% CO2 test, took part in the randomised, double-blind, cross-over, incomplete block design study. After receiving treatment or placebo, the volunteers were subjected to three 7% CO2 challenges each for a time of 20 min. The treatment consisted of the administration of the following three active drugs: a single dose of benzodiazepine alprazolam (0.75 mg) and a single dose of the NK1 antagonists vestipitant (GW597599) (15 mg) and vofopitant (GR205171) (25 mg). Anxiety during the challenge was evaluated with Visual Analogue Scale-Anxiety (VAS-A) and with Panic Symptom List (PSL III-R). Respiratory parameters, heart rate and skin conductance were also recorded. Compared with placebo, vestipitant showed a significant reduction (p<0.05) in anxiety assessed on the VAS-A scale (ΔVAS-A%) while alprazolam significantly (p<0.01) attenuated the PSL III-R total score. Vofopitant did not show any anxiolytic effect. In the comparison analysis between placebo and drugs, none of the respiratory and other physiological parameters showed a statistically significant difference.

  13. Effects of helium and air inhalation on the innate and early adaptive immune system in healthy volunteers ex vivo

    PubMed Central

    2012-01-01

    Background Helium inhalation protects myocardium, brain and endothelium against ischemia/reperfusion injury in animals and humans, when applied according to specific “conditioning” protocols. Before widespread use of this “conditioning” agent in clinical practice, negative side effects have to be ruled out. We investigated the effect of prolonged helium inhalation on the responsiveness of the human immune response in whole blood ex vivo. Methods Male healthy volunteers inhaled 30 minutes heliox (79%He/21%O2) or air in a cross over design, with two weeks between measurements. Blood was withdrawn at T0 (baseline), T1 (25 min inhalation) and T2-T5 (1, 2, 6, 24 h after inhalation) and incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), T-cell stimuli anti-CD3/ anti-CD28 (TCS) or RPMI (as control) for 2, 4 and 24 hours or not incubated (0 h). An additional group of six volunteers inhaled 60 minutes of heliox or air, followed by blood incubation with LPS and RPMI. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interferon-γ (IFN-γ) and interleukin-2 (IL-2) was analyzed by cytometric bead array. Statistical analysis was performed by the Wilcoxon test for matched samples. Results Incubation with LPS, LTA or TCS significantly increased TNF-α, IL-1β, IL-6, IL-8, IFN-γ and IL-2 in comparison to incubation with RPMI alone. Thirty min of helium inhalation did not influence the amounts of TNF-α, IL-1β, IL-6, IL-8, IFN-γ and IL-2 in comparison to air. Sixty min of helium inhalation did not affect cytokine production after LPS stimulation. Conclusions We conclude that 79% helium inhalation does not affect the responsiveness of the human immune system in healthy volunteers. Trial registration Dutch Trial Register: http://www.trialregister.nl/ NTR2152 PMID:23006534

  14. Safety, Pharmacokinetics, Pharmacodynamics, and Plasma Lipoprotein Distribution of Eritoran (E5564) during Continuous Intravenous Infusion into Healthy Volunteers

    PubMed Central

    Rossignol, Daniel P.; Wasan, Kishor M.; Choo, Eugene; Yau, Edwin; Wong, Nancy; Rose, Jeffrey; Moran, Jeffrey; Lynn, Melvyn

    2004-01-01

    Eritoran, a structural analogue of the lipid A portion of lipopolysaccharide (LPS), is an antagonist of LPS in animal and human endotoxemia models. Previous studies have shown that low doses (350 to 3,500 μg) of eritoran have demonstrated a long pharmacokinetic half-life but a short pharmacodynamic half-life. The present study describes the safety, pharmacokinetics and pharmacodynamics, and lipid distribution profile of eritoran during and after a 72-h intravenous infusion of 500, 2,000, or 3,500 μg/h into healthy volunteers. Except for the occurrence of phlebitis, eritoran administration over 72 h was safe and well tolerated. Eritoran demonstrated a slow plasma clearance (0.679 to 0.930 ml/h/kg of body weight), a small volume of distribution (45.6 to 49.8 ml/kg), and a relatively long half-life (50.4 to 62.7 h). In plasma, the majority (∼55%) of eritoran was bound to high-density lipoproteins. During infusion and for up to 72 h thereafter, ex vivo response of blood to 1- or 10-ng/ml LPS was inhibited by ≥85%, even when the lowest dose of eritoran (500 μg/h) was infused. Inhibition of response was dependent on eritoran dose and the concentration of LPS used as an agonist. Finally, in vitro analysis with purified lipoprotein and protein fractions from plasma obtained from healthy volunteers indicated that eritoran is inactivated by high-density but not low-density lipoproteins, very-low-density lipoproteins, or albumin. From these results, we conclude that up to 252 mg of eritoran can be safely infused into normal volunteers over 72 h and even though it associates extensively with high-density lipoproteins, antagonistic activity is maintained, even after infusion ceases. PMID:15328078

  15. Relative indexes of cutaneous blood perfusion measured by real-time laser Doppler imaging (LDI) in healthy volunteers.

    PubMed

    Seyed Jafari, S Morteza; Schawkat, Megir; Van De Ville, Dimitri; Shafighi, Maziar

    2014-07-01

    We used real-time LDI to study regional variations in microcirculatory perfusion in healthy candidates to establish a new methodology for global perfusion body mapping that is based on intra-individual perfusion index ratios. Our study included 74 (37 female) healthy volunteers aged between 22 and 30 years (mean 24.49). Imaging was performed using a recent microcirculation-imaging camera (EasyLDI) for different body regions of each volunteer. The perfusion values were reported in Arbitrary Perfusion Units (APU). The relative perfusion indexes for each candidate's body region were then obtained by normalization with the perfusion value of the forehead. Basic parameters such as weight, height, and blood pressure were also measured and analyzed. The highest mean perfusion value was reported in the forehead area (259.21APU). Mean perfusion in the measured parts of the body correlated positively with mean forehead value, while there was no significant correlation between forehead blood perfusion values and room temperature, BMI, systolic blood pressure and diastolic blood pressure (p=0.420, 0.623, 0.488, 0.099, respectively). Analysis of the data showed that perfusion indexes were not significantly different between male and female volunteers except for the ventral upper arm area (p=.001). LDI is a non-invasive, fast technique that opens several avenues for clinical applications. The mean perfusion indexes are useful in clinical practice for monitoring patients before and after surgical interventions. Perfusion values can be predicted for different body parts for patients only by taking the forehead perfusion value and using the perfusion index ratios to obtain expected normative perfusion values.

  16. The H3 antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers

    PubMed Central

    Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Gertsik, Lev; Dutta, Sandeep

    2014-01-01

    Aims ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia. Methods This was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively. Results Of the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations. Conclusions ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake. PMID:24215171

  17. The role of somatostatin (octreotide) in the regulation of melatonin secretion in healthy volunteers and in patients with primary hypothyroidism.

    PubMed

    Wikner, J; Wetterberg, L; Röjdmark, S

    1999-01-01

    Somatostatin has been found in the pineal gland of several animal species, which suggests that it may be involved in the regulation of melatonin secretion. Whether somatostatin has regulatory influence on melatonin secretion in man has never been unequivocally shown. We studied the nocturnal melatonin secretion in 8 healthy volunteers, and 6 women with untreated primary hypothyroidism, a disease state that is associated with increased nocturnal secretion of melatonin. The participants were given subcutaneous injections at 18:00 h and 23:00 h of either saline or octreotide (Sandostatin; each injection 50 microg). During the nights when the healthy volunteers were given octreotide, melatonin secretion was similar to that recorded during administration of saline. Also the urinary excretion of melatonin was of similar magnitude at these two occasions. By contrast, the GH secretion was significantly lower the nights the healthy controls were given octreotide (GH AUC 22.6+/-5.4 mU/l x h during octreotide and 126.6+/-21.9 mU/l x h during saline; p<0.01). The patients with hypothyroidism also showed similar nocturnal melatonin secretion during octreotide and saline. Urinary excretion of melatonin also remained unchanged, as did GH secretion. The total nocturnal secretion of TSH was, however, significantly reduced by octreotide (TSH AUC 562+/-136 mU/l x h during octreotide and 851+/-185 mU/l x h during saline; p<0.05), thus suggesting that 100 microg of octreotide should be sufficient to inhibit also the pinealocytes if their function were regulated by somatostatin. Since exogenous somatostatin--in the form of octreotide--fails to influence nocturnal secretion and urinary excretion of melatonin in normal subjects and in patients with primary hypothyroidism, it is reasonable to assume that endogenous somatostatin may not be an important regulator of melatonin secretion in man.

  18. Near-Infrared Fluorescence Lymphatic Imaging to Reconsider Occlusion Pressure of Superficial Lymphatic Collectors in Upper Extremities of Healthy Volunteers

    PubMed Central

    Vandermeeren, Liesbeth; Vankerckhove, Sophie; Valsamis, Jean-Baptiste; Malloizel-Delaunay, Julie; Moraine, Jean-Jacques; Liebens, Fabienne

    2016-01-01

    Abstract Background: There are very little scientific data on occlusion pressure for superficial lymphatic collectors. Given its importance in determining the transport capacity of lymphatic vessels, it is crucial to know its value. The novel method of near-infrared fluorescence lymphatic imaging (NIRFLI) can be used to visualize lymphatic flow in real time. The goal of this study was to see if this method could be used to measure the lymphatic occlusion pressure. Methods: We observed and recorded lymph flow in the upper limb of healthy volunteers through a transparent cuff using near-infrared fluorescence lymphatic imaging. After obtaining a baseline of the lymph flow without pressure inside the cuff, the cuff was inflated by increments of 10 mm Hg starting at 30 mm Hg. A NIRFLI guided manual lymphatic drainage technique named “Fill & Flush Drainage Method” was performed during the measurement to promote lymph flow. Lymphatic occlusion pressure was determined by observing when lymph flow stopped under the cuff. Results: We measured the lymphatic occlusion pressure on 30 healthy volunteers (11 men and 19 women). Mean lymphatic occlusion pressure in the upper limb was 86 mm Hg (CI ±3.7 mm Hg, α = 0.5%). No significant differences were found between age groups (p = 0.18), gender (p = 0.12), or limb side (p = 0.85). Conclusions: NIRFLI, a transparent sphygmomanometer cuff and the “Fill and Flush” manual lymphatic drainage method were used to measure the lymphatic occlusion pressure in 30 healthy humans. That combination of these techniques allows the visualization of the lymph flow in real time, while ensuring the continuous filling of the lymph collectors during the measurement session, reducing false negative observations. The measured occlusion pressures are much higher than previously described in the medical literature. PMID:27167187

  19. Clinical Evaluation of Humira(®) Biosimilar ONS-3010 in Healthy Volunteers: Focus on Pharmacokinetics and Pharmacodynamics.

    PubMed

    Dillingh, Marlous R; Reijers, Joannes A A; Malone, Karen E; Burggraaf, Jacobus; Bahrt, Kenneth; Yamashita, Liz; Rehrig, Claudia; Moerland, Matthijs

    2016-01-01

    ONS-3010 is being developed by Oncobiologics Inc. (Cranbury, NJ, USA) as a biosimilar of Humira(®). This randomized, double blind, single-center phase I study (EudraCT registration # 2013-003551-38) was performed to demonstrate pharmacokinetic (PK) biosimilarity between two reference products (Humira(®) EU and US) and ONS-3010 in healthy volunteers, and to compare the safety and immunogenicity profiles. In addition, the intended pharmacological activity was assessed and compared by application of a whole blood challenge. Hundred ninety-eight healthy volunteers received a single 40 mg subcutaneous dose of ONS-3010, Humira(®) EU, or US. The pharmacodynamic effects were assessed by lipopolysaccharide (LPS)/aluminum hydroxide whole blood challenges (n = 36; n = 12 per treatment arm; male:female, 1:1). Equivalence was demonstrated on the PK endpoints (AUC0-inf, Cmax, and AUC0-last) based on bounds of 80-125% for the ratio of the geometric means (ONS-3010/Humira(®)). The immunogenicity profiles were comparable between treatment groups, and there were no indications for differences in routine safety parameters. Administration of adalimumab resulted in the observation of dramatically reduced tumor necrosis factor-α (TNFα) levels upon stimulation with LPS/aluminum hydroxide (>99%), with no differences between the three treatment groups in terms of magnitude or duration. Adalimumab also resulted in a reduction of LPS/aluminum hydroxide-induced interleukin (IL)-8 release (maximally 30%), suggested to have a causal relationship with the anti-TNFα treatment. LPS/aluminum hydroxide-induced release of IL-1β and IL-6 was not inhibited by anti-TNFα treatment. Taken together, these data are promising for the further clinical development of ONS-3010, demonstrate the relevance of the LPS/aluminum challenge to monitor Humira(®) effects, and emphasize the value of whole blood challenges for monitoring of proximal drug effects in healthy volunteers, and potentially in

  20. Inorganic nitrate ingestion improves vascular compliance but does not alter flow-mediated dilatation in healthy volunteers.

    PubMed

    Bahra, M; Kapil, V; Pearl, V; Ghosh, S; Ahluwalia, A

    2012-05-15

    Ingestion of inorganic nitrate elevates blood and tissue levels of nitrite via bioconversion in the entero-salivary circulation. Nitrite is converted to NO in the circulation, and it is this phenomenon that is thought to underlie the beneficial effects of inorganic nitrate in humans. Our previous studies have demonstrated that oral ingestion of inorganic nitrate decreases blood pressure and inhibits the transient endothelial dysfunction caused by ischaemia-reperfusion injury in healthy volunteers. However, whether inorganic nitrate might improve endothelial function per se in the absence of a pathogenic stimulus and whether this might contribute to the blood pressure lowering effects is yet unknown. We conducted a randomised, double-blind, crossover study in 14 healthy volunteers to determine the effects of oral inorganic nitrate (8 mmol KNO(3)) vs. placebo (8 mmol KCl) on endothelial function, measured by flow-mediated dilatation (FMD) of the brachial artery, prior to and 3h following capsule ingestion. In addition, blood pressure (BP) was measured and aortic pulse wave velocity (aPWV) determined. Finally, blood, saliva and urine samples were collected for chemiluminescence analysis of [nitrite] and [nitrate] prior to and 3h following interventions. Inorganic nitrate supplementation had no effect on endothelial function in healthy volunteers (6.9±1.1% pre- to 7.1±1.1% post-KNO(3)). Despite this, there was a significant elevation of plasma [nitrite] (0.4±0.1 μM pre- to 0.7±0.2 μM post-KNO(3), p<0.001). In addition these changes in [nitrite] were associated with a decrease in systolic BP (116.9±3.8mm Hg pre- vs. 112.1±3.4 mm Hg post-KNO(3), p<0.05) and aPWV (6.5±0.1 m/s pre- to 6.2±0.1 post-KNO(3), p<0.01). In contrast KCl capsules had no effect on any of the parameters measured. These findings demonstrate that although inorganic nitrate ingestion does not alter endothelial function per se, it does appear to improve blood flow, in combination with a

  1. Clinical Evaluation of Humira® Biosimilar ONS-3010 in Healthy Volunteers: Focus on Pharmacokinetics and Pharmacodynamics

    PubMed Central

    Dillingh, Marlous R.; Reijers, Joannes A. A.; Malone, Karen E.; Burggraaf, Jacobus; Bahrt, Kenneth; Yamashita, Liz; Rehrig, Claudia; Moerland, Matthijs

    2016-01-01

    ONS-3010 is being developed by Oncobiologics Inc. (Cranbury, NJ, USA) as a biosimilar of Humira®. This randomized, double blind, single-center phase I study (EudraCT registration # 2013-003551-38) was performed to demonstrate pharmacokinetic (PK) biosimilarity between two reference products (Humira® EU and US) and ONS-3010 in healthy volunteers, and to compare the safety and immunogenicity profiles. In addition, the intended pharmacological activity was assessed and compared by application of a whole blood challenge. Hundred ninety-eight healthy volunteers received a single 40 mg subcutaneous dose of ONS-3010, Humira® EU, or US. The pharmacodynamic effects were assessed by lipopolysaccharide (LPS)/aluminum hydroxide whole blood challenges (n = 36; n = 12 per treatment arm; male:female, 1:1). Equivalence was demonstrated on the PK endpoints (AUC0–inf, Cmax, and AUC0–last) based on bounds of 80–125% for the ratio of the geometric means (ONS-3010/Humira®). The immunogenicity profiles were comparable between treatment groups, and there were no indications for differences in routine safety parameters. Administration of adalimumab resulted in the observation of dramatically reduced tumor necrosis factor-α (TNFα) levels upon stimulation with LPS/aluminum hydroxide (>99%), with no differences between the three treatment groups in terms of magnitude or duration. Adalimumab also resulted in a reduction of LPS/aluminum hydroxide-induced interleukin (IL)-8 release (maximally 30%), suggested to have a causal relationship with the anti-TNFα treatment. LPS/aluminum hydroxide-induced release of IL-1β and IL-6 was not inhibited by anti-TNFα treatment. Taken together, these data are promising for the further clinical development of ONS-3010, demonstrate the relevance of the LPS/aluminum challenge to monitor Humira® effects, and emphasize the value of whole blood challenges for monitoring of proximal drug effects in healthy volunteers, and potentially in the

  2. Respiratory responses to laboratory-generation acid fog in healthy and asthmatic volunteers

    SciTech Connect

    Avol, E.L.; Linn, W.S.; Hackney, J.D. )

    1987-01-01

    The authors discuss a program to provide a first step towards assessing acute health-related effects of acid fog exposure. Polluted ambient fog was simulated in a laboratory exposure chamber. Volunteer subjects were purposely exposed and studied during periods of exercise and rest while in the challenge atmosphere. Respiratory responses were measured by methods used to assess effects of irritant gases and dry'' respirable aerosols. When a pilot study showed no obvious unfavorable effects with ambient-like pollution conditions, the exposure concentrations for the present study were extended into the occupational range, well above ambient levels. Sulfuric acid was selected for use as the test pollutant, based upon previous research experience and the availability of fog data documenting its presence during ambient fog episodes.

  3. The lipolytic effect of beta 1- and beta 2-adrenoceptor activation in healthy human volunteers.

    PubMed Central

    Haffner, C A; Kendall, M J; Maxwell, S; Hughes, B

    1993-01-01

    1. We investigated the effect of activation beta 1- and beta 2-adrenoceptors on the process of lipolysis in human volunteers. Ten male subjects underwent a single-blind randomized cross-over trial using infusions of terbutaline (a specific beta 2-adrenoceptor agonist), xamoterol (a partial beta 1-agonist with beta 2-adrenoceptor blocking activity) and saline (placebo control). The effect of these infusions on plasma potassium, glucose, free fatty acids (FFA) (total and individual) and insulin levels was studied. 2. Terbutaline infusion induced a significant rise in plasma glucose and a fall in plasma potassium in keeping with its beta 2-adrenoceptor stimulant properties. Xamoterol infusion had no significant effect on these values. Terbutaline infusion caused a greater rise in total and individual FFA than xamoterol, but both effects were significantly different from placebo. 3. The possible reasons for these results and their implications on the beta-adrenergic control of lipolysis are discussed. PMID:8383517

  4. Relationship of echocardiographic indices to pulmonary capillary wedge pressures in healthy volunteers

    NASA Technical Reports Server (NTRS)

    Firstenberg, M. S.; Levine, B. D.; Garcia, M. J.; Greenberg, N. L.; Cardon, L.; Morehead, A. J.; Zuckerman, J.; Thomas, J. D.

    2000-01-01

    OBJECTIVES: We sought to determine the relationship between different echocardiographic indices and pulmonary capillary wedge pressures (PCWP) in normal volunteers. BACKGROUND: Indices based on tissue Doppler (TDE) and color M-mode (CMM) echocardiography have been proposed to reflect left (LV) ventricular filling pressures. These include the ratio of early diastolic transmitral velocity (E) to early myocardial velocity measured by TDE (E') and the ratio of E to the wave propagation velocity (Vp) measured from CMM images. These indices, however, have not been validated in normal individuals. METHODS: We studied seven volunteers during two phases of preload altering maneuvers, baseline, with two stages of lower body negative pressure, and repeat baseline with two stages of volume loading. The PCWP obtained from right heart catheterization was compared with diastolic indices using pulsed Doppler, TDE and CMM echocardiography. RESULTS: The PCWP ranged from 2.2 to 23.5 mm Hg. During preload alterations, significant changes in E and septal E' (both p < 0.05) but not lateral E' or Vp were observed. Furthermore, E, septal E' and E/Vp correlated with PCWP (all r > 0.80) but not combined E and TDE indices (both r < 0.15). Within individuals, a similar linear relationship was observed among E/Vp, E and septal E' (average r > 0.80). CONCLUSIONS: In subjects without heart disease, E, septal E' and E/Vp correlate with PCWP. Because the influence of ventricular relaxation is minimized, the ratio E/Vp may be the best overall index of LV filling pressures.

  5. A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.

    PubMed

    Tett, S E; Cutler, D J; Day, R O; Brown, K F

    1988-09-01

    1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/- 0.25 mg kg-1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/- 0.45 mg kg-1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half-life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min-1 based on plasma data, 96 ml min-1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/- s.d.: 7.2 +/- 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.

  6. Determination of optimal dosage regimen for amikacin in healthy volunteers by study of pharmacokinetics and bactericidal activity.

    PubMed Central

    Garraffo, R; Drugeon, H B; Dellamonica, P; Bernard, E; Lapalus, P

    1990-01-01

    The pharmacokinetics and serum killing curves of amikacin, which was administered by a 30-minute intravenous infusion of single doses of 7.5 mg/kg and then 15 mg/kg, were investigated in six healthy volunteers who received the two doses in a crossover study with a washout period of 20 days. The serum killing curves were determined for four bacterial species: Escherichia coli, Serratia marcescens, Enterobacter cloacae, and Pseudomonas aeruginosa. All strains were serum resistant, and the bactericidal activity was analyzed by separating the early phase (first 5 h) and the late phase (24 h) of the killing curve. For the early phase, the bactericidal activity was evaluated by correlating an index of surviving bacteria with amikacin concentrations. This methodology allowed determination of two parameters: the maximal effective concentration and the lowest effective concentration. For the late phase, the threshold values separating bacteriostatic and bactericidal activities were lower than 10 mg/liter for each strain. The concentration dependence of amikacin bactericidal activity was confirmed for Escherichia coli and Enterobacter cloacae and, to a lesser extent, for Serratia marcescens and Pseudomonas aeruginosa. Correlation of these data with amikacin pharmacokinetic data in volunteers indicated that a daily dose of 15 mg/kg may be effective in the treatment of Escherichia coli and Enterobacter cloacae infections. For Pseudomonas aeruginosa and Serratia marcescens, the partially time-dependent activity probably necessitates two daily administrations and combination with another antibiotic. PMID:2111658

  7. Assessment of Combined Ascorbyl Palmitate (AP) and Sodium Ascorbyl Phosphate (SAP) on Facial Skin Sebum Control in Female Healthy Volunteers.

    PubMed

    Khan, H; Akhtar, N; Ali, A

    2017-01-01

    The skin is fortified with a setup of lipophilic and hydrophilic, enzymatic and non-enzymatic antioxidant systems. Ascorbyl palmitate (AP) and sodium ascorbyl phosphate (SAP) are reported as lipophilic and hydrophilic antioxidants, respectively used for skin care. Present study was aimed to assess the combined AP (in oil phase) and SAP (in aqueous phase) via multiple emulsion (ME1) for controlling sebum secretions in healthy human females. FTIR analysis of AP and SAP was performed for identification. Multiple emulsions (ME1 and control) were prepared and analyzed for physical stability. Antioxidant activities of AP, SAP as well as ME1 (with combination of these compounds) were determined by DPPH method. 11 female volunteers were included in a single-blinded, placebo-controlled, split-face comparative study. Volunteers were instructed to apply ME1 on left cheek while control (without AP and SAP) on right cheek, for a period of 90 days. A non-invasive photometric device (Sebumeter(®)) was used for the measurement of sebum secretions on both sides of the face with subsequent time intervals. A good antioxidant activity of ME1 was observed. ME1 treatments reduced significant facial sebum secretions as compared with control/placebo treatments. It was concluded that combined AP and SAP supplementations to skin proved a promising choice for controlling facial sebum secretions and could be evaluated for undesired oily skin and acne reductions for beautifying the facial appearance.

  8. Pharmacokinetic parameters of nandrolone (19-nortestosterone) after intramuscular administration of nandrolone decanoate (Deca-Durabolin) to healthy volunteers.

    PubMed

    Wijnand, H P; Bosch, A M; Donker, C W

    1985-01-01

    Nandrolone decanoate (Deca-Durabolin) was injected intramuscularly into healthy volunteers. One group of females received one injection of 100 mg and three groups of males received one injection of 200 mg, two repeat injections of 100 mg or four repeat injections of 50 mg respectively. The serum levels of nandrolone (19-nortestosterone) were determined by radioimmunoassay and used to estimate pharmacokinetic parameters. The following pharmacokinetic parameters were found: a mean half-life of 6 days for the release of the ester from the muscular injection depot into the general circulation; a mean half-life of 4.3 h for the combined processes of hydrolysis of nandrolone decanoate and of distribution and elimination of nandrolone; a mean nandrolone serum clearance of 1.55 1 X h-1 X kg-1. The half-life of hydrolysis of nandrolone decanoate in serum was of the order of one hour or less. The data are consistent with linear kinetics.

  9. Effect of intravenous fructose on the P-31 MR spectrum of the liver: dose response in healthy volunteers.

    PubMed

    Terrier, F; Vock, P; Cotting, J; Ladebeck, R; Reichen, J; Hentschel, D

    1989-05-01

    Dynamic phosphorus-31 magnetic resonance (MR) spectroscopy of the liver after intravenous administration of fructose has been suggested as a test of liver function. To establish dose-response curves of the phosphorus metabolites in the normal human liver, each of four healthy volunteers was given two to four different fructose doses on separate days: 62.5, 125, 250, 375, or 500 mg per kilogram of body weight. P-31 MR spectra of the liver were acquired with a 2-T whole-body magnetic, both before and after fructose administration, at 2.5-minute intervals over at least 30 minutes. The fructose load caused a significant, linearly dose-dependent accumulation of phosphomonoesters (r = .72, P less than .01) and a decrease in inorganic phosphate (r = .78, P less than .005) and adenosine triphosphate (r = .73, P less than .01). On the basis of these experiments, dynamic P-31 MR spectroscopy seems promising in the assessment of liver function.

  10. Study of exteroceptive suppression of voluntary muscular activity in healthy volunteers and patients with paroxysmal neuropathic pain.

    PubMed

    Gordeev, S A; Turbina, L G; Shtang, O M

    2014-07-01

    The exteroceptive suppression of voluntary electromyographic activity of the masseter and temporal muscles was studied in healthy volunteers and patients with paroxysmal neuropathic pain (trigeminal neuralgia). The latent period of the exteroceptive suppression was prolonged and the duration of its late fragment was shortened in the patients in comparison with normal subjects. A short exteroceptive suppression period in patients with trigeminal neuralgia reflected deficient activity of inhibitory interneurons of the reflector loop and excessive activity of the antinociceptive system of the brain stem, while prolongation of the latent period reflected prolongation of inhibitory interneurons activation. A direct correlation between the degree of changes in the exteroceptive suppression parameters and pain intensity, evaluated by the patients by the visual analog scale, was detected.

  11. Effect of surface neuromuscular electrical stimulation on labial and lingual muscles in healthy volunteers.

    PubMed

    Safi, Mohammed F; Wright-Harp, Wilhelmina; Lucker, Jay R; Payne, Joan C

    2017-01-31

    Neuromuscular electrical stimulation (NMES) may have potential as a treatment for muscle weakness as it may improve strength when applied to the orofacial muscles. However, before incorporating this procedure into clinical practice, research is needed to investigate its effects on lingual and facial muscles of speech and mastication. The aim of this study was to determine what effect(s) submental and labial NMES would have on lingual and labial muscle strength in healthy participants. Fourteen healthy adults (27-49 years old) were assigned to two groups (treatment and control). A pretreatment and post-treatment test using the Iowa Oral Performance Instrument was used to measure the strength of labial and lingual muscles in both groups. Participants in the treatment group received labial and submental NMES while performing a structured labial, buccal, and lingual exercise program. In contrast, participants in the control group completed the same oral motor exercise program without stimulation.

  12. Influence of ABCB1 (P-glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers

    PubMed Central

    Jensen, Berit Packert; Roberts, Rebecca Lee; Vyas, Ritva; Bonke, Gitte; Jardine, David L; Begg, Evan James

    2012-01-01

    AIMS To investigate the influence of ABCB1 (1236-2677-3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers. METHODS Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236-2677-3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head-up tilt) were measured continuously using finger plethysmography. RESULTS There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E- and Z-10-hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min–1, P = 0.02). At tmax at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min–1 on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min–1 on head-up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group. CONCLUSION The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline. PMID:21999196

  13. A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer's disease.

    PubMed

    Bauer, Martin; Langer, Oliver; Dal-Bianco, Peter; Karch, Rudolf; Brunner, Martin; Abrahim, Aiman; Lanzenberger, Rupert; Hofmann, Andrea; Joukhadar, Christian; Carminati, Paolo; Ghirardi, Orlando; Piovesan, Paola; Forloni, Gianluigi; Corrado, Mario E; Lods, Nadège; Dudczak, Robert; Auff, Eduard; Kletter, Kurt; Müller, Markus

    2006-09-01

    This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.

  14. Effects on sleep stages and microarchitecture of caffeine and its combination with zolpidem or trazodone in healthy volunteers.

    PubMed

    Paterson, L M; Nutt, D J; Ivarsson, M; Hutson, P H; Wilson, S J

    2009-07-01

    Caffeine is the world's most popular stimulant and is known to disrupt sleep. Administration of caffeine can therefore be used in healthy volunteers to mimic the effects of insomnia and thus to test the hypnotic effects of medication. This study assessed the effects of caffeine on sleep architecture and electroencephalography (EEG) spectrum alone and in combination with two different sleep-promoting medications. Home polysomnography was performed in 12 healthy male volunteers in a double-blind study whereby subjects received placebo, caffeine (150 mg), caffeine plus zolpidem (10 mg) and caffeine plus trazodone (100 mg) at bedtime in a randomised crossover design. In addition to delaying sleep onset, caffeine decreased total sleep time (TST), sleep efficiency (SE) and stage 2 sleep without significantly altering wake after sleep onset or the number of awakenings. Zolpidem attenuated the caffeine-induced decrease in SE and increased spindle density in the caffeine plus zolpidem combination compared with placebo. Trazodone attenuated the decrease in SE and TST, and it also increased stage 3 sleep, decreased the number of awakenings and decreased the spindle density. No significant changes in rapid eye movement (REM) sleep were observed, neither was any significant alteration in slow wave activity nor other EEG spectral measures, although the direction of change was similar to that previously reported for caffeine and appeared to 'normalise' after trazodone. These data suggest that caffeine mimics some, but not all of the sleep disruption seen in insomnia and that its disruptive effects are differentially attenuated by the actions of sleep-promoting compounds with distinct mechanisms of action.

  15. Drug release from an oromucosal paste for the selective decontamination of the oropharynx (in ICU patients and healthy volunteers).

    PubMed

    Rood, Johannes; Nawzad, Haif; Kalicharan, Raween; van Steenbergen, Mies; Vromans, Herman

    2015-06-20

    Selective oropharyngeal decontamination (SOD) is used in many ICUs in the Netherlands and some other European countries. While its clinical effect has been studied intensively, no studies have been done to assess the biopharmaceutical aspects of the paste, i.e. it is not known which local concentrations exist. For this study, five healthy volunteers were subjected to 400mg of the generally used paste. Ten ICU patients were treated according to the normal standard in the ICU of the University Medical Center Utrecht. Salivary levels of the various substances were measured over time using two separate analytical methods. Also the microbial burden of the oropharynx was assessed. The results show significant variation in release, both ICU patients and healthy volunteers. The antimicrobials tobramycin and colistin showed a relatively fast release, while nystatin exhibited a controlled release-like pattern. Amphotericin B is hardly released from the formulation. The concentration of the antimicrobial agents drop to sub-MIC levels relatively fast. From a biopharmaceutical perspective, amphotericin B should be replaced by nystatin. The application of the mouth paste is subject to massive variation in daily practice; each nurse applies a different amount, in a different way. In addition, the formulation is hard to apply and unpleasant with regards to the taste and feel for the conscious patients. This is not a clinical study, but a study that aimed to give a biopharmaceutical justification for SOD Both the clinical practice and the clinically determined levels of drugs enable critical evaluation of the outcome of clinical studies performed until now.

  16. Determination of plasma topiramate concentration using LC-MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteers.

    PubMed

    Park, Jin-Hee; Park, Yoo-Sin; Lee, Min-Ho; Rhim, Si-Youn; Song, Jae-Chul; Lee, Soo-Jin; Kim, Jung-Mogg; Shaw, Leslie M; Kang, Ju-Seop

    2008-08-01

    A rapid, simple and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS/MS) for topiramate analysis in human plasma has been applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a simple liquid extraction of topiramate and prednisone (internal standard) with acetonitrile and separation by HPLC equipped with a Capcell Pak C18 column using acetonitrile-0.1% triethylamine (80:20, v/v) as a mobile phase. Detection was carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(-) and selectivity was achieved by MS/MS analysis, m/z 338.0 --> 77.5 and m/z 357.1 --> 327.2 for topiramate and prednisone, respectively. The method had a total run time of 2.5 min and showed good linearity over a working range of 20-5000 ng/mL in human plasma with a lower limit of quantification of 20 ng/mL. No metabolic compounds were found to interfere with the analysis. The inter-day and intra-day accuracy were in the ranges of 99.24-116.63 and 93.45-108.68%, respectively, and inter-day and intra-day precisions were below 6.24 and 5.25%, respectively. This method was successfully applied for pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 96 h after an oral administration of 100 mg of topiramate in 24 healthy Korean volunteers.

  17. Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers.

    PubMed

    Sae-Teaw, Manit; Johns, Jeffrey; Johns, Nutjaree Pratheepawanit; Subongkot, Suphat

    2013-08-01

    Melatonin is a naturally occurring molecule biosynthesized by the pineal gland of vertebrates; it also has been identified in many plants. It is considered an important antioxidant and may retard the development of some neurodegenerative diseases and cancer. Previous studies in humans have measured melatonin metabolites in urine and have indicated that melatonin-containing foods may provide dietary melatonin. This study tested whether the consumption of fruits or fruit juice containing melatonin would influence the serum melatonin concentration and antioxidant status. In this crossover study, 12 healthy male volunteers took either juice extracted from one kilogram of orange or pineapple or two whole bananas, with a 1-wk washout period between the fruit or fruit juices. An enzyme-linked immunosorbent (ELISA) assay was used to determine the serum melatonin concentration. Serum antioxidant capacity was determined by ferric reducing antioxidant power (FRAP) assay and oxygen radical antioxidant capacity (ORAC) assay. The highest serum melatonin concentration was observed at 120 min after fruit consumption, and compared with before consumption levels, their values were significantly increased for pineapple (146 versus 48 pg/mL P = 0.002), orange (151 versus 40 pg/mL, P = 0.005), and banana (140 versus 32 pg/mL, P = 0.008), respectively. Serum antioxidant capacity following fruit consumption also significantly increased in both the FRAP (7-14% increase, P ≤ 0.004) and ORAC (6-9% increase, P = 0.002) assays. Both the serum FRAP and ORAC values strongly correlated with serum melatonin concentration for all three fruits. These findings suggest that tropical fruit consumption increases the serum melatonin concentrations and also raises the antioxidant capacity in the serum of healthy volunteers in proportion to serum melatonin levels.

  18. Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers

    PubMed Central

    Abel, Samantha; van der Ryst, Elna; Rosario, Maria C; Ridgway, Caroline E; Medhurst, Christine G; Taylor-Worth, Richard J; Muirhead, Gary J

    2008-01-01

    Aims To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers. Methods Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed. Results Maraviroc is rapidly absorbed following oral administration, and plasma Tmax is achieved within 0.5–4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3–1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10–12 l h−1 and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. Conclusions Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate. PMID:18333861

  19. Cooking Healthy, Eating Smart (CHES): Evaluating the feasibility of using volunteers to deliver nutrition and food safety education to rural older adults

    NASA Astrophysics Data System (ADS)

    Getty, Morgan

    Due to their limited resources, rural, older adults in the United States are at risk for poor diet-related health outcomes. Nutrition education is a key component in improving health outcomes in older adults. Cooking Healthy, Eating Smart (CHES) is a nine-lesson curriculum designed to teach rural, older adults culturally appropriate nutrition and food safety information. Funding to hire health professionals to deliver such a curriculum is limited, presenting the need to explore a less expensive mode of dissemination. In this community-based, participatory research study, a formative evaluation and feasibility study were conducted to examine the use of volunteers to deliver a nutrition and food safety curriculum to rural, older adults in South Carolina. Seven focus groups were conducted with members of the South Carolina Family and Community Leaders (SCFCL) and members of the American Association of Retired Persons (AARP) in the four regions of South Carolina to explore barriers and facilitators of volunteers delivering CHES (N=65 participants). The focus group findings informed the development of the volunteer training manual. A comparative case study method was used to examine the feasibility of a volunteer-based approach by observing and describing the delivery of CHES by two groups of volunteers in SC. The case study findings, including volunteer knowledge change, self-efficacy change, curriculum experience, program experience, and project team observations of volunteers indicated that using volunteers to deliver CHES is a plausible approach with the assistance of paid staff or project team members.

  20. Study on Yang-Xu Using Body Constitution Questionnaire and Blood Variables in Healthy Volunteers

    PubMed Central

    Chen, Hong-Jhang; Lin, Yii-Jeng; Wu, Pei-Chen; Hsu, Wei-Hsiang; Hu, Wan-Chung; Wu, Trong-Neng; Chen, Fang-Pey; Lin, Yun-Lian

    2016-01-01

    Traditional Chinese medicine (TCM) formulates treatment according to body constitution (BC) differentiation. Different constitutions have specific metabolic characteristics and different susceptibility to certain diseases. This study aimed to assess the Yang-Xu constitution using a body constitution questionnaire (BCQ) and clinical blood variables. A BCQ was employed to assess the clinical manifestation of Yang-Xu. The logistic regression model was conducted to explore the relationship between BC scores and biomarkers. Leave-one-out cross-validation (LOOCV) and K-fold cross-validation were performed to evaluate the accuracy of a predictive model in practice. Decision trees (DTs) were conducted to determine the possible relationships between blood biomarkers and BC scores. According to the BCQ analysis, 49% participants without any BC were classified as healthy subjects. Among them, 130 samples were selected for further analysis and divided into two groups. One group comprised healthy subjects without any BC (68%), while subjects of the other group, named as the sub-healthy group, had three BCs (32%). Six biomarkers, CRE, TSH, HB, MONO, RBC, and LH, were found to have the greatest impact on BCQ outcomes in Yang-Xu subjects. This study indicated significant biochemical differences in Yang-Xu subjects, which may provide a connection between blood variables and the Yang-Xu BC. PMID:27340421

  1. A parallel design study to assess the bioequivalence of generic and branded hydroxychloroquine sulfate tablets in healthy volunteers.

    PubMed

    Liu, Y-M; Chen, Q; Zhang, M-Q; Liu, G-Y; Jia, J-Y; Pu, H-H; Liu, Y; Hu, C-Y; Lu, C; Wang, W; Cao, W-E; Song, B; Song, Y-X; Zhu, J-M; Yu, C

    2012-12-01

    Hydroxychloroquine (HCQ) is a racemic 4-aminoquinoline derivative that was first introduced as an antimalarial, and subsequently applied to the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Information on the pharmacokinetics of HCQ in healthy volunteers, especially in a Chinese population is limited, and this study was conducted to provide support for a generic product to obtain marketing authorization in China.The aim of the present study was to compare the pharmacokinetics and assess bioequivalence of a new generic test and the branded reference hydroxychloroquine sulfate tablets in healthy volunteers.This was a parallel, open-label, randomized, single-dose, 1-period fasting study. 54 healthy subjects were randomly assigned (1:1) to receive 200 mg hydroxychloroquine sulfate tablets of the test or the reference formulation. 15 blood samples were collected and whole blood concentrations of HCQ were determined by a validated liquid chromatography-isotopic dilution mass spectrometry method. Log-transformed Cmax and AUC0-24 values were used to test for bioequivalence. The 2 formulations were considered bioequivalent if 90% confidence intervals (CIs) for the log-transformed ratios of Cmax and AUC0-24 were within the predetermined bioequivalence range of 80-125%. Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and interviews with the subjects about adverse events.54 healthy subjects were enrolled and completed the study (mean [SD] age, height, body weight, and BMI were 23.9 [2.4] years, 168.9 [5.0] cm, 61.3 [5.4] kg, and 21.5 [1.7] kg/m2), 27 subjects per group. No formulation or sequence effects were observed. The mean values of Cmax and AUC0-24 for the test and reference formulations of HCQ (197.6 and 199.0 ng/mL, 2460.1 and 2468.3 ng/mL/h) were not significantly different. The 90% CIs of the ratios of Cmax and AUC0

  2. Pharmacokinetics of a multicomponent herbal preparation in healthy Chinese and African volunteers

    PubMed Central

    Alolga, Raphael N.; Fan, Yong; Zhang, Gang; Li, Jin; Zhao, Yi-Jing; Lelu Kakila, Jimmy; Chen, Yan; Li, Ping; Qi, Lian-Wen

    2015-01-01

    K-601 is an herbal formulation for influenza consisting of Lonicera japonica, Isatis indigotica, Rheum palmatum, Phellodendron chinense, and Scutellaria baicalensis. In this work, we characterized the chemical constituents in K-601, identified the absorbed compounds and determined their pharmacokinetics in 6 Chinese and African volunteers by liquid chromatography with time-of-flight mass spectrometry. Similarity evaluation for chromatographic fingerprint of nine different batches showed values above 0.983. Totally, 50 components were identified in K-601. Then, 15 major prototype compounds and 17 metabolites were identified in human plasma. Major metabolic pathways included glucuronidation, sulfation, methylation, demethylation, and reduction. The pharmacokinetics of the most abundant prototype compounds, berberine, jatrorrhizine, palmatine and magnoflorine were determined. Significant pharmacokinetic differences were observed between the African and Chinese subjects. The AUCs of the African is about 4–10 fold higher than that of the Chinese for the three benzylisoquinoline alkaloids. Magnoflorine, an aporphine alkaloid, was absorbed better in the Chinese than in the African. The biotransformation of K-601 by human intestinal microflora was also investigated. The major reactions included hydroxylation, methylation, demethylation, acetylation and reduction. Glucuronidation and sulfation were not observed with fecal flora. These results may be important and useful in linking data from pharmacological assays and clinical effects. PMID:26268432

  3. Population pharmacokinetics and pharmacodynamics of brief etomidate infusion in healthy volunteers.

    PubMed

    Kaneda, Kotaro; Yamashita, Susumu; Woo, Sukyung; Han, Tae-Hyung

    2011-04-01

    This study established the pharmacokinetic and pharmacodynamic relationships of the bispectral index (BIS) and Observer's Assessment of Alertness/Sedation (OAA/S) scale with effect site drug concentrations during and after brief etomidate infusion. Eighteen American Society of Anesthesiologists status I or II volunteers received etomidate (0.2%) infusion at 5 mg/min until the loss of eyelash reflexes, and spontaneous recovery was allowed. Data for plasma etomidate concentrations, BIS, and OAA/S were collected every minute and analyzed by NONMEM. A 2-compartment pharmacokinetic model and a pharmacodynamic sigmoid E(max) model fit the data best, with volumes of distribution at central and peripheral compartments of 4.45 and 74.90 L, respectively, and systemic and intercompartmental clearances of 0.63 and 3.16 L/min, respectively. t(1/2)k(e0) was 1.550 min. EC(50) values were 0.526 and 0.554 µg/mL, and gamma values were 2.25 and 6.24 for BIS and OAA/S, respectively. The prediction probability between OAA/S and BIS was 0.8. The slopes of the curves suggest that BIS is a better monitor of depth of sedation and hypnosis, whereas OAA/S may be more useful for monitoring sleep versus wakefulness. These results should be interpreted within the context of short-term etomidate infusion of less than 10 minutes.

  4. Residual effects of repeated administration of triazolam and nitrazepam in healthy volunteers.

    PubMed

    Muraoka, M; Tada, K; Nogami, Y; Ishikawa, K; Nagoya, T

    1992-01-01

    The residual effects of hypnotics were investigated with a long-acting (nitrazepam) and a short-acting (triazolam) benzodiazepine hypnotic in 8 male volunteers. Subjects received placebo, nitrazepam 5 mg, or triazolam 0.25 mg for 7 consecutive nights in a random-order, double-blind crossover design. Daytime sleepiness, psychomotor performance, EEG activity and standing steadiness were assessed in the morning after 1, 4, and 7 days of drug treatment. Plasma concentrations of nitrazepam and triazolam were also assayed. The concentration of nitrazepam increased gradually during the course of treatment and was associated with residual sedative effects on days 4 and 7. Nitrazepam produced no apparent psychomotor impairments in these studies. On the other hand, there was no evidence of drug accumulation after triazolam administration and triazolam showed no residual sedative effects or residual impairment of psychomotor performance during the experiment. Thus, short-acting hypnotics may have an advantage over long-acting hypnotics in terms of producing less residual sedative effects during chronic treatment.

  5. Effects of butoctamide hydrogen succinate and nitrazepam on psychomotor function and EEG in healthy volunteers.

    PubMed

    Tazaki, T; Tada, K; Nogami, Y; Takemura, N; Ishikawa, K

    1989-01-01

    We studied the effects of butoctamide hydrogen succinate and nitrazepam on psychomotor function and EEG in eight male volunteers aged 19-32. The hypnotic effects, effects on psychomotor performance, EEG activity and standing steadiness between BAHS 1000 mg and nitrazepam 5 mg were compared at regular intervals for 10 h. The serum levels of both drugs were also assayed. The hypnotic effects of BAHS were very weak compared to those of nitrazepam. BAHS did not exert any effects on psychomotor performance and standing steadiness during the test period. In contrast, nitrazepam impaired psychomotor performance and standing steadiness as the serum drug levels increased. Nitrazepam decreased the alpha activity and increased the beta activity in a concentration-dependent manner. BAHS did not change the alpha activity but increased beta-2 activity at Fz and Cz at 10 h of the post-drug period. BAHS was eliminated more rapidly than nitrazepam. These results indicated that BAHS, at the dose used, was less potent than nitrazepam and the effects on psychomotor performance and standing steadiness were minimal.

  6. Airflow Dynamics of Coughing in Healthy Human Volunteers by Shadowgraph Imaging: An Aid to Aerosol Infection Control

    PubMed Central

    Tang, Julian W.; Nicolle, Andre; Pantelic, Jovan; Koh, Gerald C.; Wang, Liang De; Amin, Muhammad; Klettner, Christian A.; Cheong, David K. W.; Sekhar, Chandra; Tham, Kwok Wai

    2012-01-01

    Cough airflow dynamics have been previously studied using a variety of experimental methods. In this study, real-time, non-invasive shadowgraph imaging was applied to obtain additional analyses of cough airflows produced by healthy volunteers. Twenty healthy volunteers (10 women, mean age 32.2±12.9 years; 10 men, mean age 25.3±2.5 years) were asked to cough freely, then into their sleeves (as per current US CDC recommendations) in this study to analyze cough airflow dynamics. For the 10 females (cases 1–10), their maximum detectable cough propagation distances ranged from 0.16–0.55 m, with maximum derived velocities of 2.2–5.0 m/s, and their maximum detectable 2-D projected areas ranged from 0.010–0.11 m2, with maximum derived expansion rates of 0.15–0.55 m2/s. For the 10 males (cases 11–20), their maximum detectable cough propagation distances ranged from 0.31–0.64 m, with maximum derived velocities of 3.2–14 m/s, and their maximum detectable 2-D projected areas ranged from 0.04–0.14 m2, with maximum derived expansion rates of 0.25–1.4 m2/s. These peak velocities were measured when the visibility of the exhaled airflows was optimal and compare favorably with those reported previously using other methods, and may be seen as a validation of these previous approaches in a more natural setting. However, the propagation distances can only represent a lower limit due to the inability of the shadowgraph method to visualize these cough airflows once their temperature cools to that of the ambient air, which is an important limitation of this methodology. The qualitative high-speed video footage of these volunteers coughing into their sleeves demonstrates that although this method rarely completely blocks the cough airflow, it decelerates, splits and redirects the airflow, eventually reducing its propagation. The effectiveness of this intervention depends on optimum positioning of the arm over the nose and mouth during coughing, though unsightly stains

  7. Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

    PubMed Central

    Seng, Kok-Yong; Hee, Kim-Hor; Soon, Gaik-Hong; Chew, Nicholas; Khoo, Saye H.

    2015-01-01

    In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤ Cmax ≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH. PMID:26282412

  8. Single dose pharmacokinetics of the novel transdermal donepezil patch in healthy volunteers

    PubMed Central

    Kim, Yo Han; Choi, Hee Youn; Lim, Hyeong-Seok; Lee, Shi Hyang; Jeon, Hae Sun; Hong, Donghyun; Kim, Seong Su; Choi, Young Kweon; Bae, Kyun-Seop

    2015-01-01

    Background Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer’s disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. Methods Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm2, 87.5 mg/25 cm2, or 175 mg/50 cm2. Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. Results The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74–76 hours (~2–4 hours after patch removal), and mean t1/2β was ~63.77–93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%–86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. Conclusion The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics. PMID:25792802

  9. Ultrasonographic Measurement of the Thickness of Axillary Recess Capsule in Healthy Volunteers

    PubMed Central

    2016-01-01

    Objective To evaluate the inter-rater and intra-rater reliability of ultrasonographic measurements of axillary recess (AR) thickness in healthy individuals, and to analyze the factors affecting the thickness of the AR capsule. Methods We recruited 20 healthy individuals (10 male, 10 female) with a mean age of 37 years (standard deviation ±10). Two physiatrists (an experienced and a novice rater) independently investigated the AR thickness in three rounds. The AR thickness was measured for each individual at three shoulder abduction angles (50°, 70°, and 90°). Intra-class correlation (ICC) coefficients were used to assess the reproducibility of each measurement. Results Excellent intra-rater reliability coefficients were observed at the three shoulder abduction angles, in the analysis of both raters. The inter-rater reliability coefficient was also was excellent in both studies. There were significant differences in the AR thickness, according to the angle of shoulder abduction. The AR was thicker at 50° than at 70° and 90° (all p<0.001), and the AR was thicker at 70° than at 90° (p<0.001). Height (r=0.62, p=0.003) and body mass index (r=0.52, p=0.019) were positively correlated with AR thickness. Males had a thicker AR capsule than females at all three angles (all p<0.001). Conclusion Ultrasonographic measurements of AR thickness in healthy individuals demonstrate excellent intra-rater and inter-rater reliability. AR thickness may depend on anthropometric variables and position of the shoulder. PMID:27446788

  10. Plasma levels of intermedin (adrenomedullin-2) in healthy human volunteers and patients with heart failure.

    PubMed

    Bell, David; Gordon, Brian J; Lavery, Anita; Megaw, Katie; Kinney, Michael O; Harbinson, Mark T

    2016-02-01

    Intermedin/adrenomedullin-2 (IMD) is a member of the adrenomedullin/CGRP peptide family. Less is known about the distribution of IMD than for other family members within the mammalian cardiovascular system, particularly in humans. The aim was to evaluate plasma IMD levels in healthy subjects and patients with chronic heart failure. IMD and its precursor fragments, preproIMD(25-56) and preproIMD(57-92), were measured by radioimmunoassay in 75 healthy subjects and levels of IMD were also compared to those of adrenomedullin (AM) and mid-region proadrenomedullin(45-92) (MRproAM(45-92)) in 19 patients with systolic heart failure (LVEF<45%). In healthy subjects, plasma levels (mean+SE) of IMD (6.3+0.6 pg ml(-1)) were lower than, but correlated with those of AM (25.8+1.8 pg ml(-1); r=0.49, p<0.001). Plasma preproIMD(25-56) (39.6+3.1 pg ml(-1)), preproIMD(57-92) (25.9+3.8 pg ml(-1)) and MRproAM(45-92) (200.2+6.7 pg ml(-1)) were greater than their respective bioactive peptides. IMD levels correlated positively with BMI but not age, and were elevated in heart failure (9.8+1.3 pg ml(-1), p<0.05), similarly to MRproAM(45-92) (329.5+41.9 pg ml(-1), p<0.001) and AM (56.8+10.9 pg ml(-1), p<0.01). IMD levels were greater in heart failure patients with concomitant renal impairment (11.3+1.8 pg ml(-1)) than those without (6.5+1.0 pg ml(-1); p<0.05). IMD and AM were greater in patients receiving submaximal compared with maximal heart failure drug therapy and were decreased after 6 months of cardiac resynchronization therapy. In conclusion, IMD is present in the plasma of healthy subjects less abundantly than AM, but is similarly correlated weakly with BMI. IMD levels are elevated in heart failure, especially with concomitant renal impairment, and tend to be reduced by high intensity drug or pacing therapy.

  11. The effects of 7.5% carbon dioxide inhalation on task performance in healthy volunteers.

    PubMed

    Diaper, Alison; Nutt, David J; Munafò, Marcus R; White, Joanna L; Farmer, Eric W; Bailey, Jayne E

    2012-04-01

    Studies have shown that anxiety can positively or negatively affect performance with respect to focusing of attention or distractibility, subjective workload and effort (Humphreys and Revelle, 1984). The inhalation of carbon dioxide (CO(2)) is associated with physiological and psychological effects of anxiety (Bailey et al., 2005) but its effects on performance have rarely been reported. The studies reported here looked at the effects of CO(2) inhalation on physiological and subjective measures and performance on two tasks. Eight healthy male participants completed a tracking task with a reaction time component, and 12 healthy participants (six male) completed a complex target identification task. Tasks were performed during 20-min inhalations of 7.5% CO(2)/21% O(2)/71.5% N(2) mixture or medical air. Continuous heart rate and blood pressure measures were taken, in addition to subjective measures of mood and workload. In comparison with air, CO(2) increased heart rate and blood pressure, increased subjective scores of panic, anxiety, fear, and tension, and reduced subjective scores of relaxation and happiness. Attention was focussed when inhaling CO(2) during the simple task, and central demand was greater when inhaling CO(2) during the complex task. Therefore, inhalation of 7.5% CO(2) produces effects on task performance which are consistent with anxiety.

  12. Effects of bisacodyl on ascending colon emptying and overall colonic transit in healthy volunteers

    PubMed Central

    MANABE, N.; CREMONINI, F.; CAMILLERI, M.; SANDBORN, W. J.; BURTON, D. D.

    2010-01-01

    Background and Aim The mechanism of action of bisacodyl in the unprepared human colon is unclear. Our aim was to evaluate the effect of oral bisacodyl on the overall and regional colonic transit in humans. \\ Methods In a double-blind, randomized, placebo-controlled study of 25 healthy participants, effects of oral bisacodyl (5mg p.o. per day) and placebo on colonic transit were compared. Validated scintigraphy using 111In-charcoal delivered to the ileocolonic region in a delayed-release capsule was used to measure colonic transit. The primary transit endpoints, ascending colon emptying (AC) t1/2 and geometric center (GC) of colon isotope at 24 hours (overall transit), were compared (Wilcoxon rank sum test). Results There were significant treatment effects on AC t1/2, with the bisacodyl group demonstrating accelerated emptying [median 6.5 h, interquartile range (IQR) 5.0 – 8.0 h] relative to the placebo group [11.0 h (7.0 – 17.1)], P=0.03]. Numerical differences in colonic GC 24 hours [bisacodyl median 3.0 (2.2 – 3.8), placebo 4.0 (3.1 – 4.6)] were not significant (P=0.19). There were no significant differences observed in GC 4 hours. Conclusion Oral 5mg bisacodyl accelerates AC in the unprepared colon in healthy adults; this action may contribute to the drug’s efficacy in constipation. PMID:19678812

  13. LPS infusion suppresses serum FGF21 levels in healthy adult volunteers

    PubMed Central

    Rittig, Nikolaj; Bach, Ermina; Møller, Niels; Bjerre, Mette

    2017-01-01

    Context During the inflammatory acute phase response, plasma glucose and serum triglycerides are increased in humans. Fibroblast growth factor (FGF) 21 has plasma glucose and lipid-reducing actions, but its role in the acute inflammatory response in human is unknown. Objective To investigate circulating levels of FGF21 after lipopolysaccharide (LPS) infusion. Design Two randomized, single-blinded, placebo-controlled crossover trials were used. Setting The studies were performed at a university hospital clinical research center. Patients and interventions Study 1 (LPS bolus): Eight young, healthy, lean males were investigated two times: (1) after isotonic saline injection and (2) after LPS injection (bolus of 1 ng/kg). Each study day lasted 4 h. Study 2 (continuous LPS infusion): Eight, healthy males were investigated two times: (1) during continuously isotonic saline infusion and (2) during continuous LPS infusion (0.06 ng/kg/h). Each study day lasted 4 h. Circulating FGF21 levels were quantified every second hour by an immunoassay. Results A LPS bolus resulted in a late suppression (t = 240 min) of serum FGF21 (P = 0.035). Continuous LPS infusion revealed no significant effects on FGF21 levels (P = 0.82). Conclusions Our studies show that a bolus of LPS results in decreased FGF21 levels 4 h from exposure. PMID:28069899

  14. Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages.

    PubMed

    Vlaming, M L H; van Duijn, E; Dillingh, M R; Brands, R; Windhorst, A D; Hendrikse, N H; Bosgra, S; Burggraaf, J; de Koning, M C; Fidder, A; Mocking, J A J; Sandman, H; de Ligt, R A F; Fabriek, B O; Pasman, W J; Seinen, W; Alves, T; Carrondo, M; Peixoto, C; Peeters, P A M; Vaes, W H J

    2015-08-01

    Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 μg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.

  15. From neural signatures of emotional modulation to social cognition: individual differences in healthy volunteers and psychiatric participants

    PubMed Central

    Aguado, Jaume; Baez, Sandra; Huepe, David; Lopez, Vladimir; Ortega, Rodrigo; Sigman, Mariano; Mikulan, Ezequiel; Lischinsky, Alicia; Torrente, Fernando; Cetkovich, Marcelo; Torralva, Teresa; Bekinschtein, Tristan; Manes, Facundo

    2014-01-01

    It is commonly assumed that early emotional signals provide relevant information for social cognition tasks. The goal of this study was to test the association between (a) cortical markers of face emotional processing and (b) social-cognitive measures, and also to build a model which can predict this association (a and b) in healthy volunteers as well as in different groups of psychiatric patients. Thus, we investigated the early cortical processing of emotional stimuli (N170, using a face and word valence task) and their relationship with the social-cognitive profiles (SCPs, indexed by measures of theory of mind, fluid intelligence, speed processing and executive functions). Group comparisons and individual differences were assessed among schizophrenia (SCZ) patients and their relatives, individuals with attention deficit hyperactivity disorder (ADHD), individuals with euthymic bipolar disorder (BD) and healthy participants (educational level, handedness, age and gender matched). Our results provide evidence of emotional N170 impairments in the affected groups (SCZ and relatives, ADHD and BD) as well as subtle group differences. Importantly, cortical processing of emotional stimuli predicted the SCP, as evidenced by a structural equation model analysis. This is the first study to report an association model of brain markers of emotional processing and SCP. PMID:23685775

  16. Expectation-induced placebo responses fail to accelerate wound healing in healthy volunteers: results from a prospective controlled experimental trial.

    PubMed

    Vits, Sabine; Dissemond, Joachim; Schadendorf, Dirk; Kriegler, Lisa; Körber, Andreas; Schedlowski, Manfred; Cesko, Elvir

    2015-12-01

    Placebo responses have been shown to affect the symptomatology of skin diseases. However, expectation-induced placebo effects on wound healing processes have not been investigated yet. We analysed whether subjects' expectation of receiving an active drug accelerates the healing process of experimentally induced wounds. In 22 healthy men (experimental group, n = 11; control group, n = 11) wounds were induced by ablative laser on both thighs. Using a deceptive paradigm, participants in the experimental group were informed that an innovative 'wound gel' was applied on one of the two wounds, whereas a 'non-active gel' was applied on the wound of the other thigh. In fact, both gels were identical hydrogels without any active components. A control group was informed to receive a non-active gel on both wounds. Progress in wound healing was documented via planimetry on days 1, 4 and 7 after wound induction. From day 9 onwards wound inspections were performed daily accompanied by a change of the dressing and a new application of the gel. No significant differences could be observed with regard to duration or process of wound healing, either by intraindividual or by interindividual comparisons. These data document no expectation-induced placebo effect on the healing process of experimentally induced wounds in healthy volunteers.

  17. From neural signatures of emotional modulation to social cognition: individual differences in healthy volunteers and psychiatric participants.

    PubMed

    Ibáñez, Agustín; Aguado, Jaume; Baez, Sandra; Huepe, David; Lopez, Vladimir; Ortega, Rodrigo; Sigman, Mariano; Mikulan, Ezequiel; Lischinsky, Alicia; Torrente, Fernando; Cetkovich, Marcelo; Torralva, Teresa; Bekinschtein, Tristan; Manes, Facundo

    2014-07-01

    It is commonly assumed that early emotional signals provide relevant information for social cognition tasks. The goal of this study was to test the association between (a) cortical markers of face emotional processing and (b) social-cognitive measures, and also to build a model which can predict this association (a and b) in healthy volunteers as well as in different groups of psychiatric patients. Thus, we investigated the early cortical processing of emotional stimuli (N170, using a face and word valence task) and their relationship with the social-cognitive profiles (SCPs, indexed by measures of theory of mind, fluid intelligence, speed processing and executive functions). Group comparisons and individual differences were assessed among schizophrenia (SCZ) patients and their relatives, individuals with attention deficit hyperactivity disorder (ADHD), individuals with euthymic bipolar disorder (BD) and healthy participants (educational level, handedness, age and gender matched). Our results provide evidence of emotional N170 impairments in the affected groups (SCZ and relatives, ADHD and BD) as well as subtle group differences. Importantly, cortical processing of emotional stimuli predicted the SCP, as evidenced by a structural equation model analysis. This is the first study to report an association model of brain markers of emotional processing and SCP.

  18. Population plasma and urine pharmacokinetics of ivabradine and its active metabolite S18982 in healthy Korean volunteers.

    PubMed

    Choi, Hee Youn; Bae, Kyun-Seop; Cho, Sang-Heon; Ghim, Jong-Lyul; Choe, Sangmin; Jung, Jin Ah; Lim, Hyeong-Seok

    2016-04-01

    Ivabradine, a selective inhibitor of the pacemaker current (If ), is used for heart failure and coronary heart disease and is mainly metabolized to S18982. The purpose of this study was to explore the pharmacokinetics (PK) of ivabradine and S18982 in healthy Korean volunteers. Subjects in a phase I study were randomized to receive 2.5, 5, or 10 mg of ivabradine administered every 12 hours for 4.5 days, and serial plasma and urine concentrations of ivabradine and S18982 were measured. The plasma PK of ivabradine was best described by a 2-compartment model with mixed 0- and first-order absorption, linked to a 2-compartment model for S18982. The introduction of interoccasional variabilities and period as covariate into absorption-related parameters improved the model fit. Urine data have been applied to estimate renal and nonrenal clearance, enabling a more detailed description of the elimination process. We developed a population PK model describing the plasma and urine PK of ivabradine and S18982 in healthy Korean adult males. This model might be useful for predicting the plasma and urine PK of ivabradine, potentially helping to identify the optimal dosing regimens in various clinical situations.

  19. Socioeconomic status is associated with striatal dopamine D2/D3 receptors in healthy volunteers but not in cocaine abusers

    PubMed Central

    Wiers, Corinde E.; Shokri-Kojori, Ehsan; Cabrera, Elizabeth; Cunningham, Samantha; Wong, Christopher; Tomasi, Dardo; Wang, Gene-Jack; Volkow, Nora D.

    2016-01-01

    Positron emission tomography (PET) studies in animals and humans have shown that social status is associated with striatal dopamine D2/D3 receptor (D2/D3R) availability. That is, higher social hierarchy and higher scores on questionnaires assessing social status correlated positively with striatal D2/D3R availability in animals and humans respectively. Furthermore, subordinate monkeys were vulnerable to cocaine self-administration, suggesting that alternations in social hierarchy can change D2/D3R availability and vulnerability to cocaine use. Here, we investigated whether socioeconomic status (SES) measured with the Hollingshead scale is associated with striatal D2D/3R availability using [11C]raclopride PET in 38 cocaine abusers and 42 healthy controls matched for age and education. Compared to controls, cocaine abusers showed lower D2/D3R availability in the caudate, putamen and ventral striatum (all p≤.001). Despite matching groups for education, SES scores were lower in cocaine abusers than controls (p<.001). In the control group only, SES scores significantly correlated with D2/D3R in caudate (r=.35, p=.024) and putamen (r=.39, p=.011) but not in ventral striatum (p=.61); all corrected for age. The study confirms that SES is associated with striatal D2/D3R availability in healthy human volunteers. However, reductions in D2/D3R availability in cocaine abusers may be driven by factors other than SES such as chronic cocaine exposure. PMID:26828302

  20. Development of a High-Resolution Melting Analysis Method for CYP2C19*17 Genotyping in Healthy Volunteers

    PubMed Central

    Ghasemi, Zahra; Hashemi, Mehrdad; Ejabati, Mahsa; Ebrahimi, Seyyed Meisam; Kheiri Manjili, Hamidreza; Sharafi, Ali; Ramazani, Ali

    2016-01-01

    Background: Genetic polymorphisms of drug metabolisms by cytochrome P450 (P450s) could affect drug response, attracting particular interest in the pharmacogenetics. Due to the importance of CYP2C19* 17 allele and its capability of super- fast metabolism and also lack of information about distribution of the alleles in Iranian population, this research aimed to use High Resolution Melting (HRM) method compared to PCR-RFLP for genotyping healthy Iranian population. Methods: Blood samples were collected from 100 healthy Iranian volunteers. DNA was extracted by salting out method. Real-time PCR was used for amplification of the CYP2C19 gene and the alleles were identified by HRM. Sequencing was used to confirm the amplified DNA fragments and data were analyzed using SPSS software ver.18. Results: The frequency of alleles CYP2C19*1/*1, CYP2C19*1/*17 and CYP2C19*17/*17 were estimated as 58.33, 29.1 and 11.1%, respectively. Specificity and sensitivity of HRM method were 90% and 100%, with respect to PCR-RFLP. Also, HRM analysis has been evaluated as a faster and more effective approach. Conclusion: Comparison of our results based on HRM analysis with PCR-RFLP showed that our developed method is rapid, accurate, fast and economic to study the CYP2C19*17 allele and it is appropriate for other similar population genetic studies. PMID:27920888

  1. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers.

    PubMed

    Camilleri, Michael; Bharucha, Adil E; Ueno, Ryuji; Burton, Duane; Thomforde, George M; Baxter, Kari; McKinzie, Sanna; Zinsmeister, Alan R

    2006-05-01

    Chloride channels modulate gastrointestinal neuromuscular functions in vitro. Lubiprostone, a selective type 2 chloride channel (ClC-2) activator, induces intestinal secretion and has been shown to relieve constipation in clinical trials; however, the effects of lubiprostone on gastric function and whole gut transit in humans are unclear. Our aim was to compare the effects of the selective ClC-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans. We performed a randomized, parallel-group, double-blind, placebo-controlled study evaluating the effects of lubiprostone (24 microg bid) in 30 healthy volunteers. Validated methods were used: scintigraphic gastrointestinal and colonic transit, SPECT to measure gastric volumes, and the nutrient drink ("satiation") test to measure MTV and postprandial symptoms. Lubiprostone accelerated small bowel and colonic transit, increased fasting gastric volume, and retarded gastric emptying. MTV values were reduced compared with placebo; however, the MTV was within the normal range for healthy adults in 13 of 14 participants, and there was no significant change compared with baseline measurements. Lubiprostone had no significant effect on postprandial gastric volume or aggregate symptoms but did decrease fullness 30 min after the fully satiating meal. Thus the ClC-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation.

  2. Subjective and neurovegetative changes in healthy volunteers and panic patients performing simulated public speaking.

    PubMed

    Parente, Alexandre C B V; Garcia-Leal, Cybele; Del-Ben, Cristina M; Guimarães, Francisco S; Graeff, Frederico G

    2005-12-01

    Drug-free symptomatic panic patients, drug-treated nonsymptomatic patients and healthy controls were submitted to simulated public speaking. Subjective anxiety, cognitive impairment and discomfort measured by the visual analog mood scale as well as skin conductance level were higher in symptomatic patients than in controls at the beginning of the experimental session, nonsymptomatic patients lying in between. Subjective sedation, spontaneous fluctuations of skin conductance, heart rate and blood pressure were similar in the three groups. Preparation and performance of speech decreased sedation while increasing anxiety, cognitive impairment, level and fluctuations of skin conductance, heart rate and blood pressure. Anxiety, cognitive impairment and conductance level were less increased in symptomatic patients than in controls. Electrodermal activity, but not cardiovascular measures of sympathetic arousal correlated with anticipatory anxiety. Chronic treatment with serotonin uptake inhibitors attenuated the differences between panic patients and controls, supporting the participation of serotonin in panic disorder.

  3. Metabolism of [3H]pentosan polysulfate sodium (PPS) in healthy human volunteers.

    PubMed

    Simon, M; McClanahan, R H; Shah, J F; Repko, T; Modi, N B

    2005-08-01

    Pentosan polysulfate sodium (PPS) is the active ingredient in ELMIRON, a drug approved for the relief of bladder pain associated with interstitial cystitis. The study objective was to characterize the pharmacokinetic and metabolic profiles of PPS following oral dosing of [3H]PPS. As specific assays for PPS do not exist, metabolic profiling was accomplished through multiple fraction collections and radiochromatographic techniques. Two groups of eight healthy female subjects sequentially received a single oral dose of 200 microCi [3H]PPS supplemented with 300 mg unlabelled PPS or 300 microCi [3H]PPS supplemented with 450 mg unlabelled PPS. Most of the administered dose (84%) was excreted in faeces as intact PPS, and a smaller percentage (6%) was excreted in urine. In summary, orally administered PPS was very poorly absorbed, with the majority of the drug being excreted in faeces as intact PPS and in urine as low molecular weight and desulfated PPS.

  4. Effect of sulodexide on plasma transforming growth factor-beta1 in healthy volunteers.

    PubMed

    Borawski, Jacek; Dubowski, Miroslaw; Pawlak, Krystyna; Mysliwiec, Michal

    2010-02-01

    It is unknown whether the glycosaminoglycan drug sulodexide interferes with transforming growth factor-beta1--a member of heparin-binding family and a potent regulator of human biology and diseases. Hence, a 2-week pilot study was performed in 11 healthy men. Sulodexide was initially administered intravenously in a single dose, then--orally for 12 days and--again intravenously on study completion. Initial injection had no effect on activated form of the growth factor measured in plasma after 10 and 120 min; no change was also observed after 120 min from drug ingestion on day 7. On final intravenous administration, the growth factor levels increased by almost 60% after 10 min and remained elevated; the 120-min levels directly correlated with sulodexide dosage. Baseline cytokine levels decreased during the 2-week trial by more than 50%. In conclusion, transforming growth factor-beta1 release and likely downregulation of its expression may constitute novel pharmacological effects of sulodexide.

  5. Dysesthesia symptoms produced by sensorimotor incongruence in healthy volunteers: an electroencephalogram study

    PubMed Central

    Katayama, Osamu; Osumi, Michihiro; Kodama, Takayuki; Morioka, Shu

    2016-01-01

    Objectives Pathological pain such as phantom limb pain is caused by sensorimotor incongruence. Several studies with healthy participants have clearly indicated that dysesthesia, which is similar to pathological pain, is caused by incongruence between proprioception and/or motor intention and visual feedback. It is not clear to what extent dysesthesia may be caused by incongruence between motor intention and visual feedback or by incongruence between proprioception and visual feedback. The aim of this study was to clarify the neurophysiology of these factors by analyzing electroencephalograms (EEGs). Methods In total, 18 healthy participants were recruited for this study. Participants were asked to perform repetitive flexion/extension exercises with their elbows in a congruent/incongruent position while viewing the activity in a mirror. EEGs were performed to determine cortical activation during sensorimotor congruence and incongruence. Results In the high-frequency alpha band (10–12 Hz), numeric rating scale scores of a feeling of peculiarity were significantly correlated with event-related desynchronization/synchronization under the incongruence and proprioception conditions associated with motor intention and visual feedback (right inferior parietal region; r=−0.63, P<0.01) and between proprioception and visual feedback (right temporoparietal region; r=−0.49 and r=−0.50, P<0.05). In these brain regions, there was a region in which incongruence between proprioception and visual feedback and between motor intention and visual feedback caused an increase in activity. Conclusion The present findings suggest that neural mechanisms of dysesthesia are caused by incongruence between proprioception associated with motor intention and visual feedback and, in particular, are a result of incongruence between proprioception only and visual feedback. PMID:27994482

  6. Dissociation of Motor Task-Induced Cortical Excitability and Pain Perception Changes in Healthy Volunteers

    PubMed Central

    Volz, Magdalena S.; Mendonca, Mariana; Pinheiro, Fernando S.; Cui, Huashun; Santana, Marcus; Fregni, Felipe

    2012-01-01

    Background There is evidence that interventions aiming at modulation of the motor cortex activity lead to pain reduction. In order to understand further the role of the motor cortex on pain modulation, we aimed to compare the behavioral (pressure pain threshold) and neurophysiological effects (transcranial magnetic stimulation (TMS) induced cortical excitability) across three different motor tasks. Methodology/Principal Findings Fifteen healthy male subjects were enrolled in this randomized, controlled, blinded, cross-over designed study. Three different tasks were tested including motor learning with and without visual feedback, and simple hand movements. Cortical excitability was assessed using single and paired-pulse TMS measures such as resting motor threshold (RMT), motor-evoked potential (MEP), intracortical facilitation (ICF), short intracortical inhibition (SICI), and cortical silent period (CSP). All tasks showed significant reduction in pain perception represented by an increase in pressure pain threshold compared to the control condition (untrained hand). ANOVA indicated a difference among the three tasks regarding motor cortex excitability change. There was a significant increase in motor cortex excitability (as indexed by MEP increase and CSP shortening) for the simple hand movements. Conclusions/Significance Although different motor tasks involving motor learning with and without visual feedback and simple hand movements appear to change pain perception similarly, it is likely that the neural mechanisms might not be the same as evidenced by differential effects in motor cortex excitability induced by these tasks. In addition, TMS-indexed motor excitability measures are not likely good markers to index the effects of motor-based tasks on pain perception in healthy subjects as other neural networks besides primary motor cortex might be involved with pain modulation during motor training. PMID:22470548

  7. Effects of a nitrate-rich meal on arterial stiffness and blood pressure in healthy volunteers.

    PubMed

    Liu, Alex H; Bondonno, Catherine P; Croft, Kevin D; Puddey, Ian B; Woodman, Richard J; Rich, Lisa; Ward, Natalie C; Vita, Joseph A; Hodgson, Jonathan M

    2013-11-30

    An increase in nitrate intake can augment circulating nitrite and nitric oxide. This may lead to lower blood pressure and improved vascular function. Green leafy vegetables, such as spinach, are rich sources of nitrate. We aimed to assess the acute effects of a nitrate-rich meal containing spinach on arterial stiffness and blood pressure in healthy men and women. Twenty-six participants aged 38-69years were recruited to a randomized controlled cross-over trial. The acute effects of two energy-matched (2000kJ) meals, administered in random order, were compared. The meals were either high nitrate (220mg of nitrate derived from spinach [spinach]) or low nitrate [control]. Outcome measurements were performed pre-meal and at specific time points up to 210min post meal. Spinach resulted in an eightfold increase in salivary nitrite and a sevenfold increase in salivary nitrate concentrations from pre-meal (P<0.001) to 120min post meal. Spinach compared with control resulted in higher large artery elasticity index (P<0.001), and lower pulse pressure (P<0.001) and systolic blood pressure (P<0.001). Post meal carotid-femoral pulse wave velocity (P=0.07), augmentation index (P=0.63), small artery elasticity index (P=0.98) and diastolic blood pressure (P=0.13) were not significantly altered by spinach relative to control. Therefore, consumption of a nitrate-rich meal can lower systolic blood pressure and pulse pressure and increase large artery compliance acutely in healthy men and women. If sustained, these effects could contribute to better cardiovascular health.

  8. Catechol-O-methyltransferase val158met genotype determines effect of reboxetine on emotional memory in healthy male volunteers

    PubMed Central

    Gibbs, Ayana A.; Bautista, Carla E.; Mowlem, Florence D.; Naudts, Kris H.; Duka, Dora T.

    2014-01-01

    Background Catechol-O-methyltransferase (COMT) metabolizes catecholamines in the prefrontal cortex (PFC). A common polymorphism in the COMT gene (COMT val158met) has pleiotropic effects on cognitive and emotional processing. The met allele has been associated with enhanced cognitive processing but impaired emotional processing relative to the val allele. Methods We genotyped healthy, white men in relation to the COMT val158met polymorphism. They were given a single 4 mg dose of the selective noradrenaline reuptake inhibitor (NRI) reboxetine or placebo in a randomized, double-blind between-subjects model and then completed an emotional memory task 2 hours later. Results We included 75 men in the study; 41 received reboxetine and 34 received placebo. In the placebo group, met/met carriers did not demonstrate the usual memory advantage for emotional stimuli that was observed in val carriers. Reboxetine restored this emotional enhancement of memory in met/met carriers, but had no significant effect in val carriers. Limitations We studied only men, thus limiting the generalizability of our findings. We also relied on self-reported responses to screening questions to establish healthy volunteer status, and in spite of the double-blind design, participants were significantly better than chance at identifying their intervention allocation. Conclusion Emotional memory is impaired in healthy met homozygotes and selectively improved in this group by reboxetine. This has potential translational implications for the use of reboxetine, which is currently licensed as an antidepressant in several countries, and edivoxetine, a new selective NRI currently in development. PMID:24467942

  9. Comparison of salivary and calculated free cortisol levels during low and standard dose of ACTH stimulation tests in healthy volunteers.

    PubMed

    Elbuken, Gulsah; Tanriverdi, Fatih; Karaca, Zuleyha; Kula, Mustafa; Gokahmetoglu, Selma; Unluhizarci, Kursad; Kelestimur, Fahrettin

    2015-03-01

    Salivary cortisol (SC) has been increasingly used as a surrogate biomarker of free cortisol (FC) for the assessment of hypothalamo-pituitary-adrenal (HPA) axis, but there are not enough data regarding its use during ACTH stimulation tests. Therefore, we aimed to determine the responses of SC, calculated free cortisol (cFC) and free cortisol index (FCI) to ACTH stimulation tests in healthy adults. Forty-four healthy volunteers (24 men and 20 women) were included in the study. Low-dose (1 µg) and standard-dose (250 µg) ACTH stimulation tests were performed on two consecutive days. Basal and stimulated total cortisol (TC) and cortisol-binding globulin (CBG) levels and SC levels were measured during both doses of ACTH stimulation tests. cFC (by Coolens' equation) and FCI levels were calculated from simultaneously measured TC and CBG levels. The minimum SC, cFC, FCI levels after low-dose ACTH stimulation test were 0.21, 0.33, 16.06 µg/dL, and after standard-dose ACTH were 0.85, 0.46, 26.11 µg/dL, respectively, in healthy individuals who all had TC responses higher than 20 µg/dL. Peak CBG levels after both doses of ACTH stimulation tests were found to be higher in women than in men. So, by its effect, peak cFC and FCI levels were found to be lower in female than in male group. Neither TC nor SC levels were affected by gender. cFC and FCI levels depend on CBG levels and they are affected by gender. Cut-off levels for SC, cFC, FCI levels after both low- and standard-dose ACTH stimulation are presented. Studies including patients with adrenal insufficiency would be helpful to see the diagnostic value of these suggested cut-off levels.

  10. Effects of Right Lower Limb Orthopedic Immobilization on Braking Function: An On-The-Road Experimental Study With Healthy Volunteers.

    PubMed

    Murray, Jean-Christophe; Tremblay, Marc-André; Corriveau, Hélène; Hamel, Mathieu; Cabana, François

    2015-01-01

    Little is known about how immobilization of the right lower limb might affect driving. The purpose of the present study was to evaluate the effect of 2 types of immobilization on the emergency braking time of healthy subjects during actual driving conditions. The emergency braking times of 14 healthy volunteers were assessed in a closed circuit under 3 conditions: wearing running shoes, wearing an Aircast Walker(®), or wearing a walking cast on their right lower limb. An instrumented car was used to measure the emergency braking times during braking tests with and without a distractor. The foot movement times were significantly increased with both immobilization devices compared with the running shoe (p < .01). The median total braking time with the running shoe during emergency braking without a distractor was 0.452 (interquartile range, 25th to 75th [IQR], 0.413 to 0.472) second. The results obtained with the Aircast Walker(®) or the walking cast were significantly longer (p < .01), at 0.480 (IQR, 0.431 to 0.537) second and 0.512 (IQR, 0.451 to 0.535) second, respectively. When a distractor was added, the total braking time with the running shoe, Aircast Walker(®), and walking cast was 0.489 (IQR, 0.429 to 0.575), 0.516 (IQR, 0.459 to 0.586), and 0.510 (IQR, 0.469 to 0.570) second, respectively, with no statistically significant differences among these 3 conditions. Wearing an immobilization device on the right lower limb minimally lengthens the emergency braking time in healthy drivers under actual driving conditions. Clinicians must nonetheless exercise caution when advising a driver wearing an orthopedic immobilization, because driving a motor vehicle is a complex psychomotor task that goes well beyond the emergency braking time.

  11. The effect of acute alcohol intoxication on gut wall integrity in healthy male volunteers; a randomized controlled trial.

    PubMed

    de Jong, W J; Cleveringa, A M; Greijdanus, B; Meyer, P; Heineman, E; Hulscher, J B

    2015-02-01

    The aim of the study is to determine the effect of acute alcohol consumption on enterocytes. Chronic alcohol consumption has been known to induce a decrease in gut wall integrity in actively drinking alcoholics and patients with alcohol-induced liver disease. Data on the extent of the damage induced by acute alcohol consumption in healthy human beings is scarce. Studies show that heavy incidental alcohol consumption is a growing problem in modern society. Data on this matter may provide insights into the consequences of this behavior for healthy individuals. In a randomized clinical trial in crossover design, 15 healthy volunteers consumed water one day and alcohol the other. One blood sample was collected pre-consumption, five every hour post-consumption, and one after 24 h. Intestinal fatty acid binding protein (I-FABP) was used as a marker for enterocyte damage. Liver fatty acid binding protein (L-FABP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) were used as markers for hepatocyte damage. Lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) were used as a measure of translocation. Interleukin-6 (IL-6) was used to assess the acute inflammatory response to endotoxemia. Alcohol consumption caused a significant increase in serum I- and L-FABP levels, compared to water consumption. Levels increased directly post-consumption and decreased to normal levels within 4 h. LBP, sCD14, and IL-6 levels were not significantly higher in the alcohol group. Moderate acute alcohol consumption immediately damages the enterocyte but does not seem to cause endotoxemia.

  12. Development of tolerance after repeated administration of a selective muscarinic M1 antagonist biperiden in healthy human volunteers.

    PubMed

    Salin-Pascual, R J; Granados-Fuentes, D; Galicia-Polo, L; Nieves, E; Gillin, J C

    1993-02-01

    The muscarinic antagonist biperiden produces a dose-dependent inhibition of (REM) sleep on acute administration. The present study addressed the possibility of pharmacological tolerance after repeated biperiden administration. Six healthy volunteers were studied under sleep laboratory conditions in the following situations: one acclimatization, night, two baseline (that were averaged), 4 nights of biperiden administration, and 4 nights of placebo recovery administration. Six milligrams of biperiden and placebo were administered in identical capsules. Volunteers and technicians were blind to the order of the administration of the capsules. REM sleep time was reduced during the first and the second night, but was not significantly different in comparison with baseline by the third night. During placebo recovery nights, REM sleep time was not different from baseline. REM sleep latency was increased during the first and second nights of biperiden administration, but tolerance to this effect was observed by the third night. On placebo nights a dramatic shortening of REM latency was observed. The present findings support the hypothesis that anticholinergic drugs, even a selective M1 antagonist such as biperiden, induce tolerance soon after administration. A similar effect has been reported with scopolamine, a nonselective muscarinic antagonist, but the main difference is that biperiden withdrawal was not followed by an REM sleep rebound. The observed effect on REM sleep latency during placebo administration may be related to a supersensitivity to muscarinic M-1 receptors that trigger the first REM sleep period. Because short REM latency has been the main finding in the sleep of depressed patients, some implications of the present findings are discussed.

  13. Comparative pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, trovafloxacin, and moxifloxacin after single oral administration in healthy volunteers.

    PubMed

    Lubasch, A; Keller, I; Borner, K; Koeppe, P; Lode, H

    2000-10-01

    In an open, randomized, six-period crossover study, the pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin were compared after a single oral dose in 12 healthy volunteers (6 men and 6 women). The volunteers received 250 mg of ciprofloxacin, 400 mg of gatifloxacin, 600 mg of grepafloxacin, 500 mg of levofloxacin, 400 mg of moxifloxacin, and 200 mg of trovafloxacin. The concentrations of the six fluoroquinolones in serum and urine were measured by a validated high-performance liquid chromatography method. Blood and urine samples were collected before and at different time points up to 48 h after medication. Levofloxacin had the highest peak concentration (C(max), in micrograms per milliliter) (6.21+/-1.34), followed by moxifloxacin (4.34+/-1.61) and gatifloxacin (3.42+/-0.74). Elimination half-lives ranged from 12.12+/-3.93 h (grepafloxacin) to 5.37+/-0.82 h (ciprofloxacin). The total areas under the curve (AUC(tot), in microgram-hours per milliliter) for levofloxacin (44.8+/-4.4), moxifloxacin (39.3+/-5.35), and gatifloxacin (30+/-3.8) were significantly higher than that for ciprofloxacin (5.75+/-1.25). Calculated from a normalized dose of 200 mg, the highest C(max)s (in micrograms per milliliter) were observed for levofloxacin (2.48 +/-0.53), followed by moxifloxacin (2.17+/-0.81) and trovafloxacin (2.09+/-0.58). The highest AUC(tot) (in microgram-hours per milliliter) for a 200-mg dose were observed for moxifloxacin (19.7+/-2.67) and trovafloxacin (19.5+/-3.1); the lowest was observed for ciprofloxacin (4.6+/-1.0). No serious adverse event was observed during the study period. The five recently developed fluoroquinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin) showed greater bioavailability, longer half-lives, and higher C(max)s than ciprofloxacin.

  14. Modafinil combined with cognitive training is associated with improved learning in healthy volunteers--a randomised controlled trial.

    PubMed

    Gilleen, J; Michalopoulou, P G; Reichenberg, A; Drake, R; Wykes, T; Lewis, S W; Kapur, S

    2014-04-01

    Improving cognition in people with neuropsychiatric disorders remains a major clinical target. By themselves pharmacological and non-pharmacological approaches have shown only modest effects in improving cognition. In the present study we tested a recently-proposed methodology to combine CT with a 'cognitive-enhancing' drug to improve cognitive test scores and expanded on previous approaches by delivering combination drug and CT, over a long intervention of repeated sessions, and used multiple tasks to reveal the cognitive processes being enhanced. We also aimed to determine whether gains from this combination approach generalised to untrained tests. In this proof of principle randomised-controlled trial thirty-three healthy volunteers were randomised to receive either modafinil or placebo combined with daily cognitive training over two weeks. Volunteers were trained on tasks of new-language learning, working memory and verbal learning following 200 mg modafinil or placebo for ten days. Improvements in trained and untrained tasks were measured. Rate of new-language learning was significantly enhanced with modafinil, and effects were greatest over the first five sessions. Modafinil improved within-day learning rather than between-day retention. No enhancement of gains with modafinil was observed in working memory nor rate of verbal learning. Gains in all tasks were retained post drug-administration, but transfer effects to broad cognitive abilities were not seen. This study shows that combining CT with modafinil specifically elevates learning over early training sessions compared to CT with placebo and provides a proof of principle experimental paradigm for pharmacological enhancement of cognitive remediation.

  15. Detection of novel Chlamydiae and Legionellales from human nasal samples of healthy volunteers.

    PubMed

    Corsaro, Daniele; Venditti, Danielle

    2015-07-01

    Chlamydiae are intracellular bacterial parasites of eukaryotes, ranging from amoebae to humans. They comprise many novel members and are investigated as emerging pathogens. Environmental studies highlighted similarities between the ecologies of chlamydiae and legionellae, both groups being important agents of respiratory infections. Herein, we analyzed nasal samples from healthy persons, searching for the presence of amoebae, chlamydiae and legionellae. From a total of 25 samples, we recovered by PCR eight samples positive to chlamydiae and six samples positive to legionellae. Among these samples, four were positive to both organisms. The sequencing of 16S rDNAs allowed to identify (i) among Chlamydiae: Parachlamydia acanthamoebae, Chlamydophila psittaci, Chlamydophila felis, and members of Rhabdochlamydiaceae, Simkaniaceae and E6 lineage and (ii) among Legionellaceae: Legionella longbeachae, Legionella bozemanii and Legionella impletisoli. Unexpectedly, we also recovered Diplorickettsia sp. Amoebae collected from nasal mucosae, Acanthamoeba and Vermamoeba, were endosymbiont-free, and chlamydiae revealed refractory to amoeba coculture. This study shows common exposure to chlamydiae and legionellae and suggests open air activities like gardening as a probable additional source of infection.

  16. The effect of focused attention and open monitoring meditation on attention network function in healthy volunteers.

    PubMed

    Ainsworth, Ben; Eddershaw, Rachael; Meron, Daniel; Baldwin, David S; Garner, Matthew

    2013-12-30

    Mindfulness meditation techniques are increasingly popular both as a life-style choice and therapeutic adjunct for a range of mental and physical health conditions. However, little is known about the mechanisms through which mindfulness meditation and its constituent practices might produce positive change in cognition and emotion. Our study directly compared the effects of Focused Attention (FA) and Open-Monitoring (OM) meditation on alerting, orienting and executive attention network function in healthy individuals. Participants were randomized to three intervention groups: open-focused meditation, focused attention, and relaxation control. Participants completed an emotional variant of the Attention Network Test (ANT) at baseline and post-intervention. OM and FA practice improved executive attention, with no change observed in the relaxation control group. Improvements in executive attention occurred in the absence of change in subjective/self-report mood and cognitive function. Baseline levels of dispositional/trait mindfulness were positively correlated with executive control in the ANT at baseline. Our results suggest that mindfulness meditation might usefully target deficits in executive attention that characterise mood and anxiety disorders.

  17. Acute ingestion of alcohol and cardiac autonomic modulation in healthy volunteers.

    PubMed

    Bau, Paulo F D; Moraes, Ruy S; Bau, Claiton H D; Ferlin, Elton L; Rosito, Guido A; Fuchs, Flávio D

    2011-03-01

    Arrhythmogenic effects of alcohol may be intermediated by its effects over heart rate variability (HRV). Most studies about the effects of alcohol over HRV were observational and did not explore the temporal influence of alcohol ingestion over autonomic modulation. The aim of this study was to verify if an acute ingestion of alcohol has a time-dependent influence over time-domain indices of HRV. The effect of the ingestion of 60 g of ethanol or placebo over autonomic modulation was compared in healthy men (35 per group), with 18-25 years of age, before and during 17 h after ingestion. Alcohol promoted a fall in the standard deviation of all normal R-R intervals, root mean square of successive differences, and percentage of pairs of adjacent R-R intervals differing by more than 50 ms and in two indices of the three-dimensional return map, by a period up to 10 h after the ingestion of alcohol, accompanied by an increase in heart rate. The indices returned to values similar of the control group 10 h after ingestion. The effects over HRV indices were attenuated by adjustment for heart rate. The ingestion of alcohol induces a broad cardiovascular adaptation secondary to vagal withdrawal and sympathetic activation that may be responsible for arrhythmogenic effects of alcohol ingestion.

  18. Adrenergic Effect on Cytokine Release After Ex Vivo Healthy Volunteers' Whole Blood LPS Stimulation.

    PubMed

    Papandreou, Vasiliki; Kavrochorianou, Nadia; Katsoulas, Theodoros; Myrianthefs, Pavlos; Venetsanou, Kyriaki; Baltopoulos, George

    2016-06-01

    Catecholamines are molecules with immunomodulatory properties in health and disease. Several studies showed the effect of catecholamines when administered to restore hemodynamic stability in septic patients. This study investigates the effect of norepinephrine and dobutamine on whole blood cytokine release after ex vivo lipopolysaccharide (LPS) stimulation. Whole blood collected from healthy individuals was stimulated with LPS, in the presence of norepinephrine or dobutamine at different concentrations, with or without metoprolol, a β1 receptor antagonist. Cytokine measurement was performed in isolated cell culture supernatants with ELISA. Results are expressed as mean ± SEM and compared with Mann-Whitney rank-sum test. Both norepinephrine and dobutamine significantly reduced TNF-α and IL-6 production after ex vivo LPS stimulation of whole blood in a dose-dependent manner, and this effect was partially reversed by the presence of metoprolol. Norepinephrine and dobutamine reduce the LPS-induced production of pro-inflammatory cytokines, thus possibly contributing to altered balance between the inflammatory and anti-inflammatory responses, which are vital for a successful host response to severe disease, shock, and sepsis.

  19. Pomegranate extract induces ellagitannin metabolite formation and changes stool microbiota in healthy volunteers.

    PubMed

    Li, Zhaoping; Henning, Susanne M; Lee, Ru-Po; Lu, Qing-Yi; Summanen, Paula H; Thames, Gail; Corbett, Karen; Downes, Julia; Tseng, Chi-Hong; Finegold, Sydney M; Heber, David

    2015-08-01

    The health benefits of pomegranate (POM) consumption are attributed to ellagitannins and their metabolites, formed and absorbed in the intestine by the microbiota. In this study twenty healthy participants consumed 1000 mg of POM extract daily for four weeks. Based on urinary and fecal content of the POM metabolite urolithin A (UA), we observed three distinct groups: (1) individuals with no baseline UA presence but induction of UA formation by POM extract consumption (n = 9); (2) baseline UA formation which was enhanced by POM extract consumption (N = 5) and (3) no baseline UA production, which was not inducible (N = 6). Compared to baseline the phylum Actinobacteria was increased and Firmicutes decreased significantly in individuals forming UA (producers). Verrucomicrobia (Akkermansia muciniphila) was 33 and 47-fold higher in stool samples of UA producers compared to non-producers at baseline and after 4 weeks, respectively. In UA producers, the genera Butyrivibrio, Enterobacter, Escherichia, Lactobacillus, Prevotella, Serratia and Veillonella were increased and Collinsella decreased significantly at week 4 compared to baseline. The consumption of pomegranate resulted in the formation of its metabolites in some but not all participants. POM extract consumption may induce health benefits secondary to changes in the microbiota.

  20. Effects of Mangifera indica (Careless) on Microcirculation and Glucose Metabolism in Healthy Volunteers.

    PubMed

    Buchwald-Werner, Sybille; Schön, Christiane; Frank, Sonja; Reule, Claudia

    2017-02-10

    A commercial Mangifera indica fruit powder (Careless) showed beneficial acute effects on microcirculation in a randomized, double-blind, crossover pilot study. Here, long-term effects on microcirculation and glucose metabolism were investigated in a double-blind, randomized, placebo-controlled, 3-arm parallel-design study in healthy individuals. A daily dose of 100 mg or 300 mg of the fruit powder was compared to placebo after supplementation for 4 weeks. Microcirculation and endothelial function were assessed by the Oxygen-to-see System and pulse amplitude tonometry, respectively. Glucose metabolism was assessed under fasting and postprandial conditions by capillary glucose and HbA1c values.Microcirculatory reactive hyperemia flow increased, especially in the 100 mg group (p = 0.025). The 300 mg of the M. indica fruit preparation reduced postprandial glucose levels by trend if compared to placebo (p = 0.0535) accompanied by significantly lower HbA1c values compared to baseline. Furthermore, 300 mg intake significantly improved postprandial endothelial function in individuals with decreased endothelial function after high-dose glucose intake (p = 0.0408; n = 11).In conclusion, the study suggests moderate beneficial effects of M. indica fruit preparation on microcirculation, endothelial function, and glucose metabolism.

  1. Hypoglycemic effect of Lupinus mutabilis in healthy volunteers and subjects with dysglycemia.

    PubMed

    Fornasini, M; Castro, J; Villacrés, E; Narváez, L; Villamar, M P; Baldeón, M E

    2012-01-01

    Metabolic syndrome and type-2 diabetes are increasing health problems that negatively affect health care systems worldwide. There is a constant urge to develop new therapies with better effects, lower side effects at lower prices to treat these diseases. Lupinus species and their derivates are good candidates to be used as hypoglycaemic agents. A phase II clinical trial was conducted to assess the role of raw Lupinus mutabilis on blood glucose and insulin in normoglycemic and dysglycemic subjects. Results show that consumption of L. mutabilis by normal weight healthy young individuals did not change importantly blood glucose and insulin levels. On the other hand, consumption of similar doses of lupinus by dysglycemic individuals (fasting glucose > 100 mg/dL) decreased significantly blood glucose. Lupinus effects were greater in those subjects with higher basal glucose levels. Glucose lowering effects of lupinus were not observed after soy intake that was used as control. A statistically significant reduction in insulin levels was also observed in the lupinus group compared with the soy group after 60 minutes of treatment. Furthermore, only treatment with lupinus improved insulin resistance in dysglycemic subjects. These data demonstrate that lupinus consumption could be a feasible and low cost alternative to treat chronic hyperglycemic diseases.

  2. Comparative Pharmacokinetics and Bioavailability of Dilacor XR and Cardizem CD in Healthy Volunteers.

    PubMed

    Argenti, Domenick; Huang, Mei-Yung; Heald, Donald; Ziemniak, John

    1995-01-01

    The objective of this investigation was to compare the single-dose and steady-state pharmacokinetic profiles of Dilacor XR to Cardizem CD. The study enrolled 24 healthy males and was divided into three parts: a single intravenous 25-mg bolus dose of diltiazem HCl (Cardizem Injectable) followed by a two-way crossover comparison of single and multiple once-daily 240-mg oral doses of Dilacor XR and Cardizem CD. Plasma samples were analyzed for diltiazem using a specific and sensitive HPLC assay. Statistical analysis and deconvolution were performed on the data. A 1- and 3-hour lag time in diltiazem absorption was noted following the administration of Dilacor XR and Cardizem CD, respectively. Statistically significant differences were noted in mean single- and multiple-dose t(max) values with Cardizem CD taking approximately twice as long as Dilacor XR to reach C(max). Dilacor XR was equivalent to Cardizem CD with respect to AUC((0--infty infinity)) and C(max). Equivalent minimum and average steady-state plasma diltiazem concentrations were noted after multiple-dose administration. Deconvolution of the single-dose data also showed similar mean bioavailabilities for the respective formulations but revealed dissimilarities in each product's absorption profile that may reflect observed differences in absorption lag time and t(max).

  3. Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers.

    PubMed

    Winder-Rhodes, S E; Chamberlain, S R; Idris, M I; Robbins, T W; Sahakian, B J; Müller, U

    2010-11-01

    Previous research has demonstrated cognitive-enhancing effects of modafinil in humans and generated evidence for its therapeutic potential in psychiatric disorders. The neurochemical basis of these effects remains unresolved although a role for α1-adrenoceptors has been hypothesised. In this within-subject, double-blind, placebo-controlled study, 12 healthy male adults received modafinil (300 mg), the α1-adrenoceptor antagonist prazosin (3 mg), both together and placebo on separate occasions at least 5 days apart. Cognitive effects were assessed using a well-validated testing battery focusing on executive and working memory functions. Blood pressure, heart rate and salivary α-amylase (sAA) were measured at hourly intervals. Cognitive effects of modafinil and prazosin were identified at the difficult levels of the One-Touch Stockings of Cambridge (OTSOC) planning task. Prazosin antagonized the error-reducing effect of modafinil when the agents were given together. In contrast, the combined agents acted synergistically to increase time taken to complete OTSOC problems compared with placebo. The tachycardic and sAA-elevating effects of prazosin were also potentiated by concurrent modafinil administration. The current data suggest that the cognitive effects of modafinil on performance accuracy and latency are dissociable in terms of their neurochemical mechanisms. Our findings support the hypothesised involvement of α1-adrenoceptors in some of the cognitive-enhancing effects of modafinil and warrant further investigation.

  4. Tolerability of intramuscular and intradermal delivery by CELLECTRA® adaptive constant current electroporation device in healthy volunteers

    PubMed Central

    Diehl, Malissa C; Lee, Jessica C; Daniels, Stephen E; Tebas, Pablo; Khan, Amir S; Giffear, Mary; Sardesai, Niranjan Y; Bagarazzi, Mark L

    2013-01-01

    DNA vaccines are being developed as a potentially safe and effective immunization platform. However, translation of DNA vaccines into a clinical setting has produced results that have fallen short of those generated in a preclinical setting. Various strategies are being developed to address this lack of potency, including improvements in delivery methods. Electroporation (EP) creates transient increases in cell membrane permeability, thus enhancing DNA uptake and leading to a more robust immune response. Here, we report on the safety and tolerability of delivering sterile saline via intramuscular (IM) or intradermal (ID) injection followed by in vivo electroporation using the CELLECTRA® adaptive constant current device in healthy adults from two open-label studies. Pain, as assessed by VAS, was highest immediately after EP but diminishes by about 50% within 5 min. Mean VAS scores appear to correlate with the amount of energy delivered and depth of needle insertion, especially for intramuscular EP. Mean scores did not exceed 7 out of 10 or 3 out of 10 for IM and ID EP, respectively. The majority of adverse events included mild to moderate injection site reactions that resolved within one day. No deaths or serious adverse events were reported during the course of either study. Overall, injection followed by EP with the CELLECTRA® device was well-tolerated and no significant safety concerns were identified. These studies support the further development of electroporation as a vaccine delivery method to enhance immunogenicity, particularly for diseases in which traditional vaccination approaches are ineffective. PMID:24051434

  5. Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/ zidovudine, and ethinyloestradiol/ levonorgestrel in healthy volunteers

    PubMed Central

    Abel, Samantha; Russell, Deborah; Whitlock, Lyndsey A; Ridgway, Caroline E; Muirhead, Gary J

    2008-01-01

    Aims To assess the effect of maraviroc on the pharmacokinetics of midazolam, a sensitive probe CYP3A4 substrate; lamivudine/zidovudine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs); and ethinyloestradiol/levonorgestrel, a combination oral contraceptive. Methods Three randomized, double-blind, placebo-controlled studies were conducted in healthy subjects to assess the effect of maraviroc on pharmacokinetics of other drugs. Two, two-period crossover studies were conducted to assess (i) the effect of steady-state maraviroc (300 mg b.i.d.) on pharmacokinetics of midazolam; and (ii) the effect of steady-state maraviroc (300 mg b.i.d.) on the pharmacokinetics of lamivudine/zidovudine. A third two-way crossover study was conducted to evaluate the effect of steady-state maraviroc (100 mg b.i.d.) on the pharmacokinetics of 30 μg ethinyloestradiol/150 μg levonorgestrel (Microgynon®). Results The geometric mean ratios for Cmax and AUC for each of the compounds tested in the presence and absence of maraviroc were between 92% and 121%. There were no notable differences in Tmax, t1/2 or CLR (where measured) for any of the compounds. Conclusions Maraviroc had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate midazolam, the NRTIs zidovudine/lamivudine, or the oral contraceptive steroids ethinyloestradiol and levonorgestrel. PMID:18333862

  6. Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh

    SciTech Connect

    Sarker, Shafiqul Alam; McCallin, Shawna; Barretto, Caroline; Berger, Bernard; Pittet, Anne-Cecile; Sultana, Shamima; Krause, Lutz; Huq, Sayeda; Bibiloni, Rodrigo; Bruttin, Anne; Reuteler, Gloria; Bruessow, Harald

    2012-12-20

    The genomic diversity of 99 T4-like coliphages was investigated by sequencing an equimolar mixture with Illumina technology and screening them against different databases for horizontal gene transfer and undesired genes. A 9-phage cocktail was given to 15 healthy adults from Bangladesh at a dose of 3 Multiplication-Sign 10{sup 9} and 3 Multiplication-Sign 10{sup 7} plaque-forming units and placebo respectively. Phages were detected in 64% of the stool samples when subjects were treated with higher titer phage, compared to 30% and 28% with lower-titer phage and placebo, respectively. No Escherichia coli was present in initial stool samples, and no amplification of phage was observed. One percent of the administered oral phage was recovered from the feces. No adverse events were observed by self-report, clinical examination, or from laboratory tests for liver, kidney, and hematology function. No impact of oral phage was seen on the fecal microbiota composition with respect to bacterial 16S rRNA from stool.

  7. A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers.

    PubMed

    Agarwal, Suresh K; Kriel, Robert L; Cloyd, James C; Coles, Lisa D; Scherkenbach, Lisa A; Tobin, Michael H; Krach, Linda E

    2015-01-01

    Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures.

  8. Influence of exercise on visceral pain: an explorative study in healthy volunteers

    PubMed Central

    van Weerdenburg, Laura JGM; Brock, Christina; Drewes, Asbjørn Mohr; van Goor, Harry; de Vries, Marjan; Wilder-Smith, Oliver HG

    2017-01-01

    Background and objectives Contradictory results have been found about the effect of different exercise modalities on pain. The aim of this study was to investigate the early effects of aerobic and isometric exercise on different types of experimental pain, including visceral pain, compared to an active control condition. Methods Fifteen healthy subjects (6 women, mean [standard deviation] age 25 [6.5] years) completed 3 interventions consisting of 20 minutes of aerobic cycling, 12 minutes of isometric knee extension and a deep breathing procedure as active control. At baseline and after each intervention, psychophysical tests were performed, including electrical stimulation of the esophagus, pressure pain thresholds and the cold pressor test as a measure for conditioned pain modulation. Participants completed the Medical Outcome Study Short-Form 36 and State-Trait Anxiety Inventory prior to the experiments. Data were analyzed using two-way repeated measures analysis of variance. Results No significant differences were found for the psychophysical tests after the interventions, compared to baseline pain tests and the control condition. Conclusion No hypoalgesic effect of aerobic and isometric exercise was found. The evidence for exercise-induced hypoalgesia appears to be not as consistent as initially thought, and caution is recommended when interpreting the effects of exercise on pain. PMID:28096689

  9. Preserved Learning during the Symbol–Digit Substitution Test in Patients with Schizophrenia, Age-Matched Controls, and Elderly

    PubMed Central

    Cornelis, Claudia; De Picker, Livia J.; Hulstijn, Wouter; Dumont, Glenn; Timmers, Maarten; Janssens, Luc; Sabbe, Bernard G. C.; Morrens, Manuel

    2015-01-01

    Objective: Speed of processing, one of the main cognitive deficits in schizophrenia is most frequently measured with a digit–symbol-coding test. Performance on this test is additionally affected by writing speed and the rate at which symbol–digit relationships are learned, two factors that may be impaired in schizophrenia. This study aims to investigate the effects of sensorimotor speed, short-term learning, and long-term learning on task performance in schizophrenia. In addition, the study aims to explore differences in learning effects between patients with schizophrenia and elderly individuals. Methods: Patients with schizophrenia (N = 30) were compared with age-matched healthy controls (N = 30) and healthy elderly volunteers (N = 30) during the Symbol–Digit Substitution Test (SDST). The task was administered on a digitizing tablet, allowing precise measurements of the time taken to write each digit (writing time) and the time to decode symbols into their corresponding digits (matching time). The SDST was administered on three separate days (day 1, day 2, day 7). Symbol–digit repetitions during the task represented short-term learning and repeating the task on different days represented long-term learning. Results: The repetition of the same symbol–digit combinations within one test and the repetition of the test over days resulted in significant decreases in matching time. Interestingly, these short-term and long-term learning effects were about equal among the three groups. Individual participants showed a large variation in the rate of short-term learning. In general, patients with schizophrenia had the longest matching time whereas the elderly had the longest writing time. Writing time remained the same over repeated testing. Conclusion: The rate of learning and sensorimotor speed was found to have a substantial influence on the SDST score. However, a large individual variation in learning rate should be taken into account in the

  10. Population pharmacokinetics of zonisamide after oral administration in healthy Chinese volunteers.

    PubMed

    Qiu, Xuewen; Dai, Qing; Sun, Fengjun; Liu, Yao; Yang, Bo; Xiang, Rongfeng; Yu, Mingjie; Xiong, Lirong; Bi, Shanshan; Lu, Wei; Chen, Yongchuan; Xia, Peiyuan

    2016-05-01

    To develop a population-based pharmacokinetic model for the oral antiepileptic drug zonisamide using a cohort of healthy (nonepileptic) subjects and evaluate the effect of individual factors on the pharmacokinetics of zonisamide. 30 young adults (21-39 years) in good health were randomly assigned to 3 equal groups (1:1 sex ratio) for single-dose administration of zonisamide at 200 mg, 300 mg, or 400 mg. An additional 9 subjects (22-24 years) were administered once daily zonisamide at 300 mg for 14 days, and comprised the multiple dosing group. Venous blood samples were collected for analysis prior to (baseline, 0 hours) and after (1-300 hours) drug administration, providing 607 total samples used to build the pharmacokinetic model. The population pharmacokinetic analysis was performed by ICON's nonlinear mixed-effect modeling (NONMEM) software. Validation of the final model was carried out by nonparametric bootstrapping and visual predictive check. The zonisamide pharmacokinetics was best described by a two-compartment model with first-order elimination. In the final model, the estimated value of clearance (CL) was 23.25 L/h, the volume of distribution of the central compartment (Vc) was 34.50 L, the intercompartmental clearance (Q) was 20.22 L/h, and the Ka was 0.026 h(-1). The peripheral volume of distribution (Vp) was 1,429 L for single dose and 1,003 L for multiple doses. Body weight was the significant covariate affecting CL, Vc, Vp, and Q. Otherwise, female subjects had a lower Q than male subjects. The pharmacokinetics of zonisamide after oral administration could be described using a linear first-order elimination two-compartment model, which may provide a reference for clinical use of zonisamide in Chinese adults.

  11. High-dose diazepam facilitates core cooling during cold saline infusion in healthy volunteers.

    PubMed

    Hostler, David; Northington, William E; Callaway, Clifton W

    2009-08-01

    Studies have suggested that inducing mild hypothermia improves neurologic outcomes after traumatic brain injury, major stroke, cardiac arrest, or exertional heat illness. While infusion of cold normal saline is a simple and inexpensive method for reducing core temperature, human cold-defense mechanisms potentially make this route stressful or ineffective. We hypothesized that intravenous administration of diazepam during a rapid infusion of 30 mL.kg-1 of cold (4 degrees C) 0.9% saline to healthy subjects would be more comfortable and reduce core body temperature more than the administration of cold saline alone. Fifteen subjects received rapidly infused cold (4 degrees C) 0.9% saline. Subjects were randomly assigned to receive, intravenously, 20 mg diazepam (HIGH), 10 mg diazepam (LOW), or placebo (CON). Main outcomes were core temperature, skin temperature, and oxygen consumption. Data for the main outcomes were analyzed with generalized estimating equations to identify differences in group, time, or a group x time interaction. Core temperature decreased in all groups (CON, 1.0 +/- 0.2 degrees C; LOW, 1.4 +/- 0.2 degrees C; HIGH, 1.5 +/- 0.2 degrees C), while skin temperature was unchanged. Mean (95% CI) oxygen consumption was 315.3 (253.8, 376.9) mL.kg-1.min-1 in the CON group, 317.9 (275.5, 360.3) in the LOW group, and 226.1 (216.4, 235.9) in the HIGH group. Significant time and group x time interaction was observed for core temperature and oxygen consumption (p < 0.001). Administration of high-dose diazepam resulted in decreased oxygen consumption during cold saline infusion, suggesting that 20 mg of intravenous diazepam may reduce the shivering threshold without compromising respiratory or cardiovascular function.

  12. Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers.

    PubMed

    Teo, S K; Colburn, W A; Thomas, S D

    1999-11-01

    Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open-label, single-dose, three-way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects reported adverse events, none of which was serious or unexpected. Celgene formulations were bioequivalent when comparing Cmax, tmax, and AUC. There was significant variability in plasma levels from the Tortuga formulation, giving a mean profile that was distinctly different from the two Celgene formulations with a lower Cmax value and a longer terminal phase. The lower Cmax was probably due to slower absorption. The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half-life of 15 hours compared to about 5 to 6 hours for the Celgene formulations. Confidence intervals for Cmax between the Tortuga and the Celgene formulations were outside the 80% to 125% range, indicating a lack of bioequivalence. Extent of absorption, as measured by AUC0-infinity, was approximately equal for all three formulations. Terminal half-life for Tortuga was two to three times longer compared to the Celgene formulations and is clear evidence for absorption rate limitations. The two Celgene formulations showed similar pharmacokinetic parameters with profiles that were best described by a one-compartment model with first-order absorption and elimination. The authors conclude that Celgene's clinical trial and commercial thalidomide formulations are similar to each other and distinctly

  13. Experimental orofacial pain and sensory deprivation lead to perceptual distortion of the face in healthy volunteers.

    PubMed

    Dagsdóttir, Lilja Kristín; Skyt, Ina; Vase, Lene; Baad-Hansen, Lene; Castrillon, Eduardo; Svensson, Peter

    2015-09-01

    Patients suffering from persistent orofacial pain may sporadically report that the painful area feels "swollen" or "differently," a phenomenon that may be conceptualized as a perceptual distortion because there are no clinical signs of swelling present. Our aim was to investigate whether standardized experimental pain and sensory deprivation of specific orofacial test sites would lead to changes in the size perception of these face areas. Twenty-four healthy participants received either 0.2 mL hypertonic saline (HS) or local anesthetics (LA) into six regions (buccal, mental, lingual, masseter muscle, infraorbital and auriculotemporal nerve regions). Participants estimated the perceived size changes in percentage (0 % = no change, -100 % = half the size or +100 % = double the size), and somatosensory function was checked with tactile stimuli. The pain intensity was rated on a 0-10 Verbal Numerical Rating Scale (VNRS), and sets of psychological questionnaires were completed. HS and LA were associated with significant self-reported perceptual distortions as indicated by consistent increases in perceived size of the adjacent face areas (P ≤ 0.050). Perceptual distortion was most pronounced in the buccal region, and the smallest increase was observed in the auriculotemporal region. HS was associated with moderate levels of pain VNRS = 7.3 ± 0.6. Weak correlations were found between HS-evoked perceptual distortion and level of dissociation in two regions (P < 0.050). Experimental pain and transient sensory deprivation evoked perceptual distortions in all face regions and overall demonstrated the importance of afferent inputs for the perception of the face. We propose that perceptual distortion may be an important phenomenon to consider in persistent orofacial pain conditions.

  14. Comparative effects of quinine and quinidine on glucose metabolism in healthy volunteers.

    PubMed Central

    Davis, T M; Karbwang, J; Looareesuwan, S; Turner, R C; White, N J

    1990-01-01

    1. To investigate the relative effects of quinine and quinidine on glucose metabolism, 11 healthy males aged 17-32 years were given three separate 1 h intravenous infusions; normal saline alone, quinine dihydrochloride 10 mg base kg-1 body weight (BW) in normal saline, and quinidine dihydrochloride 10 mg base kg-1 BW in normal saline. A constant infusion of 5 mg glucose kg-1 ideal BW min-1 was given for 1 h before and during each study. 2. Assessment of pancreatic beta cell function and tissue insulin sensitivity from plasma glucose and insulin concentrations at the end of the first hour using the Continuous Infusion of Glucose with Model Assessment (CIGMA) technique confirmed normal glucose tolerance for each subject on each test day. 3. Plasma glucose concentrations at 1 h were similar to those at 2 h. There was no significant difference between the plasma glucose profiles during the three infusion regimes (P greater than 0.05). Plasma insulin rose significantly during the second hour (P less than 0.0001); increments after quinine (geometric mean [-1 s.d- +1 s.d.]; 47.0 [27.8-79.4] mu l-1) were significantly greater than those after quinidine (19.8 [6.1-65.2] mu l-1) and saline (7.5 [0-21.5] mu l-1; P less than 0.05). Plasma quinine concentrations at the end of the infusion (6.5 +/- 4.4 mg l-1) correlated with insulin increments during the second hour (r = 0.662, P = 0.028) and were significantly greater than those of quinidine (3.0 +/- 0.8 mg l-1; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2223418

  15. Multiple dose bioequivalence study with josamycin propionate, a drug with highly variable kinetics, in healthy volunteers.

    PubMed

    Van Hoogdalem, E J; Terpstra, I J; Krauwinkel, W J; Volkers-Kamermans, N J; Baven, A L; Verschoor, J S

    1996-05-01

    Josamycin is a macrolide antibiotic with considerable intra- and interindividual variability in kinetics. In the present study bioequivalence of an intact and dispersed josamycin Solutab tablet, containing 1,000 mg of josamycin in the form of josamycin propionate ester, was tested versus a Josacine 1,000 mg reference sachet. The design of this bioequivalence study was adapted to the drug's pharmacokinetic variability, comprising testing in steady-state, testing the reference in replicate, and maintaining a widened bioequivalence margin. The study was performed in a group of 24 male and 12 female healthy subjects, according to a 3-treatment 4-period crossover design. Blood sampling for establishing josamycin propionate and josamycin base serum level profiles were collected during the 12 h dosing interval on day 4. Steady-state serum levels were reached on day 4. With the reference sachet mean peak levels of 1.02 micrograms/ml and 0.36 microgram/ml were observed for parent drug and metabolite, respectively, reached at peak times of 1.5 h and 1.8 h. Comparable profiles were observed with the intact and dispersed Solutab tablets, both tending towards higher serum levels than the sachet. In terms of josamycin propionate levels as well as josamycin base levels, the intact and dispersed Solutab tablet was bioequivalent with the referent sachet within the preset 0.70-1.43 margins. Variability in josamycin kinetics proved to be substantial, maximum differences in peak levels and AUC values being about 10-fold between individuals, and 3-fold within individuals. Retrospectively, the multiple dosing regimen appeared not to result in a clear reduction of intrasubject variability.

  16. High-glycaemic index and -glycaemic load meals increase the availability of tryptophan in healthy volunteers.

    PubMed

    Herrera, Christopher P; Smith, Keir; Atkinson, Fiona; Ruell, Patricia; Chow, Chin Moi; O'Connor, Helen; Brand-Miller, Jennie

    2011-06-01

    The purpose of the present study was to determine the influence of the glycaemic index (GI) and glycaemic load (GL) on the ratio of tryptophan (TRP) relative to other large neutral amino acids (LNAA). Ten healthy men (age 22·9 (sd 3·4) years; BMI 23·5 (sd 1·6) kg/m2) underwent standard GI testing, and later consumed each of a mixed-macronutrient (1915 kJ; 66·5 % carbohydrate (CHO), 17 % protein and 16·5 % fat) high-GI (MHGI), an isoenergetic, mixed-macronutrient low-GI (MLGI) and a CHO-only (3212 kJ; 90 % CHO, 8 % protein, 2 % fat) high-GI (CHGI) meal on separate days. The GI, GL and insulin index values (e.g. area under the curve) were largest after the CHGI meal (117, 200, 158), followed by the MHGI (79, 59, 82) and MLGI (51, 38, 56) meals, respectively (all values were significantly different, P < 0·05). After the MHGI and MLGI meals but not after the CHGI meal, TRP was elevated at 120 and 180 min (P < 0·05). After the CHGI, LNAA was lower compared with the MLGI (P < 0·05); also the rate of decline in LNAA was higher after CHGI compared with MHGI and MLGI (both comparisons P < 0·05). The percentage increase from baseline in TRP:LNAA after CHGI (23 %) was only marginally higher than after the MHGI meal (17 %; P = 0·38), but it was threefold and nearly significantly greater than MLGI (8 %; P = 0·05). The present study demonstrates that the postprandial rise in TRP:LNAA was increased by additional CHO ingestion and higher GI. Therefore, the meal GL appears to be an important factor influencing the postprandial TRP:LNAA concentration.

  17. Bioequivalence study of two risedronate sodium film-coated tablet formulations in healthy volunteers.

    PubMed

    Simanjuntak, R; Setiawati, E; Yunaidi, D A; Handayani, L R; Setiawati, A; Utami, B S; Rosa, T A; Sholeh, A B

    2014-03-01

    The present study was performed to compare the bioavailability of 2 risedronate sodium 35 mg film-coated tablet formulations (test formulation and reference formulation). Prior to the present study, in vitro comparative dissolution test has been conducted for test and reference formulations. Dissolution profiles shown that more than 85% of the drug is dissolved within 15 min at pH 1.2, pH 4.5, and pH 6.8.This study was a randomized, single-blind, 2-period, 2-sequence cross-over study which included 48 evaluable healthy adult male and female subjects under fasting condition. In each of the 2 study periods (separated by a washout of 3 weeks) a single dose of test or reference drug was administered. The pharmacokinetic parameters assessed in this study were cumulative urinary excretion from drug administration to 72 h (Ae72h) and maximum urine excretion rate (dAe/dtmax). These parameters were determined from urine concentrations of risedronate and urine volume. Urinary concentrations of the drug were determined by high performance liquid chromatographic method with UV detector.The geometric mean ratios (90% CI) of the test drug/reference drug for risedronate were 106.60% (92.34-123.07%) for Ae72h and 104.75% (88.86-123.47%) for dA/dtmax. The geometric mean ratios calculated for Ae72h and dA/dtmax of risedronate were within the bioequivalence range (80.00-125.00% for Ae72h and dA/dtmax). It was concluded that the 2 risedronate sodium film-coated tablets (test and reference drugs) were bioequivalent.

  18. Pharmacokinetics of Ferric Pyrophosphate Citrate, a Novel Iron Salt, Administered Intravenously to Healthy Volunteers

    PubMed Central

    Swinkels, Dorine W.; Ikizler, T. Alp; Gupta, Ajay

    2016-01-01

    Abstract Ferric pyrophosphate citrate (Triferic) is a water‐soluble iron salt that is administered via dialysate to maintain iron balance and hemoglobin in hemodialysis patients. This double‐blind, randomized, placebo‐controlled, single‐, ascending‐dose study was conducted to evaluate the pharmacokinetics and safety of intravenous ferric pyrophosphate citrate in 48 healthy iron‐replete subjects (drug, n = 36; placebo, n = 12). Single doses of 2.5, 5.0, 7.5, or 10 mg of ferric pyrophosphate citrate or placebo were administered over 4 hours, and single doses of 15 or 20 mg of ferric pyrophosphate citrate or placebo were administered over 12 hours via intravenous infusion. Serum total iron (sFetot), transferrin‐bound iron (TBI), hepcidin‐25, and biomarkers of oxidative stress and inflammation were determined using validated assays. Marked diurnal variation in sFetot was observed in placebo‐treated subjects. Concentrations of sFetot and TBI increased rapidly after drug administration, with maximum serum concentrations (Cmax) reached at the end of infusion. Increases in baseline‐corrected Cmax and area under the concentration‐time curve from 0 to the time of the last quantifiable concentration (AUC0‐t) were dose proportional up to 100% transferrin saturation. Iron was rapidly cleared (apparent terminal phase half‐life 1.2‐2 hours). No significant changes from baseline in serum hepcidin‐25 concentration were observed at end of infusion for any dose. Biomarkers of oxidative stress and inflammation were unaffected. Intravenous doses of ferric pyrophosphate citrate were well tolerated. These results demonstrate that intravenous ferric pyrophosphate citrate is rapidly bound to transferrin and cleared from the circulation without increasing serum hepcidin levels or biomarkers of oxidative stress or inflammation. PMID:27557937

  19. A combined stress hormone infusion decreases in vivo protein synthesis in human T lymphocytes in healthy volunteers.

    PubMed

    Januszkiewicz, A; Essén, P; McNurlan, M A; Ringdén, O; Garlick, P J; Wernerman, J

    2001-11-01

    In vivo protein synthesis decreases in mononuclear cells following a combined stress hormone infusion given to healthy volunteers as a human trauma model. Here, the purpose was to further investigate this finding and to measure in vivo protein synthesis in isolated T lymphocytes. Furthermore, the effects of stress hormones on the lymphocyte subpopulations and mononuclear cells, characterized by flow cytometry and phytohemagglutinin (PHA)-induced and unstimulated proliferative responses in vitro, were elucidated. Healthy volunteers (n = 16) were randomized into 2 groups to receive either a stress hormone or a saline infusion for 6 hours. In vivo protein synthesis was studied before and after the treatment by measuring the incorporation of stable isotopically-labeled phenylalanine into lymphocyte and mononuclear cell proteins. Protein synthesis decreased after stress hormone infusion in both cell populations: in T lymphocytes from 13.0% +/- 0.7%/d (mean +/- SD) to 8.6% +/- 2.1%/d (P <.01) and in mononuclear cells from 13.3% +/- 1.2%/d to 6.3 +/- 2.0%/d (P <.001). No change in proliferative responsiveness in vitro was observed. The stress hormone infusion produced a decrease in the percentage of T helper CD3/CD4 from 41% to 18% (P <.001), T cytotoxic CD3/CD8 from 27% to 15% (P <.001), as well as total T CD3 cells from 69% to 35% (P <.001). There was an increase in the percentage of natural killer (NK) cells CD16/CD56 from 17% to 55% (P <.001). Determination of phenotypes expressed on activated T lymphocytes showed that CD3/HLA-DR was unchanged and CD3/CD25 decreased from 14% to 7% (P <.01) in the stress hormone group. The study showed that the decrease of in vivo protein synthesis was 34% in T lymphocytes as compared with 53% in mononuclear cells, when determined immediately after a 6-hour stress hormone infusion. This change was associated with a pronounced decrease in all lymphocyte subpopulations, except for the NK cells, which increased substantially.

  20. A new high-absorption-rate Paracetamol 500-mg formulation: a comparative bioavailability study in healthy volunteers

    PubMed Central

    Portolés, Antonio; Puerro, Miguel; Terleira, Ana; Rodríguez, Angel; Caturla, Maria-Cruz; Fernández, Nieves; Vargas, Emilio

    2003-01-01

    Background: Paracetamol is often the analgesic or antipyretic of choice, especially for patients for whom salicylates or other nonsteroidal anti-inflammatory drugs are contraindicated. Objective: The aim of this study was to compare the absorption rate of a new tablet formulation of paracetamol (500 mg) with a reference formulation of paracetamol at the same dose. Methods: This was a single-center, Phase I, open-label, randomized, 2-period, crossover, single-dose, comparative bioavailability clinical trial. During both study periods, healthy volunteers were given a single oral dose of a more hydrophilic test formulation of paracetamol, or a reference formulation. Fifteen plasma samples were obtained to determine paracetamol concentrations and to calculate kinetic parameters. Results: The study participants comprised 24 healthy volunteers (12 men, 12 women; mean [SD] age, 22.8 [1.5] years). The pharmacokinetic parameters calculated for the test versus the reference formulation were as follows: median time to maximum concentration (Tmax), 0.42 versus 0.75 hour; mean (SD) maximum plasma drug concentration (Cmax), 9.85 (2.40) μg/mL versus 8.33 (2.22) μg/mL; and mean (SD) area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞), 30.16 (8.87) μg·h/mL versus 28.49 (8.57) μg · h/mL. The 90% CIs of the ratios were as follows: base e logarithm (Ln)-transformed Cmax, 105.08% to 137.59%; Ln-AUC0–∞, 102.02% to 110.43%; and the difference in Tmax, −0.375 to −0.085 hours. Conclusions: The speed of release and absorption was statistically significantly higher with the test formulation compared with the reference one (evaluated using Tmax, Cmax, and Cmax/AUC parameters). This speed is especially important for a rapid analgesic or antipyretic effect. PMID:24944391

  1. Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers

    SciTech Connect

    Galtier, F.; Mura, T.; Raynaud de Mauverger, E.; Chevassus, H.; Farret, A.; Gagnol, J.-P.; Costa, F.; Dupuy, A.; and others

    2012-09-15

    Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca{sup 2+} homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca{sup 2+} spark properties were evaluated on a muscle biopsy 4 days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38 ± 5.68 vs − 1.15 ± 4.32 UI/L, P < 0.001) and CK (− 24.3 ± 99.1 ± 189.3vs 48.3 UI/L, P = 0.01) and a trend to an elevation of isoprostanes (193 ± 408 vs12 ± 53 pmol/mmol creatinine, P = 0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca{sup 2+} sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca{sup 2+} spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca{sup 2+} spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r = 0.71, P = 0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication. -- Highlights: ► Statin use may be limited by side effects, particularly myopathy. ► Statins might impair mitochondrial function and muscle Ca2+ signaling in muscle. ► This was tested among healthy volunteers receiving simvastatin 80 mg daily for 8 weeks. ► CK

  2. A Randomized Phase 1 Dose Escalation Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Trabodenoson in Healthy Adult Volunteers

    PubMed Central

    Laties, Alan; Rich, Cadmus C.; Stoltz, Randall; Humbert, Vernon; Brickman, Chaim; McVicar, William

    2016-01-01

    Abstract Purpose: To investigate the safety, tolerability, and pharmacokinetics of trabodenoson, a highly selective adenosine mimetic targeting the adenosine A1 receptor. Methods: In Part 1, 60 healthy adult volunteers were randomized to 14 days of twice-daily topical monocular application of placebo or trabodenoson (200, 400, 800, 1,600, 2,400, or 3,200 μg). In Part 2, 10 subjects were randomized to placebo or 8 escalating doses of bilateral trabodenoson (total daily doses: 1,800–6,400 μg). Results: The incidence of treatment-related adverse events in Part 1 was similar in the trabodenoson (27.8%) and placebo (25.0%) groups. Most were mild in intensity. The most common adverse events (AEs) for trabodenoson and placebo were headache (25.0% vs. 33%, respectively) and eye pain (11.1% vs. 4.2%, respectively). Ocular AEs were infrequent (16.7% and 17.9%, respectively), were self-limited, lasted <24 h, and were typically mild in intensity. The most common ocular AE was eye pain (9.5% and 3.6%, respectively), with a single observation of ocular hyperemia (200 μg trabodenoson). Trabodenoson was rapidly absorbed [median time to maximum concentration (tmax): ∼0.08 to 0.27 h] and eliminated (t½: 0.48–2.0 h), with no evidence of drug accumulation. Systemic exposure to topical trabodenoson was dose related but not dose proportional, with a plateau effect at doses ≥2,400 mg per eye. No clinically significant treatment-related systemic AEs were observed, and increasing systemic exposure had no effect on heart rate or blood pressure. Conclusions: Ocular doses of trabodenoson up to 3,200 μg per eye were safe and well tolerated in the eye and resulted in no detectable systemic effects in healthy adult volunteers. PMID:27046445

  3. Ethyl glucuronide concentrations in hair: a controlled alcohol-dosing study in healthy volunteers.

    PubMed

    L Crunelle, Cleo; Cappelle, Delphine; Yegles, Michel; De Doncker, Mireille; Michielsen, Peter; Dom, Geert; van Nuijs, Alexander L N; Maudens, Kristof E; Covaci, Adrian; Neels, Hugo

    2016-03-01

    Ethyl glucuronide (EtG) is a minor phase II metabolite of alcohol that accumulates in hair. It has been established as a sensitive marker to assess the retrospective consumption of alcohol over recent months using a cut-off of ≥7 pg/mg hair to assess repeated alcohol consumption. The primary aim was to assess whether amounts of alcohol consumed correlated with EtG concentrations in hair. Additionally, we investigated whether the current applied cut-off value of 7 pg/mg hair was adequate to assess the regular consumption of low-to-moderate amounts of alcohol. A prospective controlled alcohol-dosing study in 30 healthy individuals matched on age and gender. Individuals were instructed to drink no alcohol (N = 10), 100 g alcohol per week (N = 10) or 150 g alcohol per week (N = 10) for 12 consecutive weeks, before and after which hair was collected. Throughout the study, compliance to daily alcohol consumption was assessed by analyzing urine EtG three times weekly. Participants in the non-drinking group had median EtG concentrations of 0.5 pg/mg hair (interquartile range (IQR) 1.7 pg/mg; range < 0.21-4.5 pg/mg). Participants consuming 100 and 150 g alcohol per week showed median EtG concentrations of 5.6 pg/mg hair (IQR 4.7 pg/mg; range 2.0-9.8 pg/mg) and 11.3 pg/mg hair (IQR 5.0 pg/mg; range 7.7-38.9 pg/mg), respectively. Hair EtG concentrations between the three study groups differed significantly from one another (p < 0.001). Hair EtG concentrations can be used to differentiate between repeated (low-to-moderate) amounts of alcohol consumed over a long time period. For the assessment of repeated alcohol use, we propose that the current cut-off of 7 pg/mg could be re-evaluated.

  4. Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers

    PubMed Central

    Abel, Samantha; Russell, Deborah; Taylor-Worth, Richard J; Ridgway, Caroline E; Muirhead, Gary J

    2008-01-01

    Aims To evaluate the influence of cytochrome P450 (CYP) 3A4 inhibitors on the clinical pharmacokinetics of maraviroc, a novel CCR5 antagonist. Methods Four open-label, randomized, placebo-controlled studies were conducted in healthy subjects to assess the effect of separate and distinct combinations of CYP3A4 inhibitors on the steady-state pharmacokinetics of maraviroc. Study 1 was a two-way crossover study investigating the influence of saquinavir (SQV; 1200 mg t.i.d.) and ketoconazole (400 mg q.d.) on the pharmacokinetics of maraviroc (100 mg b.i.d.). All subjects received maraviroc for 7 days in both study periods. Cohort 1 subjects also received SQV or placebo and cohort 2 subjects also received ketoconazole or placebo. Study 2 was a parallel-group study including four treatment groups investigating the effects of ritonavir-boosted lopinavir (LPV/r; 400 mg/100 mg b.i.d.), ritonavir-boosted saquinavir (SQV/r; 1000 mg/100 mg b.i.d.), and low-dose ritonavir (RTV; 100 mg b.i.d.) on the steady-state pharmacokinetics of maraviroc (100 mg b.i.d.), and exploring whether maraviroc dose adjustment can compensate for interaction effects. Treatment lasted 28 days and comprised three distinct phases: (i) maraviroc alone on days 1–7; (ii) maraviroc + interactant on days 8–21; and (iii) maraviroc (adjusted dose) + interactant on days 22–28. Study 3 was a two-way crossover study investigating the effects of atazanavir (ATZ; 400 mg q.d.) and ritonavir-boosted atazanavir (ATZ/r; 300 mg/100 mg b.i.d.) on the pharmacokinetics of maraviroc (300 mg b.i.d.). All subjects received maraviroc on days 1–14 of both study periods. Subjects also received ATZ on days 1–7 and ATZ/r on days 8–14 of one treatment period, and placebo on days 1–14 of the other treatment period. Study 4 was a two-way crossover study investigating the effects of ritonavir-boosted tipranavir (TPV/r; 500 mg/200 mg b.i.d.) on the pharmacokinetics of maraviroc (150 mg b.i.d.). Subjects received maraviroc

  5. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran.

    PubMed

    Glund, Stephan; Moschetti, Viktoria; Norris, Stephen; Stangier, Joachim; Schmohl, Michael; van Ryn, Joanne; Lang, Benjamin; Ramael, Steven; Reilly, Paul

    2015-05-01

    Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.

  6. Acute effects of beer on endothelial function and haemodynamics: a single-blind, cross-over study in healthy volunteers

    PubMed Central

    Karatzi, Kalliopi; Rontoyanni, Victoria G.; Protogerou, Athanase D.; Georgoulia, Aggeliki; Xenos, Konstantinos; Chrysou, John; Sfikakis, Petros P.; Sidossis, Labros S.

    2015-01-01

    Objective Moderate consumption of beer is associated with lower cardiovascular (CV) risk. To explore the underlying mechanisms we studied the acute effects of the constituents of beer (alcohol and antioxidants), on established predictors of CV risk: endothelial function, aortic stiffness, pressure wave reflections and aortic pressure. Research Methods & Proceedures In a randomized, single – blind, cross - over study 17 healthy, non-smoking, volunteers (28.5±5.2 years and 24.4±2.5 BMI) consumed in 3 separate days, at least one week apart: a) 400 ml of beer & 400 ml water, b) 800 ml of dealcoholized beer (same amount of polyphenols), and c) 67 ml of vodka & 733 ml water (same amount of alcohol). Each time aortic stiffness (pulse wave velocity, pressure wave reflections (Aix), aortic and brachial pressure (Sphygmocor device) and endothelial function (brachial flow mediated dilatation) were assessed at fast and 1 and 2 hours postprandial. Results Aortic stiffness was significantly and similarly reduced by all 3 interventions. However, endothelial function was significantly improved only after beer consumption (average of 1.33%, CI 0.15-2.53). Although wave reflections were significantly reduced by all 3 interventions (average of beer: 9.1%, dealcoholized beer: 2.8%, vodka 8.5%, all CI within limits of significance), the reduction was higher after beer consumption compared todealcoholized beer (p=0.018). Pulse pressure amplification (i.e. brachial/aortic) was increased by all 3 test drinks. Conclusions Beer improves acutely parameters of arterial function and structure, in healthy non-smokers. This benefit seems to be mediated by the additive or synergistic effects of alcohol and anti-oxidants and merits further investigation. PMID:23810643

  7. Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa.

    PubMed

    Goole, J; Van Gansbeke, B; Pilcer, G; Deleuze, Ph; Blocklet, D; Goldman, S; Pandolfo, M; Vanderbist, F; Amighi, K

    2008-11-19

    In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.

  8. Development of a prolonged-release gastroretentive tablet formulation of ciprofloxacin hydrochloride: pharmacokinetic characterization in healthy human volunteers.

    PubMed

    Mostafavi, Abolfazl; Emami, Jaber; Varshosaz, Jaleh; Davies, Neal M; Rezazadeh, Mahboubeh

    2011-05-16

    The fluroquinolone anti-biotic ciprofloxacin is primarily dissolved and absorbed from the upper part of the GI tract. We, therefore, aimed to develop a prolonged release gastroretentive (GT) formulation of ciprofloxacin that could be administered once daily with a conventional tablet (CT). A variety of polymers and effervescent properties were utilized to optimize the desired disposition profile. Tablets were prepared by the direct compression technique and evaluated for physical properties, swelling, floating, and drug release. In vivo studies were also carried out on the optimized GT formulation and CT in healthy volunteers. A very sensitive and reliable HPLC method was developed to measure plasma concentration of ciprofloxacin. The duration of floating times were predominantly >24 h and floating lag times <20 s. The drug release mechanism followed zero order kinetics. C(max), T(max), and AUC(0-∞) of GT vs CT were 0.945±0.29 vs 2.1±0.46 μg/ml, 6.0±1.42 vs 1.42±0.59 h and 8.54±1.87 vs 9.45±2.12 μg/ml/h, respectively. Pharmacokinetic parameters indicate that the developed GT formulation extended the pharmacokinetic profile achieved with CT. The C(max)/MIC and AUC(0-∞)/MIC, which are indicative of eradication of pathogens, following co-administration of GT with CT were comparable to those of twice-daily administration of CT alone.

  9. Pattern Classification of Working Memory Networks Reveals Differential Effects of Methylphenidate, Atomoxetine, and Placebo in Healthy Volunteers

    PubMed Central

    Marquand, Andre F; De Simoni, Sara; O'Daly, Owen G; Williams, Steven CR; Mourão-Miranda, Janaina; Mehta, Mitul A

    2011-01-01

    Stimulant and non-stimulant drugs can reduce symptoms of attention deficit/hyperactivity disorder (ADHD). The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for ADHD treatment, but their differential effects on human brain function remain unclear. We combined event-related fMRI with multivariate pattern recognition to characterize the effects of MPH and ATX in healthy volunteers performing a rewarded working memory (WM) task. The effects of MPH and ATX on WM were strongly dependent on their behavioral context. During non-rewarded trials, only MPH could be discriminated from placebo (PLC), with MPH producing a similar activation pattern to reward. During rewarded trials both drugs produced the opposite effect to reward, that is, attenuating WM networks and enhancing task-related deactivations (TRDs) in regions consistent with the default mode network (DMN). The drugs could be directly discriminated during the delay component of rewarded trials: MPH produced greater activity in WM networks and ATX produced greater activity in the DMN. Our data provide evidence that: (1) MPH and ATX have prominent effects during rewarded WM in task-activated and -deactivated networks; (2) during the delay component of rewarded trials, MPH and ATX have opposing effects on activated and deactivated networks: MPH enhances TRDs more than ATX, whereas ATX attenuates WM networks more than MPH; and (3) MPH mimics reward during encoding. Thus, interactions between drug effects and motivational state are crucial in defining the effects of MPH and ATX. PMID:21346736

  10. In Vivo Tissue Pharmacokinetics of Carbon-11-Labeled Clozapine in Healthy Volunteers: A Positron Emission Tomography Study

    PubMed Central

    Park, HS; Kim, E; Moon, BS; Lim, NH; Lee, BC; Kim, SE

    2015-01-01

    We investigated clozapine (CLZ) tissue pharmacokinetics in vivo by using carbon-11-labeled CLZ (11C-CLZ) and positron emission tomography (PET). Eight healthy volunteers underwent 11C-CLZ studies wherein computed tomography image acquisition was followed by PET scans (whole-body, four; brain, four). After bolus intravenous 11C-CLZ injection, PET images were acquired at various timepoints for 2–3 hours. Tissue 11C-CLZ signals were plotted over time, and pharmacokinetic parameters were determined. High 11C-CLZ radioactivity was detected in the liver and brain, implying CLZ hepatic metabolism and efficient blood–brain barrier penetration. The urinary and hepatobiliary tracts were involved in 11C-CLZ excretion. Moderate to high radioactivity was observed in the dopaminergic and serotonergic receptor-rich brain regions, indicating CLZ binding to multiple receptor types. To our knowledge, this is the first study to report the determination of 11C-CLZ tissue pharmacokinetics in humans. PET using radiolabeled drugs can provide valuable information that could complement plasma pharmacokinetic data. PMID:26225256

  11. Response of in vivo protein synthesis in T lymphocytes and leucocytes to an endotoxin challenge in healthy volunteers

    PubMed Central

    Januszkiewicz, A; Loré, K; EsséN, P; Andersson, B; Mcnurlan, M A; Garlick, P J; RingdéN, O; Andersson, J; Wernerman, J

    2002-01-01

    In vivo determination of protein synthesis in immune cells reflects metabolic activity and immunological activation. An intravenous injection of endotoxin to healthy volunteers was used as a human sepsis model, and in vivo protein synthesis of T lymphocytes and leucocytes was measured. The results were related to plasma concentrations of selected cytokines, peripheral cell counts and subpopulations of immune cells. The subjects (n = 8 + 8) were randomized to an endotoxin (4 ng/kg) or a saline group. In vivo protein synthesis was determined twice: before and 1–2·5 h after the endotoxin/saline injection. Protein synthesis decreased in isolated T lymphocytes, but increased in leucocytes. Plasma levels of TNF-α, IL-8, IL-6, IL-1 ra and IL-10 were elevated, whereas IL-2 and IFN-γ, produced predominantly by T lymphocytes, did not change in response to endotoxin. Neutrophils increased, whereas lymphocytes and monocytes decreased 2·5 h after the endotoxin injection. Flow cytometry revealed a drop in total CD3+ T lymphocytes and CD56+ natural killer cells, accompanied by an increase in CD15+ granulocytes. In summary, in vivo protein synthesis decreased in T lymphocytes, while the total leucocyte population showed a concomitant increase immediately after the endotoxin challenge. The changes in protein synthesis were accompanied by alterations in immune cell subpopulations and in plasma cytokine levels. PMID:12390314

  12. Pharmacokinetics of colistin and colistimethate sodium after a single 80-mg intravenous dose of CMS in young healthy volunteers.

    PubMed

    Couet, W; Grégoire, N; Gobin, P; Saulnier, P J; Frasca, D; Marchand, S; Mimoz, O

    2011-06-01

    Colistin pharmacokinetics (PK) was investigated in young healthy volunteers after a 1-h infusion of 80 mg (1 million international units (MIU)) of the prodrug colistin methanesulfonate (CMS). Concentration levels of CMS and colistin were determined in plasma and urine using a new chromatographic assay and analyzed simultaneously with a population approach after correcting the urine-related data for postexcretion hydrolysis of CMS into colistin. CMS and colistin have low volumes of distribution (14.0 and 12.4 liters, respectively), consistent with distribution being restricted to extracellular fluid. CMS is mainly excreted unchanged in urine (70% on average), with a typical renal clearance estimated at 103 ml/min-close to the glomerular filtration rate. Colistin elimination is essentially extrarenal, given that its renal clearance is 1.9 ml/min, consistent with extensive reabsorption. Colistin elimination is not limited by the formation rate because its half-life (3 h) is longer than that of CMS. The values of these pharmacokinetic parameters will serve as reference points for future comparisons with patients' data.

  13. Omeprazole does not enhance the metabolism of phenacetin, a marker of CYP1A2 activity, in healthy volunteers.

    PubMed

    Xiaodong, S; Gatti, G; Bartoli, A; Cipolla, G; Crema, F; Perucca, E

    1994-06-01

    Omeprazole has been reported to increase cytochrome P450IA2 (CYP1A2) activity in vitro, but whether this effect also occurs in vivo is controversial. To clarify this issue, the effect of omeprazole (20 mg/day for 8 days) on the kinetics and metabolism of phenacetin, an in vivo marker of CYP1A2 activity, was examined in 10 healthy volunteers. The pharmacokinetic parameters of phenacetin and metabolically derived paracetamol on the 8th day of omeprazole administration were very similar to those observed in a control session in the absence of omeprazole administration, the only significant difference being a higher peak plasma phenacetin concentration during omeprazole treatment. It is concluded that at the dosage used omeprazole does not increase the rate of oxidative and conjugative reactions involved in the metabolism of phenacetin and paracetamol respectively. These data are consistent with the hypothesis that omeprazole is generally devoid of inducing effects on CYP1A2 activity in vivo, at least in a Caucasian population with a low prevalence of the omeprazole-mephenytoin poor metabolizer phenotype.

  14. Calcitonin Gene-Related Peptide Modulates Heat Nociception in the Human Brain - An fMRI Study in Healthy Volunteers

    PubMed Central

    Asghar, Mohammad Sohail; Becerra, Lino; Larsson, Henrik B. W.; Borsook, David; Ashina, Messoud

    2016-01-01

    Background Intravenous infusion of calcitonin-gene-related-peptide (CGRP) provokes headache and migraine in humans. Mechanisms underlying CGRP-induced headache are not fully clarified and it is unknown to what extent CGRP modulates nociceptive processing in the brain. To elucidate this we recorded blood-oxygenation-level-dependent (BOLD) signals in the brain by functional MRI after infusion of CGRP in a double-blind placebo-controlled crossover study of 27 healthy volunteers. BOLD-signals were recorded in response to noxious heat stimuli in the V1-area of the trigeminal nerve. In addition, we measured BOLD-signals after injection of sumatriptan (5-HT1B/1D antagonist). Results Brain activation to noxious heat stimuli following CGRP infusion compared to baseline resulted in increased BOLD-signal in insula and brainstem, and decreased BOLD-signal in the caudate nuclei, thalamus and cingulate cortex. Sumatriptan injection reversed these changes. Conclusion The changes in BOLD-signals in the brain after CGRP infusion suggests that systemic CGRP modulates nociceptive transmission in the trigeminal pain pathways in response to noxious heat stimuli. PMID:26990646

  15. The impact of multi-walled carbon nanotubes with different amount of metallic impurities on immunometabolic parameters in healthy volunteers.

    PubMed

    Vitkina, T I; Yankova, V I; Gvozdenko, T A; Kuznetsov, V L; Krasnikov, D V; Nazarenko, A V; Chaika, V V; Smagin, S V; Tsatsakis, A Μ; Engin, A B; Karakitsios, S P; Sarigiannis, D A; Golokhvast, K S

    2016-01-01

    The impact of two types of multi-walled carbon nanotubes (MWCNTs) (12-14 nm) with different content of metallic impurities (purified and unpurified nanotubes) on peroxidation processes, the status of immune cells in healthy volunteers and gene expression combined to pathway analysis was studied in vitro. From the study it was shown that the main mechanism of action for both types of MWCNTs is induction of oxidative stress, the intensity of which is directly related to the amount of metallic impurities. Unpurified MWCNTs produced twice as high levels of oxidation than the purified CNTs inducing thus more intense mitochondrial dysfunction. All the above were also verified by gene expression analysis of 2 different human cellular cultures (lung epithelium and keratinoma cells) and the respective pathway analysis; modulation of genes activating the NFkB pathway is associated to inflammatory responses. This may cause a perturbation in the IL-6 signaling pathway in order to regulate inflammatory processes and compensate for apoptotic changes. A plausible hypothesis for the immunological effects observed in vivo, are considered as the result of the synergistic effect of systemic (mediated by cells of the routes of exposure) and local inflammation (blood cells).

  16. Pharmacokinetic Profiles of Active Components After Oral Administration of a Kampo Medicine, Shakuyakukanzoto, to Healthy Adult Japanese Volunteers.

    PubMed

    Sadakane, Chiharu; Watanabe, Junko; Fukutake, Miwako; Nisimura, Hiroaki; Maemura, Kazuya; Kase, Yoshio; Kono, Toru

    2015-11-01

    Shakuyakukanzoto (SKT), a traditional Japanese (Kampo) medicine, has been used by patients with muscle cramps and abdominal pains. In this trial, we analyzed plasma concentrations of active components after SKT was administered as a single oral dose of 2.5 or 5.0 g/day per person. The study was a randomized, open-label, two-arm, two-period, crossover trial conducted in healthy Japanese volunteers. Albiflorin (ALB), paeoniflorin (PAE), glycycoumarin (GCM), isoliquiritigenin (ILG), glycyrrhetic acid (GA), and glycyrrhetic acid-3-O-monoglucuronide were targeted, and the plasma concentration of each component was measured using a liquid chromatography-tandem mass spectrometry method. The pharmacokinetic parameters were calculated, and the linearity was assessed. All targeted components were detected in the plasma after oral administration of SKT. ALB, PAE, GCM, and ILG were detected at an early stage. The linearity was observed for the maximum plasma concentration of GCM, ILG, and GA and for the area under the plasma concentration-time curve of GA. In this trial, we demonstrated for the first time in humans that these components were absorbed into the blood after oral administration of SKT. The results of this pharmacokinetic trial in humans are also important and useful for understanding the mechanism of action of SKT, verifying the active components predicted in basic research, and conducting pharmacokinetics and safety studies in the future.

  17. Effect of acid secretion blockade by omeprazole on the relative bioavailability of orally administered furazolidone in healthy volunteers

    PubMed Central

    Calafatti, Silvana A; Ortiz, Rodrigo A M; Deguer, Maristela; Martinez, Márcio; Pedrazzoli, José

    2001-01-01

    Aims The administration of omeprazole may interfere with the absorption of orally administered drugs by reducing gastric pH and hence tablet dissolution. The aim of this study was to investigate the effects of a 5 day administration of omeprazole on the pharmacokinetics of furazolidone. Methods Eighteen healthy (nine male and nine female) volunteers were selected. The study had an open randomized two-period crossover design with a 21 day washout period between the phases. Serum concentrations of furazolidone were measured by reversed-phase h.p.l.c. with ultraviolet detection. Results Administration of omeprazole caused a significant reduction of Cmax [0.34 µg ml−1 (range 0.25–0.43) vs 0.24 µg ml−1 (range 0.15–0.34)] with no significant delay in absorption tmax [2.5 h (range 1.85–3.0) vs 2.4 h (range 2.06–2.71)]. Conclusions Furazolidone was rapidly absorbed after oral administration. Short-term treatment with omeprazole did alter the relative bioavailability of this drug, probably through an effect on absorption kinetics or first-pass metabolism. PMID:11488780

  18. Bioequivalence evaluation of two roxithromycin formulations in healthy human volunteers by high performance liquid cromatography coupled to tandem mass spectrometry.

    PubMed

    Motta, M; Ribeiro, W; Ifa, D R; Moares, M E; Moraes, M O; Corrado, A P; De Nucci, G

    1999-01-01

    The bioequivalence of two different formulations containing roxithromycin (SPE-712-1). Oral suspension 300 mg/15 mL as test formulation and Rotram, tablets 300 mg as reference formulation, both by Schering Plough S.A., Brazil) was evaluated in 24 healthy volunteers of both sexes (12 male and 12 female). The study was conducted open with randomized two-period crossover design and a 14-day washout period. Each subject received 300 mg of each roxithromycin formulation. Plasma samples were obtained over a 72-hour interval and roxithromycin concentrations were analyzed by combined LC-MS/MS with positive ion electrospray ionization using selected ion monitoring method. From the plasma roxithromycin concentration vs time curves the following pharmacokinetic parameters were obtained: AUC(0-72 h), AUC(0-infinity), Cmax, t1/2 ratios and tmax individual differences. The 90% for confidence interval (CI) of geometric mean SPE-712-L/Rotram individual percent ratio were 105.0-128.3% for AUC(0-72 h), and 78.4-96.9 for Cmax. Although this 90% CI were marginally outside the interval proposed by the Food and Drug Administration, the probability assessed by the two-one sided West for ratios was included in the 0.8-1.25 interval, as we concluded that SPE-712-L oral suspension formulation was bioequivalent to Rotram tablet formulation for the extent and rate of absorption.

  19. Non-invasive determination of respiratory effort in spontaneous breathing and support ventilation: a validation study with healthy volunteers.

    PubMed

    Lopez-Navas, Kristel; Brandt, Sebastian; Strutz, Merle; Gehring, Hartmut; Wenkebach, Ullrich

    2014-08-01

    The proper setting of support ventilation aims to follow the patients' demands, ensuring adequate assistance to their respiratory effort. Effort assessment is thus necessary. But invasive procedures like measuring transdiaphragmatic pressure (Pdi) are impractical in long-term ventilation. Our purpose was therefore the development of the Occlusion+Delta (O+D) method for non-invasive continuous assessment of effort, quantified by the inspiratory pressure-time-product (PTPinsp), during ventilatory support. Flow and airway pressure were measured from 25 healthy volunteers at three effort levels. For the non-invasive method, short expiratory occlusions were executed each three to seven cycles to estimate resistance and compliance with a fitting algorithm fed with the differences between occluded and undisturbed cycles. Signals and estimates were then used to calculate the effort. For the validation of O+D, its estimations were compared to the results from invasive measurement of Pdi using balloon catheters. The agreement between PTPinsp from the invasive measurement and the proposed alternative was confirmed by regression analysis (PTP(O+D)=1.13PTP(Pdi)- 0.85, R²=0.84) and calculation of their differences (mean±SD=1.78±7.18 cm H2O s). Repeated execution of the non-invasive O+D method facilitates a safe automatic assessment of respiratory mechanics and breathing effort, promoting the rapid recognition of changes in patient's demands and the adaptation of support.

  20. The Effect of Chronic Alprazolam Intake on Memory, Attention, and Psychomotor Performance in Healthy Human Male Volunteers.

    PubMed

    Chowdhury, Zahid Sadek; Morshed, Mohammed Monzur; Shahriar, Mohammad; Bhuiyan, Mohiuddin Ahmed; Islam, Sardar Mohd Ashraful; Bin Sayeed, Muhammad Shahdaat

    2016-01-01

    Alprazolam is used as an anxiolytic drug for generalized anxiety disorder and it has been reported to produce sedation and anterograde amnesia. In the current study, we randomly divided 26 healthy male volunteers into two groups: one group taking alprazolam 0.5 mg and the other taking placebo daily for two weeks. We utilized the Cambridge Neuropsychological Test Automated Battery (CANTAB) software to assess the chronic effect of alprazolam. We selected Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) tests for memory, Rapid Visual Information Processing (RVP) for attention, and Choice Reaction Time (CRT) for psychomotor performance twice: before starting the treatment and after the completion of the treatment. We found statistically significant impairment of visual memory in one parameter of PAL and three parameters of DMS in alprazolam group. The PAL mean trial to success and total correct matching in 0-second delay, 4-second delay, and all delay situation of DMS were impaired in alprazolam group. RVP total hits after two weeks of alprazolam treatment were improved in alprazolam group. But such differences were not observed in placebo group. In our study, we found that chronic administration of alprazolam affects memory but attentive and psychomotor performance remained unaffected.

  1. Closed and open breathing circuit function in healthy volunteers during exercise at Mount Everest base camp (5300 m).

    PubMed

    McMorrow, R C N; Windsor, J S; Hart, N D; Richards, P; Rodway, G W; Ahuja, V Y; O'Dwyer, M J; Mythen, M G; Grocott, M P W

    2012-08-01

    We present a randomised, controlled, crossover trial of the Caudwell Xtreme Everest (CXE) closed circuit breathing system vs an open circuit and ambient air control in six healthy, hypoxic volunteers at rest and exercise at Everest Base Camp, at 5300 m. Compared with control, arterial oxygen saturations were improved at rest with both circuits. There was no difference in the magnitude of this improvement as both circuits restored median (IQR [range]) saturation from 75%, (69.5-78.9 [68-80]%) to > 99.8% (p = 0.028). During exercise, the CXE closed circuit improved median (IQR [range]) saturation from a baseline of 70.8% (63.8-74.5 [57-76]%) to 98.8% (96.5-100 [95-100]%) vs the open circuit improvement to 87.5%, (84.1-88.6 [82-89]%; p = 0.028). These data demonstrate the inverse relationship between supply and demand with open circuits and suggest that ambulatory closed circuits may offer twin advantages of supplying higher inspired oxygen concentrations and/or economy of gas use for exercising hypoxic adults.

  2. Whole-Brain In-vivo Measurements of the Axonal G-Ratio in a Group of 37 Healthy Volunteers

    PubMed Central

    Mohammadi, Siawoosh; Carey, Daniel; Dick, Fred; Diedrichsen, Joern; Sereno, Martin I.; Reisert, Marco; Callaghan, Martina F.; Weiskopf, Nikolaus

    2015-01-01

    The g-ratio, quantifying the ratio between the inner and outer diameters of a fiber, is an important microstructural characteristic of fiber pathways and is functionally related to conduction velocity. We introduce a novel method for estimating the MR g-ratio non-invasively across the whole brain using high-fidelity magnetization transfer (MT) imaging and single-shell diffusion MRI. These methods enabled us to map the MR g-ratio in vivo across the brain's prominent fiber pathways in a group of 37 healthy volunteers and to estimate the inter-subject variability. Effective correction of susceptibility-related distortion artifacts was essential before combining the MT and diffusion data, in order to reduce partial volume and edge artifacts. The MR g-ratio is in good qualitative agreement with histological findings despite the different resolution and spatial coverage of MRI and histology. The MR g-ratio holds promise as an important non-invasive biomarker due to its microstructural and functional relevance in neurodegeneration. PMID:26640427

  3. Response of in vivo protein synthesis in T lymphocytes and leucocytes to an endotoxin challenge in healthy volunteers.

    PubMed

    Januszkiewicz, A; Loré, K; Essén, P; Andersson, B; McNurlan, M A; Garlick, P J; Ringdén, O; Andersson, J; Wernerman, J

    2002-11-01

    In vivo determination of protein synthesis in immune cells reflects metabolic activity and immunological activation. An intravenous injection of endotoxin to healthy volunteers was used as a human sepsis model, and in vivo protein synthesis of T lymphocytes and leucocytes was measured. The results were related to plasma concentrations of selected cytokines, peripheral cell counts and subpopulations of immune cells. The subjects (n = 8 + 8) were randomized to an endotoxin (4 ng/kg) or a saline group. In vivo protein synthesis was determined twice: before and 1-2.5 h after the endotoxin/saline injection. Protein synthesis decreased in isolated T lymphocytes, but increased in leucocytes. Plasma levels of TNF-alpha, IL-8, IL-6, IL-1 ra and IL-10 were elevated, whereas IL-2 and IFN-gamma, produced predominantly by T lymphocytes, did not change in response to endotoxin. Neutrophils increased, whereas lymphocytes and monocytes decreased 2.5 h after the endotoxin injection. Flow cytometry revealed a drop in total CD3+ T lymphocytes and CD56+ natural killer cells, accompanied by an increase in CD15+ granulocytes. In summary, in vivo protein synthesis decreased in T lymphocytes, while the total leucocyte population showed a concomitant increase immediately after the endotoxin challenge. The changes in protein synthesis were accompanied by alterations in immune cell subpopulations and in plasma cytokine levels.

  4. Effects of four different meal types on the population pharmacokinetics of single-dose rifapentine in healthy male volunteers.

    PubMed

    Zvada, Simbarashe P; Van Der Walt, Jan-Stefan; Smith, Peter J; Fourie, P Bernard; Roscigno, Giorgio; Mitchison, Denis; Simonsson, Ulrika S H; McIlleron, Helen M

    2010-08-01

    Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.

  5. Evaluation of the ease of taking mini-tablets compared with other tablet formulations in healthy volunteers.

    PubMed

    Hayakawa, Yoshiyuki; Uchida, Shinya; Namiki, Noriyuki

    2016-03-10

    "Mini-tablets" (MTs) are tablets of diameter≤3mm and have been widely studied and developed. However, reports comparing MTs with other tablet formulations are few. We wished to evaluate the ease of taking a MT quantitatively in comparison with an orally disintegrating mini-tablet (ODMT), conventional tablet (CT) and conventional orally disintegrating tablet (ODT). Four types of tablets were prepared. We prepared tablets of two diameters (3mm for MTs and ODMTs vs. 8mm for CTs and ODTs) and two formulations (MTs and CTs vs. ODMTs and ODTs). Our randomized crossover trial in 18 healthy volunteers (8 men and 10 women; mean age, 22.5years) indicated that the visual analog scale (VAS) score for the ease and amount of water required for intake of MTs was significantly lower than those of CTs. An ODMT required the least amount of water and smallest VAS score for the ease of taking a tablet. Our results showed that the advantage of MTs with regard to the ease of taking and decreased amount of water required was exerted for a unit of dosing comprising <5 tablets. These data suggested the usefulness of MTs and the importance of the number of MTs for comfortable consumption by patients.

  6. The Effect of Chronic Alprazolam Intake on Memory, Attention, and Psychomotor Performance in Healthy Human Male Volunteers

    PubMed Central

    Chowdhury, Zahid Sadek; Morshed, Mohammed Monzur; Shahriar, Mohammad; Bhuiyan, Mohiuddin Ahmed; Islam, Sardar Mohd. Ashraful

    2016-01-01

    Alprazolam is used as an anxiolytic drug for generalized anxiety disorder and it has been reported to produce sedation and anterograde amnesia. In the current study, we randomly divided 26 healthy male volunteers into two groups: one group taking alprazolam 0.5 mg and the other taking placebo daily for two weeks. We utilized the Cambridge Neuropsychological Test Automated Battery (CANTAB) software to assess the chronic effect of alprazolam. We selected Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) tests for memory, Rapid Visual Information Processing (RVP) for attention, and Choice Reaction Time (CRT) for psychomotor performance twice: before starting the treatment and after the completion of the treatment. We found statistically significant impairment of visual memory in one parameter of PAL and three parameters of DMS in alprazolam group. The PAL mean trial to success and total correct matching in 0-second delay, 4-second delay, and all delay situation of DMS were impaired in alprazolam group. RVP total hits after two weeks of alprazolam treatment were improved in alprazolam group. But such differences were not observed in placebo group. In our study, we found that chronic administration of alprazolam affects memory but attentive and psychomotor performance remained unaffected. PMID:27462136

  7. Caffeine in sport. Urinary excretion of caffeine in healthy volunteers after intake of common caffeine-containing beverages.

    PubMed

    van der Merwe, P J; Müller, F R; Müller, F O

    1988-08-20

    The presence of a concentration of caffeine greater than or equal to 15 micrograms/ml in urine of athletes participating in competitive sport is a disqualifying factor. A study was conducted to establish how much caffeine needs to be ingested--in the form of coffee, tea or Coca-Cola--to approach or exceed this limit. Nine healthy volunteers participated in a randomised cross-over study and received caffeine in the form of these beverages, ingested within 15 minutes, in doses ranging from 1.52 mg/kg to 17.53 mg/kg. The latter dose is equivalent to nearly 8 cups of ordinary percolated coffee. The maximum caffeine concentration in urine recorded was 14 micrograms/ml, 3 hours after ingestion. A significant correlation was found between the caffeine dose and the maximum urinary concentration. The mean recovery of caffeine in urine was between 0.74% and 0.91% of the administered dose. The nature of the beverage did not appear to influence the degree of caffeine excretion. It is concluded that if a concentration of 15 micrograms caffeine/ml urine is recorded, it can safely be accepted that the athlete purposely ingested large amounts of the substance, in whatever form.

  8. Effects of chromosomal variations on pharmacokinetic activity of zolpidem in healthy volunteers: an array-based comparative genomic hybridization study.

    PubMed

    Moon, Ho-Jin; Choi, Jin Soo; Park, E-Jin; Kang, Chin-Yang; Jeon, Yang-Whan; Lee, Kweon-Haeng; Rha, Hyoung Kyun; Han, Sang-Ick

    2007-05-18

    Zolpidem has been known as a very safe and effective hypnotic drug used to treat a variety of patients with insomnia. Even though the same dose of the medicine is administered to each patient, the blood level of zolpidem and the time required to obtain peak concentration are not consistent among different people. We evaluated the relationship between the peak concentrations of zolpidem and chromosomal imbalances using a high-resolution genome-wide array-based comparative genomic hybridization (CGH) in 16 healthy volunteers in order to detect the genetic factors underlying the variations. The present study showed that chromosomal losses were detected in the 4q35.2, 9p13.1 and 9p12 regions, and those gains were indicated in the 2p14, 11q13.4 and 15q11.2 regions. The abnormal regions were confirmed by fluorescence in situ hybridization (FISH) and real-time PCR. It is suggested that array-CGH analysis may be used as a measure for pharmacogenomic applications in the patients with insomnia and for further exploration of candidate genomic regions implicated in sleep disturbances.

  9. Fluorescence detection of tramadol in healthy Chinese volunteers by high-performance liquid chromatography and bioequivalence assessment.

    PubMed

    Zhou, Xiao; Liu, Ji

    2015-01-01

    This study developed a revised high-performance liquid chromatography fluorescence method to determine plasma tramadol concentration, and thereby to examine the bioequivalence of two tramadol formulations among healthy male Chinese volunteers. The study used a double-blind, randomized, 2×2 crossover-design principle. Calculated pharmacokinetic parameters for both formulations were consistent with previous reports. According to the observation of vital signs and laboratory measurement, no subjects had any adverse reactions. The geometric mean ratios (90% confidence interval) of the test drug/reference drug for tramadol were 100.2% (95.3%-103.4%) for the area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration, 99.6% (94.2%-102.7%) for the AUC from administration to infinite time, and 100.8% (93.1%-106.4%) for maximum concentration. For the 90% confidence intervals of the test/reference AUC ratio and maximum concentration ratio of tramadol, both were in the acceptance range for bioequivalence. According to the two preparations by pharmacokinetic parameter statistics, the half-life, mean residence time, and clearance values showed no significant statistical differences. Therefore, the conclusion of this study was that the two tramadol formulations (tablets and capsules) were bioequivalent.

  10. Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers.

    PubMed

    Frey, Reiner; Mück, Wolfgang; Unger, Sigrun; Artmeier-Brandt, Ulrike; Weimann, Gerrit; Wensing, Georg

    2008-12-01

    Preclinical data indicate that the nitric oxide-independent soluble guanylate cyclase activator cinaciguat (BAY 58-2667), which is a new drug in development for patients with heart failure, induces vasodilation preferentially in diseased vessels. This study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat. Seventy-six healthy volunteers were included in this randomized, placebo-controlled study. Cinaciguat (50-250 microg/h) was administered intravenously for up to 4 hours in a maximum of 6 individuals per dose group. No serious adverse events were reported. Four-hour infusions (50-250 microg/h) decreased diastolic blood pressure and increased heart rate (all P values < .05) versus placebo, without significantly reducing systolic blood pressure (P between 0.07 and 0.56). At higher doses (150-250 microg/h), 4-hour infusions decreased mean arterial pressure and increased plasma cyclic guanosine monophosphate levels (all P values < .05). Pharmacokinetics showed dose-proportionality with low interindividual variability. Plasma concentrations declined below 1.0 microg/L within 30 minutes of cessation of infusion. Cinaciguat had potent cardiovascular effects reducing preload and afterload, warranting further investigation in patients with heart failure.

  11. A randomized placebo controlled trial to evaluate the effects of butamirate and dextromethorphan on capsaicin induced cough in healthy volunteers

    PubMed Central

    Faruqi, Shoaib; Wright, Caroline; Thompson, Rachel; Morice, Alyn H

    2014-01-01

    Aims The examination of cough reflex sensitivity through inhalational challenge can be utilized to demonstrate pharmacological end points. Here we compare the effect of butamirate, dextromethorphan and placebo on capsaicin-induced cough in healthy volunteers. Methods In this randomized, placebo-controlled, six way crossover study the effect of dextromethrophan 30 mg, four doses of butamirate and placebo was evaluated on incremental capsaicin challenges performed at baseline and 2, 4, 6, 8, 12 and 24 h following dosing. The primary end point was the area under the curve (AUC(0,12h)) of log10 C5 from pre-dose to 12 h after dosing. Plasma butamirate metabolites were analyzed to evaluate pharmacokinetic and pharmacodynamic relationships. Results Thirty-four subjects (13 males, median age 25 years) completed the study. Cough sensitivity decreased from baseline in all arms of the study. Dextromethorphan was superior to placebo (P = 0.01) but butamirate failed to show significant activity with maximum attenuation at the 45 mg dose. There was no apparent relationship between pharmacokinetic and pharmacodynamic parameters for butamirate. Conclusions We have demonstrated for the first time that dextromethorphan attenuates capsaicin challenge confirming its broad activity on the cough reflex. The lack of efficacy of butamirate could be due to formulation issues at higher doses. PMID:24995954

  12. The effect of a first-generation H1-antihistamine on postural control: a preliminary study in healthy volunteers.

    PubMed

    Chihara, Yasuhiro; Sato, Ayako; Ohtani, Michiteru; Fujimoto, Chisato; Hayashi, Takahiro; Nishijima, Hironobu; Yagi, Masato; Iwasaki, Shinichi

    2013-11-01

    First-generation H1-antihistamines are known to cause fatigue and drowsiness, due to their poor receptor selectivity and their high penetration rate of the blood-brain barrier. However, little is known about the effects of first-generation H1-antihistamines on postural stability. The purpose of this study was to evaluate the effects of d-chlorpheniramine on postural stability using posturography with and without foam rubber. A double-blind study with three parallel groups was conducted. Twenty-seven healthy young volunteers (mean age 21.9 years) were recruited and orally administered d-chlorpheniramine, 2 or 4 mg, or placebo. Postural sway was measured every hour up to 8 h after administration. Two-legged stance tasks were performed by each subject in four conditions: eyes open or eyes closed and with or without foam rubber. Inter-group comparisons showed that the group receiving 4-mg d-chlorpheniramine showed significantly larger sway in the eyes open with foam rubber condition (visual and vestibular information available, somatosensory information reduced). Inter-subject analysis in the 4-mg d-chlorpheniramine group showed that the effect of d-chlorpheniramine on postural control was variable. Our results suggest that among the three main sensory systems responsible for postural control (visual, vestibular, and somatosensory), d-chlorpheniramine may have a larger effect on the visual and/or vestibular systems in susceptible individuals.

  13. The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine ('Ecstasy') in healthy volunteers.

    PubMed

    Liechti, M E; Vollenweider, F X

    2000-01-01

    MDMA (3,4-methylenedioxymethamphetamine) or 'Ecstasy' is a widely used recreational drug that produces a state of heightened mood but also cardiovascular and vegetative side-effects. In animals, MDMA releases serotonin and, to a lesser extent, dopamine and norepinephrine. The release of serotonin can be blocked by serotonin uptake inhibitors such as citalopram. It is unknown to what extent this mechanism is also responsible for the physiological side-effects of MDMA seen in humans. We investigated the effect of citalopram pretreatment (40 mg i.v.) on vegetative and cardiovascular effects of MDMA (1.5 mg/kg p.o.) in a double-blind placebo-controlled study in 16 healthy volunteers. MDMA moderately increased blood pressure and heart rate, slightly elevated body temperature and produced a broad range of acute and short-term side-effects. Citalopram reduced all these MDMA-induced physiological changes except for body temperature. These findings suggest that physiological effects of MDMA in humans are partially due to an interaction of MDMA with the serotonin carrier and a subsequent release of serotonin.

  14. Systemic and Mucosal Immune Responses to Sublingual or Intramuscular Human Papilloma Virus Antigens in Healthy Female Volunteers

    PubMed Central

    Giemza, Raphaela; Beddows, Simon; Oeser, Clarissa; Lewis, David J. M.

    2012-01-01

    The sublingual route has been proposed as a needle-free option to induce systemic and mucosal immune protection against viral infections. In a translational study of systemic and mucosal humoral immune responses to sublingual or systemically administered viral antigens, eighteen healthy female volunteers aged 19–31 years received three immunizations with a quadravalent Human Papilloma Virus vaccine at 0, 4 and 16 weeks as sublingual drops (SL, n = 12) or intramuscular injection (IM, n = 6). IM antigen delivery induced or boosted HPV-specific serum IgG and pseudovirus-neutralizing antibodies, HPV-specific cervical and vaginal IgG, and elicited circulating IgG and IgA antibody secreting cells. SL antigens induced ∼38-fold lower serum and ∼2-fold lower cervical/vaginal IgG than IM delivery, and induced or boosted serum virus neutralizing antibody in only 3/12 subjects. Neither route reproducibly induced HPV-specific mucosal IgA. Alternative delivery systems and adjuvants will be required to enhance and evaluate immune responses following sublingual immunization in humans. Trial Registration ClinicalTrials.gov NCT00949572 PMID:22438987

  15. Validation of indirect calorimetry for measurement of energy expenditure in healthy volunteers undergoing pressure controlled non-invasive ventilation support.

    PubMed

    Siirala, Waltteri; Noponen, Tommi; Olkkola, Klaus T; Vuori, Arno; Koivisto, Mari; Hurme, Saija; Aantaa, Riku

    2012-02-01

    The aim of this validation study was to assess the reliability of gas exchange measurement with indirect calorimetry among subjects who undergo non-invasive ventilation (NIV). Oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured in twelve healthy volunteers. Respiratory quotient (RQ) and resting energy expenditure (REE) were then calculated from the measured VO2 and VCO2 values. During the measurement period the subjects were breathing spontaneously and ventilated using NIV. Two different sampling air flow values 40 and 80 l/min were used. The gas leakage from the measurement setup was assessed with a separate capnograph. The mean weight of the subjects was 93 kg. Their mean body mass index was 29 (range 22-40) kg/m2. There was no statistically significant difference in the measured values for VO2, VCO2, RQ and REE during NIV-supported breathing and spontaneous breathing. The change of sampling air flow had no statistically significant effect on any of the above parameters. We found that REE can be accurately measured with an indirect calorimeter also during NIV-supported breathing and the change of sampling air flow does not distort the gas exchange measurement. A higher sampling air flow in indirect calorimetry decreases the possibility for air leakages in the measurement system and increases the reliability of REE measurement.

  16. Omeprazole impairs the absorption of mycophenolate mofetil but not of enteric-coated mycophenolate sodium in healthy volunteers.

    PubMed

    Kees, M G; Steinke, T; Moritz, S; Rupprecht, K; Paulus, E M; Kees, F; Bucher, M; Faerber, L

    2012-08-01

    In 2 crossover studies, 12 healthy volunteers (6 male/6 female) received a single oral dose of mycophenolate mofetil (MMF) 1000 mg or an equimolar dose of enteric-coated mycophenolate sodium (EC-MPS) 720 mg fasting with and without coadministered omeprazole 20 mg bid. The plasma concentrations of mycophenolic acid (MPA) and of the inactive metabolite mycophenolic acid glucuronide (MPA-G) were measured by high-performance liquid chromatography (HPLC). In addition, dissolution of MMF 500 mg or EC-MPS 360 mg tablets was determined using an USP paddle apparatus in aqueous buffer of pH 1 to 7. The bioavailability of MPA following administration of MMF or EC-MPS was similar except for the time to peak concentration, which was longer in the EC-MPS group. Concomitant treatment with omeprazole lowered significantly C(max) and AUC(12h) of MPA following administration of MMF. The pharmacokinetics of EC-MPS was not affected. Dissolution of MMF in aqueous buffer decreased dramatically at pH above 4.5. The EC-MPS tablet was stable up to pH 5. Above, EC-MPS was quantitatively disintegrated and MPS quantitatively dissolved. There is strong evidence that impaired absorption of MMF with concomitant proton pump inhibitors is due to incomplete dissolution of MMF in the stomach at elevated pH.

  17. Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers

    PubMed Central

    van Rongen, A; Kervezee, L; Brill, MJE; van Meir, H; den Hartigh, J; Guchelaar, H-J; Meijer, JH; Burggraaf, J; van Oosterhout, F

    2015-01-01

    Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24-hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24-hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24-hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24-hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes. PMID:26380154

  18. Pentagastrin-induced hemoconcentration in healthy volunteers and patients with panic disorder: effect of pretreatment with ethinyl estradiol.

    PubMed

    Le Melledo, Jean Michel; Perez-Parada, Jorge; Morrow, Jarret; Bellavance, Francois; Lara, Nathalie; Jahandar, Farideh; Granger, Robert; Tait, Glendon; McManus, Karen

    2011-01-01

    Panic disorder has been associated with both an increased risk of coronary events as well as an increased risk of stroke. Hemoconcentration, with both a decrease in plasma volume and an increase in plasma viscosity, is a possible contributor to the risk of acute ischemic events. Our objectives were to demonstrate the process of hemoconcentration in response to induced panic symptoms and to assess the effect of pretreatment with ethinyl estradiol on panic-induced hemoconcentration. Fifteen male patients with panic disorder and 10 male healthy volunteers were included in a double-blind cross-over placebo-controlled design consisting of two injections of pentagastrin following randomized pretreatment with placebo and ethinyl estradiol. Plasma levels of hematocrit and hemoglobin were assessed at baseline and post-injections, and used to calculate an indirect estimation of the change in plasma volume. Pentagastrin-induced panic symptoms were associated with a mean decrease in plasma volume of 4.8% in the placebo pretreatment condition. Pretreatment with ethinyl estradiol attenuated this effect. The acute hemoconcentration observed in relation to pentagastrin-induced panic symptoms may be relevant to the increased risk of stroke and acute coronary events found in patients with panic disorder.

  19. Pharmacological experiments in healthy volunteers with bopindolol, a long-acting beta-adrenoceptor blocking drug with partial agonist activity.

    PubMed Central

    Aellig, W H

    1985-01-01

    Bopindolol is a potent and specific beta-adrenoceptor antagonist with partial agonist activity. In animal experiments it blocks both beta 1- and beta 2-adrenoceptors and possesses a long duration of action. In the present study in healthy volunteers bopindolol was about ten times more potent than pindolol in reducing isoprenaline-induced and exercise-induced tachycardia. In experiments on exercise-induced tachycardia an oral dose of 2 mg produced a near maximum reduction of exercise heart rate, occurring within 2 to 3 h of administration. With higher doses (up to 12 mg) the maximum effect was reached earlier (between 1 and 2 h). The long duration of action of bopindolol observed in animal studies was confirmed in man. Twenty-four hours after 4 and 10 mg bopindolol more than 2/3 of the maximum effect was still present. After 48 h 38% of the maximum effect of 4 mg and 50% of that of 12 mg remained. Even at 72 and 96 h exercise-induced tachycardia was still significantly lowered after both doses of the drug. When bopindolol was administered once daily for 5 days there was a slight increase in the maximum reduction of exercise-induced tachycardia during treatment with 1 mg/day but not with 4 mg/day, which produced a near maximum effect. PMID:2862891

  20. Pharmacokinetics of Ganoderic Acids A and F after Oral Administration of Ling Zhi Preparation in Healthy Male Volunteers

    PubMed Central

    Teekachunhatean, Supanimit; Sadja, Sasinun; Ampasavate, Chadarat; Chiranthanut, Natthakarn; Rojanasthien, Noppamas; Sangdee, Chaichan

    2012-01-01

    The objectives of this paper were to evaluate the pharmacokinetics of ganoderic acids A and F after a single oral dose of the water extract of MG2-strain Ling Zhi (MG2FB-WE) and to assess the influence of food on the pharmacokinetics in 12 healthy male volunteers. This study was a single-dose, open-label, randomized, two-phase crossover study with at least 2 wk washout period. Each subject was randomly assigned to receive a single oral dose of 3,000 mg of MG2FB-WE in granular formulation dissolved in 200 mL of warm water, either under a fasting condition, or immediately after a standard breakfast (fed condition). Blood samples were collected immediately before and at specific time points until 8 h after MG2FB-WE administration. Plasma ganoderic acids A and F concentrations were determined by using liquid chromatography-mass spectrometry (LC-MS) technique. In conclusion, the pharmacokinetic profile of both ganoderic acids under a fasting condition was characterized by rapid absorption from the gastrointestinal tract (Tmax at approximately 30 min) and a short elimination half-life (<40 min). Food significantly decreased Cmax and delayed Tmax, but did not affect the extent of ganoderic acid A absorption. However, concomitant food intake markedly impeded both rate and extent of ganoderic acid F absorption. PMID:22577465

  1. Heschl's gyrification pattern is related to speech-listening hemispheric lateralization: FMRI investigation in 281 healthy volunteers.

    PubMed

    Tzourio-Mazoyer, N; Marie, D; Zago, L; Jobard, G; Perchey, G; Leroux, G; Mellet, E; Joliot, M; Crivello, F; Petit, L; Mazoyer, B

    2015-01-01

    This study investigates the structure-function relationships between the anatomy of Heschl's gyri (HG) and speech hemispheric lateralization in 281 healthy volunteers (135 left-handers). Hemispheric lateralization indices (HFLIs) were calculated with Wilke's method from the activations obtained via functional magnetic resonance imaging while listening to lists of words (LIST). The mean HFLI during LIST was rightward asymmetrical, and left-handers displayed a trend toward decreased rightward asymmetry. The correlations between LIST BOLD contrast maps and individual HFLIs demonstrated that among the cortical areas showing significant asymmetry during LIST, only phonological regions explained HFLI variability. Significant positive correlations were present among the left HG, supramarginal gyri, and the anterior insula. Significant negative correlations occurred in the mid-part of the right superior temporal sulcus. Left HG had the largest functional activity during LIST and explained 10% of the HFLI variance. There was a strong anatomo-functional link in the HG: duplication was associated with a decrease in both the surface area of the anterior HG and HG functional activity. Participants with a single left HG exhibited leftward anatomical and functional asymmetry of HG, but participants with a left duplication lost either anatomical and/or functional leftward asymmetries. Finally, manual preference was related to HG anatomy, but not to HG functional asymmetries measured during LIST. The anatomical characteristics of left-handers (lower occurrence of right HG duplication and a smaller surface area of the right first HG) thus appeared to be unrelated to variations in speech lateralization with handedness.

  2. A Randomized Controlled Trial on the Effect of Tapentadol and Morphine on Conditioned Pain Modulation in Healthy Volunteers

    PubMed Central

    Martini, Chris; van Velzen, Monique; Drewes, Asbjørn; Aarts, Leon; Dahan, Albert; Niesters, Marieke

    2015-01-01

    Background Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neurons, influence pain perception in humans. Defects in descending pain control are linked to chronic pain states and its restoration may be a valuable analgesic tool. Conditioned pain modulation (CPM) is a surrogate marker of descending inhibition that reduces the perception of pain from a primary test stimulus during application of a conditioning stimulus. Here the effects of the analgesics tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and morphine, a strong mu-opioid receptor agonist, were tested on CPM in a randomized, double-blind, placebo-controlled crossover trial in 12 healthy pain-free volunteers, to understand possible differences in mechanism of action between these opioids. Methods and Results On three occasions CPM responses were obtained 60-90 and 120-150 min following intake of tapentadol (100 mg immediate release tablet), morphine (40 mg immediate release tablet) or placebo. At both time points, CPM was detectable after treatment with placebo and tapentadol (peak pain ratings reduced by 20-30% after application of the conditioning stimulus) but not after morphine. Compared to placebo morphine displayed significantly less CPM: mean treatment difference 18.2% (95% CI 3.4 to 32.9%) at 60-90 min after drug intake and 19.5% (95% CI 5.7 to 33.2%) at 120-150 min after drug intake (p = 0.001). No difference in CPM between placebo and tapentadol was detected: mean treatment difference 1.5% (95% CI -11.6 to 14.6%) at 60-90 min after drug intake and 1.5% (95% CI -16.0 to 18.9%) at 120-150 min after drug intake (p = 0.60). Conclusions Our data show that in volunteers morphine affects CPM, while tapentadol was without effect despite identical experimental conditions. These data confirm that tapentadol’s main mechanism of action is distinct from that of morphine and likely related to the effect of adrenergic

  3. Efficacy of Moringa oleifera leaf powder as a hand- washing product: a crossover controlled study among healthy volunteers

    PubMed Central

    2014-01-01

    Background Moringa oleifera is a plant found in many tropical and subtropical countries. Many different uses and properties have been attributed to this plant, mainly as a nutritional supplement and as a water purifier. Its antibacterial activity against different pathogens has been described in different in vitro settings. However the potential effect of this plant leaf as a hand washing product has never been studied. The aim of this study is to test the efficacy of this product using an in vivo design with healthy volunteers. Methods The hands of fifteen volunteers were artificially contaminated with Escherichia coli. Moringa oleifera leaf powder was tested as a hand washing product and was compared with reference non-medicated liquid soap using a cross over design following an adaptation of the European Committee for Standardization protocol (EN 1499). In a second part of tests, the efficacy of the established amount of Moringa oleifera leaf powder was compared with an inert powder using the same protocol. Results Application of 2 and 3 g of dried Moringa oleifera leaf powder (mean log10-reduction: 2.44 ± 0.41 and 2.58 ± 0.34, respectively) was significantly less effective than the reference soap (3.00 ± 0.27 and 2.99 ± 0.26, respectively; p < 0.001). Application of the same amounts of Moringa oleifera (2 and 3 g) but using a wet preparation, was also significantly less effective than reference soap (p < 0.003 and p < 0.02, respectively). However there was no significant difference when using 4 g of Moringa oleifera powder in dried or wet preparation (mean log10-reduction: 2.70 ± 0.27 and 2.91 ± 0.11, respectively) compared with reference soap (2.97 ± 0.28). Application of calcium sulphate inert powder was significantly less effective than the 4 g of Moringa oleifera powder (p < 0.01). Conclusion Four grams of Moringa oleifera powder in dried and wet application had the same effect as non-medicated soap

  4. Comprehensive detection and identification of bacterial DNA in the blood of patients with sepsis and healthy volunteers using next-generation sequencing method - the observation of DNAemia.

    PubMed

    Gosiewski, T; Ludwig-Galezowska, A H; Huminska, K; Sroka-Oleksiak, A; Radkowski, P; Salamon, D; Wojciechowicz, J; Kus-Slowinska, M; Bulanda, M; Wolkow, P P

    2017-02-01

    Blood is considered to be a sterile microenvironment, in which bacteria appear only periodically. Previously used methods allowed only for the detection of either viable bacteria with low sensitivity or selected species of bacteria. The Next-Generation Sequencing method (NGS) enables the identification of all bacteria in the sample with their taxonomic classification. We used NGS for the analysis of blood samples from healthy volunteers (n = 23) and patients with sepsis (n = 62) to check whether any bacterial DNA exists in the blood of healthy people and to identify bacterial taxonomic profile in the blood of septic patients. The presence of bacterial DNA was found both in septic and healthy subjects; however, bacterial diversity was significantly different (P = 0.002) between the studied groups. Among healthy volunteers, a significant predominance of anaerobic bacteria (76.2 %), of which most were bacteria of the order Bifidobacteriales (73.0 %), was observed. In sepsis, the majority of detected taxa belonged to aerobic or microaerophilic microorganisms (75.1 %). The most striking difference was seen in the case of Actinobacteria phyla, the abundance of which was decreased in sepsis (P < 0.001) and Proteobacteria phyla which was decreased in the healthy volunteers (P < 0.001). Our research shows that bacterial DNA can be detected in the blood of healthy people and that its taxonomic composition is different from the one seen in septic patients. Detection of bacterial DNA in the blood of healthy people may suggest that bacteria continuously translocate into the blood, but not always cause sepsis; this observation can be called DNAemia.

  5. Comparison of the after-effects of transcranial direct current stimulation over the motor cortex in patients with stroke and healthy volunteers.

    PubMed

    Suzuki, Kanjiro; Fujiwara, Toshiyuki; Tanaka, Naofumi; Tsuji, Tetsuya; Masakado, Yoshihisa; Hase, Kimitaka; Kimura, Akio; Liu, Meigen

    2012-11-01

    It is known that weak transcranial direct current stimulation (tDCS) induces persistent excitability changes in the cerebral cortex. There are, however, few studies that compare the after-effects of anodal versus cathodal tDCS in patients with stroke. This study assessed the after-effects of tDCS over the motor cortex in patients with hemiparetic stroke and healthy volunteers. Seven stroke patients and nine healthy volunteers were recruited. Ten minutes of anodal and cathodal tDCS (1 mA) and sham stimulation were applied to the affected primary motor cortex (M1) on different days. In healthy subjects, tDCS was applied to the right M1. Before and after tDCS, motor-evoked potentials (MEPs) in the first dorsal interosseous (FDI) muscle and silent period were measured. Anodal tDCS increased the MEPs of the affected FDI in patients with stroke as well as in healthy subjects. Cathodal tDCS increased the MEPs of the affected FDI in patients with stroke. In healthy subjects, however, cathodal tDCS decreased the MEPs. We found no significant change in the duration of the silent period after anodal or cathodal tDCS. We found that both anodal and cathodal tDCS increased the affected M1 excitability in patients with stroke. It is thought that the after-effects of tDCS are different in patients with stroke compared with healthy subjects.

  6. Evaluation of the satiating properties of a nutraceutical product containing Garcinia cambogia and Ascophyllum nodosum extracts in healthy volunteers.

    PubMed

    Mayer, Marcos A; Finlayson, Graham; Fischman, Daniela; de Paz, Carolina; Telleriarte, Martín R; Ferrero, Alejandro J; Bobillo, Cecilia; Fernández, Belisario E

    2014-04-01

    A nutraceutical product composed of a combination of Garcinia cambogia, l-carnitine and a seaweed extract of Ascophyllum nodosum has been recently developed. The aim of the present study was to characterize its effects on subjective satiety sensations and food preferences in healthy volunteers. In a crossover design, 28 subjects (21 females and 7 males, aged 31 ± 5, BMI 22.6 ± 1.7) were randomly assigned to receive the active treatment (LIS) or placebo (PL) over one week. At the end of each treatment period, subjects were instructed to consume ad libitum a test meal. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preferences Questionnaire and visual analog scales, before and after meal, over three hours. There were no differences in energy intake between study groups. LIS was associated with a reduction in subjective hunger sensations (p = 0.018) and to an increase in satiety (p = 0.02) and fullness (p = 0.01) ratings. The preference for high fat foods was reduced after consuming the test meal in both study groups. There was a significant effect of LIS treatment on food explicit liking and implicit wanting, as evidenced by an increase in preference for sweet foods (relative to savory foods; p = 0.03 and p = 0.004, respectively), but no differences were observed regarding the preference for low or high fat foods (NS). These results provide proof of principle for the satiating properties of a nutraceutical containing Garcinia cambogia, Ascophyllum nodosum extract and l-carnitine and suggest that it might be useful as an appetite modulator.

  7. Intra-Parenchymal Renal Resistive Index Variation (IRRIV) Describes Renal Functional Reserve (RFR): Pilot Study in Healthy Volunteers.

    PubMed

    Samoni, Sara; Nalesso, Federico; Meola, Mario; Villa, Gianluca; De Cal, Massimo; De Rosa, Silvia; Petrucci, Ilaria; Brendolan, Alessandra; Rosner, Mitchell H; Ronco, Claudio

    2016-01-01

    An increase of glomerular filtration rate after protein load represents renal functional reserve (RFR) and is due to afferent arteriolar vasodilation. Lack of RFR may be a risk factor for acute kidney injury (AKI), but is cumbersome to measure. We sought to develop a non-invasive, bedside method that would indirectly measure RFR. Mechanical abdominal pressure, through compression of renal vessels, decreases blood flow and activates the auto-regulatory mechanism which can be measured by a fall in renal resistive index (RRI). The study aims at elucidating the relationship between intra-parenchymal renal resistive index variation (IRRIV) during abdominal pressure and RFR. In healthy volunteers, pressure was applied by a weight on the abdomen (fluid-bag 10% of subject's body weight) while RFR was measured through a protein loading test. We recorded RRI in an interlobular artery after application of pressure using ultrasound. The maximum percentage reduction of RRI from baseline was compared in the same subject to RFR. We enrolled 14 male and 16 female subjects (mean age 38 ± 14 years). Mean creatinine clearance was 106.2 ± 16.4 ml/min/1.73 m(2). RFR ranged between -1.9 and 59.7 with a mean value of 28.9 ± 13.1 ml/min/1.73 m(2). Mean baseline RRI was 0.61 ± 0.05, compared to 0.49 ± 0.06 during abdominal pressure; IRRIV was 19.6 ± 6.7%, ranging between 3.1% and 29.2%. Pearson's coefficient between RFR and IRRIV was 74.16% (p < 0.001). Our data show the correlation between IRRIV and RFR. Our results can lead to the development of a "stress test" for a rapid screen of RFR to establish renal susceptibility to different exposures and the consequent risk for AKI.

  8. Nanosizing of a poorly soluble drug: technique optimization, factorial analysis, and pharmacokinetic study in healthy human volunteers

    PubMed Central

    Elsayed, Ibrahim; Abdelbary, Aly Ahmed; Elshafeey, Ahmed Hassen

    2014-01-01

    Context Diacerein (DCN) has low aqueous solubility (3.197 mg/L) and, consequently, low oral bioavailability (35%–56%). To increase both the solubility and dissolution rate of DCN while maintaining its crystalline nature, high pressure homogenization was used but with only a few homogenization cycles preceded by a simple bottom-up technique. Methods The nanosuspensions of DCN were prepared using a combined bottom-up/top-down technique. Different surfactants – polyvinyl alcohol, sodium deoxycholate, and sodium dodecyl sulfate – with different concentrations were used for the stabilization of the nanosuspensions. Full factorial experimental design was employed to investigate the influence of formulation variables on nanosuspension characteristics using Design-Expert® Software. Particle size (PS), zeta potential, saturation solubility, in vitro dissolution, and drug crystallinity were studied. Moreover, the in vivo performance of the optimized formula was assessed by bioavailability determination in healthy human volunteers. Results The concentration of surfactant had a significant effect on both the PS and polydispersity index values. The 1% surfactant concentration showed the lowest PS and polydispersity index values compared with other concentrations. Both type and concentration of surfactant had significant effects on the zeta potential. Formula F8 (containing 1% sodium deoxycholate) and Formula F12 (containing 1% sodium dodecyl sulfate) had the highest desirability values (0.952 and 0.927, respectively). Hence, they were selected for further characterization. The saturated solubility and mean dissolution time, in the case of F8 and F12, were significantly higher than the coarse drug powder. Techniques utilized in the nanocrystals’ preparation had no effect on DCN crystalline state. The selected formula (F12) showed a higher bioavailability compared to the reference market product with relative bioavailability of 131.4%. Conclusion The saturation

  9. Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers.

    PubMed

    Gijsman, Harm J; van Gerven, Joop M A; de Kam, Marieke L; Schoemaker, Rik C; Pieters, Monique S M; Weemaes, Margo; de Rijk, Roel; van der Post, Jeroen; Cohen, Adam F

    2002-04-01

    Single-dose administration of 5-hydroxytryptophan (5-HTP) is regularly used as a challenge test of the serotonergic system. The use of 5-HTP has been limited by an apparent small window between the occurrence of neuroendocrine endpoints and the occurrence of side effects. Therefore, many dosing strategies have been tried with and without concurrent administration of carbidopa, a peripheral inhibitor of the decarboxylation from 5-HTP to serotonin. The aim of the current study was to assess the relation between pharmacokinetics and pharmacodynamics of 5-HTP. Twelve healthy male volunteers were included in a placebo-controlled, randomized, four-way crossover, double-blind, single-dose investigation of oral 5-HTP with or without coadministration of carbidopa. The four dose regimens were placebo, 5-HTP 100 mg, 5-HTP 200 mg, and 5-HTP 100 mg with coadministration of carbidopa 100 mg and 50 mg at 3 hours before and 3 hours after the administration of 5-HTP, respectively. The last regimen resulted in a doubling of the elimination half-life, an apparent clearance at least 14 times smaller, and a 15.4 times greater area under the curve compared with 5-HTP 100 mg without carbidopa. Furthermore, it was the only regimen to induce a significant change in cortisol and prolactin. It did not induce any change in subjective psychologic symptoms or cardiovascular parameters, but it was the only regimen to induce some nausea in three participants. The authors conclude that this regimen of 5-HTP 100 mg plus carbidopa is a relatively simple, effective, and tolerable challenge of the presynaptic serotonergic system. Further increase of the dose of 5-HTP might improve the size of the effect on endpoints as long as the tolerability remains good.

  10. Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers.

    PubMed

    Cao, Ying Jun; Flexner, Charles W; Dunaway, Shelia; Park, Jeong-Gun; Klingman, Karin; Wiggins, Ilene; Conley, Jeanne; Radebaugh, Christine; Kashuba, Angela D; MacFarland, Ron; Becker, Stephen; Hendrix, Craig W

    2008-05-01

    AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C(max)), 934 h x ng/ml (313 to 2,127 h x ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C(max) of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC(0-infinity) by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.

  11. Bioequivalence studies of film-coated tablet and chewable tablet generic formulations of montelukast in healthy volunteers.

    PubMed

    Cánovas, Mercedes; Arcabell, Marta; Martínez, Gemma; Canals, Mirela; Cabré, Francesc

    2011-01-01

    Two studies were conducted in order to assess the bioequivalence of montelukast (CAS 151767-02-1) 10 mg film-coated tablet (FCT) and 5 mg chewable tablet (CT) test formulations in comparison with the original brands. Under fasting conditions, healthy male and female volunteers received one 10 mg FCT or 5 mg CT orally as a single dose of a test or reference formulation. Both studies were designed as open-label, randomized, two-period, two-sequence, crossover studies with a 7-day washout interval. Plasma samples were collected up to 24 h after drug administration and montelukast levels were determined by a validated LC/ MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental analysis and were statistically compared by analysis of variance for test and reference formulation. Bioequivalence between products was determined by calculating 90% confidence interval of the ratio test/reference of least-square means of logarithmically transformed Cmax and AUC0-t parameters. AUC0-infinity was also analysed to obtain additional information. The calculated 90% confidence intervals for the ratios of Cmax and AUC0-t parameters were 89.33-110.52 and 92.06-109.46, respectively, in the FCT study, and 91.58-101.86 and 92.15-98.83, respectively, in the CT study, which are all within the bioequivalence acceptance range of 80-125%. Based on the results, it can be concluded that the evaluated test FCT and CT formulations are bioequivalent to their respective reference formulation in terms of rate and extent of absorption.

  12. Pharmacokinetic study of a new oral buffered acetylsalicylic acid (ASA) formulation in comparison with plain ASA in healthy volunteers.

    PubMed

    Viganò, G; Garagiola, U; Gaspari, F

    1991-01-01

    A single-blind, randomized, crossover pharmacokinetic study was carried out to investigate the bioavailability of a new oral buffered 325 mg acetylsalicylic acid (ASA) formulation (ASPIRINA 03) in comparison with a 325 mg plain tablet. Twelve healthy volunteers of both sexes, aged between 20 and 37 years, received buffered or plain ASA on two separate occasions with a wash-out interval of at least two weeks. ASA and salicylic acid (SA) plasma levels were determined by a chromatographic method. The results showed no difference between the area under concentration time curve (AUC0-infinity) ASA values of both formulations (p = 0.19), and buffered ASA relative bioavailability was 102.49% (= bioequivalence). A significant difference was found between the AUC0-30 min ASA values: 90.5 micrograms. min/ml with buffered and 67.7 micrograms. min/ml with the plain tablet (p less than 0.05). The buffered ASA time of maximum concentration was shorter (28 +/- 8 min) than the plain one (38 +/- 19 min, p less than 0.05). The plasma concentrations and pharmacokinetic parameters of SA were not significantly different after the administration of the two ASA formulations. The plain ASA tablet had a significantly lower (p less than 0.05) dissolution rate than buffered ASA tablet. Moreover, the buffered ASA tablet significantly (p less than 0.01) increased the pH by 0.5 units. In conclusion, the bioavailability of the new oral buffered ASA was equivalent to that of plain ASA, but the plasma concentration peak was reached in a shorter time.

  13. Venlafaxine's effects on healthy volunteers' driving, psychomotor, and vigilance performance during 15-day fixed and incremental dosing regimens.

    PubMed

    O'Hanlon, J F; Robbe, H W; Vermeeren, A; van Leeuwen, C; Danjou, P E

    1998-06-01

    Effects of venlafaxine, an antidepressant acting by selective serotonin and norepinephrine reuptake inhibition with a potency ratio of 5:1, were assessed in a standardized, actual driving test, a battery of psychomotor tests (Critical Flicker/Fusion Frequency, Critical Tracking, Divided Attention), and a 45-minute vigilance test (Mackworth Clock). Thirty-seven healthy volunteers, 22 of whom completed the study, received venlafaxine in fixed (37.5 mg twice a day) and incremental (37.5-75 mg twice a day) doses as well as mianserin (10-20 mg three times a day) and placebo according to a 4-period (15 days each), double-blind, crossover design. Testing occurred on days 1 and 7 and after dose increments, on days 8 and 15. Plasma concentrations of venlafaxine and its active metabolite were measured on test days for confirming compliance. Venlafaxine had no significant effect on the primary driving parameter (standard deviation of lateral position) and failed to impair psychomotor performance. Mianserin profoundly and consistently impaired driving and psychomotor performance. However, both drugs significantly impaired vigilance performance. Maximal effects occurred on day 1 with mianserin and similarly on day 7 with venlafaxine in both series. The increment in venlafaxine's dose on day 8 did not increase this effect. The drug's selectively impairing effect on vigilance is shared by other "serotonergic" anxiolytics and antidepressants, suggesting that interference with 5-HT transmission reduces arousal in particularly monotonous tasks or environments. This study concludes that venlafaxine does not generally affect driving ability and should be safe for use by patients who drive.

  14. A two-way cross-over bioequivalence study comparing two products of diclofenac sodium suppositories in healthy human volunteers.

    PubMed

    Hasan, Mazen; Otoom, Sameer; Najib, Naji; Sallam, El-Sayed

    2004-12-01

    This report presents the results of two treatment cross-over investigations on 20 healthy male volunteers to assess the bioequivalence of two suppository products of diclofenac sodium. The study was carried out under US Food and Drug Administration Guidelines. The two products were voltaren (100 mg) suppository (Ciba-Giegy), as a reference product, and Inflaban (100 mg) suppository (The Arab Pharmaceutical Manufacturing Company, Ltd. "APM"), as a test product. Both products were administered rectally as a single dose (100 mg) separated by a one-week wash-out period. Following drug administration, blood samples were collected over 12 hr, and serum harvested from the blood was analyzed for diclofenac sodium using a sensitive and specific high performance liquid chromatographic assay. The results of this investigation indicated that there were no statistically significant differences between the two products in either the mean concentration-time profiles or in the obtained pharmacokinetic parameters, including area under the serum concentration-time curve for 12 hr (AUC(0-12h)), lag time between product administration and first appearance of the drug in serum (T(lag)), peak serum concentration (C(max)), and time to reach this peak serum concentration (T(max)). Concerning the relative extent of absorption, assessed by the AUC ratio (Inflaban/Voltaren) for 12 hr, the average value was found to be 1.00+/-0.09 with a 95% confidence limits (C.L.) of 0.82-1.18. Thus, these findings clearly indicate that the two products are bioequivalent in terms of rate and extent of drug absorption.

  15. Psychomotor and cognitive effects of 15-minute inhalation of methoxyflurane in healthy volunteers: implication for post-colonoscopy care

    PubMed Central

    Nguyen, Nam Q.; Burgess, Jenna; Debreceni, Tamara L.; Toscano, Leanne

    2016-01-01

    Background and study aims: Colonoscopy with portal inhaled methoxyflurane (Penthrox) is highly feasible with low sedation risk and allows earlier discharge. It is unclear if subjects can return to highly skilled psychomotor skill task shortly after Penthrox assisted colonoscopy. We evaluated the psychomotor and cognitive effects of 15-minute inhalation of Penthrox in adults. Patients and methods: Sixty healthy volunteers (18 to 80 years) were studied on 2 occasions with either Penthrox or placebo in a randomized, double-blind fashion. On each occasion, the subject’s psychomotor function was examined before, immediately, 30, 60, 120, 180 and 240 min after a 15-minute inhalation of studied drug, using validated psychomotor tests (Digit Symbol Substitution Test (DSST), auditory reaction time (ART), eye-hand coordination (EHC) test, trail making test (TMT) and logical reasoning test (LRT). Results: Compared to placebo, a 15-minute Penthrox inhalation led to an immediate but small impairment of DSST (P < 0.001), ART (P < 0.001), EHC (P < 0.01), TMT (P = 0.02) and LRT (P = 0.04). In all subjects, the performance of all 5 tests normalized by 30 minutes after inhalation, and was comparable to that with placebo. Although increasing age was associated with a small deterioration in psychomotor testing performance, the magnitude of Penthrox effects remained comparable among all age groups. Conclusions: In all age groups, a 15-minute Penthrox inhalation induces acute but short-lasting impairment of psychomotor and cognitive performance, which returns to normal within 30 minutes , indicating that subjects who have colonoscopy with Penthrox can return to highly skilled psychomotor skills tasks such as driving and daily work the same day. PMID:27853742

  16. Lack of interaction between a new antihistamine, mizolastine, and lorazepam on psychomotor performance and memory in healthy volunteers.

    PubMed Central

    Patat, A; Perault, M C; Vandel, B; Ulliac, N; Zieleniuk, I; Rosenzweig, P

    1995-01-01

    1. The possible interaction between a new H1 antihistamine, mizolastine, and lorazepam was assessed in a randomised, double-blind, cross-over, placebo-controlled study involving 16 healthy young male volunteers who received mizolastine 10 mg or placebo once daily for 8 days with a 1 week wash-out interval. The interaction of mizolastine, at steady-state, with a single oral dose of lorazepam or placebo was assessed on days 6 or 8 of each treatment period. 2. Psychomotor performance and cognitive function were evaluated using objective tests (critical flicker fusion threshold, choice reaction time, tapping, arithmetic calculation, body sway) and self-ratings (visual analogue scale, ARCI) before and at 2, 4, 6 and 8 h after dosing. Short-term memory (Sternberg memory scanning immediate free recall of a word list) and long-term memory (delayed free recall and recognition of words and pictures) were assessed before and at 3 h after dosing. Pharmacodynamic interactions were evaluated by repeated measures ANOVA in a 2 x 2 factorial interaction model. 3. Mizolastine, 10 mg once daily, at steady-state, was devoid of sedation and detrimental effect on skilled performance and memory. 4. In contrast, a single 2 mg dose of lorazepam produced marked impairment of psychomotor performance, cognitive functions (significant reduction in flicker fusion threshold, tapping and arithmetic calculation and increase in reaction times and body sway) and subjective sedation from 2 to 8 h after dosing. In addition, lorazepam induced an anterograde amnesia, characterised by a decrease in delayed free recall and recognition, and a deficit in short term memory.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7756096

  17. PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

    PubMed Central

    Rani, Aradhana; Betz, Andreas; Pak, Yvonne; Haberstock‐Debic, Helena; Pandey, Anjali; Hollenbach, Stanley; Gretler, Daniel D.; Mant, Tim; Jurcevic, Stipo; Sinha, Uma

    2016-01-01

    Abstract The spleen tyrosine kinase (SYK) regulates immune cell activation in response to engagement of a variety of receptors, making it an intriguing target for the treatment of inflammatory and autoimmune disorders as well as certain B‐cell malignancies. We have previously reported on the discovery and preclinical characterization of PRT062607, a potent and highly selective inhibitor of SYK that exhibits robust anti‐inflammatory activity in a variety of animal models. Here we present data from our first human studies aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of PRT062607 in healthy volunteers following single and multiple oral administrations. PRT062607 demonstrated a favorable PK profile and the ability to completely inhibit SYK activity in multiple whole‐blood assays. The PD half‐life in the more sensitive assays was approximately 24 hours and returned to predose levels by 72 hours. Selectivity for SYK was observed at all dose levels tested. Analysis of the PK/PD relationship indicated an IC50 of 324 nM for inhibition of B‐cell antigen receptor‐mediated B‐cell activation and 205 nM for inhibition of FcεRI‐mediated basophil degranulation. PRT062607 was safe and well tolerated across the entire range of doses. Clinical PK/PD was related to in vivo anti‐inflammatory activity of PRT062607 in the rat collagen‐induced arthritis model, which predicts that therapeutic concentrations may be safely achieved in humans for the treatment of autoimmune disease. PRT062607 has a desirable PK profile and is capable of safely, potently, and selectively suppressing SYK kinase function in humans following once‐daily oral dosing. PMID:27406873

  18. Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers

    PubMed Central

    Olofsen, Erik; Noppers, Ingeborg; Niesters, Marieke; Kharasch, Evan; Aarts, Leon; Sarton, Elise; Dahan, Albert

    2012-01-01

    Background The N-methyl-D-receptor antagonist ketamine is metabolized in the liver into its active metabolite norketamine. No human data are available on the relative contribution of norketamine to ketamine-induced analgesia and side effects. One approach to assess the ketamine and norketamine contributions is by measuring ketamine-effect at varying ketamine and norketamine plasma concentrations using the CYP450 inducer rifampicin. Methods In 12 healthy male volunteers the effect of rifampicin versus placebo pretreatment on S-ketamine (a 2-h infusion of 20 mg/h)-induced analgesia and cognition was quantified. The relative ketamine and norketamine contribution to effect was estimated using a linear additive population pharmacokinetic-pharmacodynamic model. Results S-ketamine produced significant analgesia, psychotropic effects (drug high), and cognitive impairment (including memory impairment, reduced psychomotor speed, reduced reaction time, reduced cognitive flexibility). Modeling revealed a negative contribution of S-norketamine to S-ketamine-induced analgesia and absence of contribution to cognitive impairment. At ketamine and norketamine effect concentrations of 100 ng/ml and 50 ng/ml, respectievly, the ketamine contribution to analgesia is −3.8 cm (visual analogue pain score) versus a contribution of norketamine of +1.5 cm, causing an overall effect −2.3 cm. The blood-effect-site equilibration half-life ranged from 0 (cognitive flexibility) to 11.8 (pain intensity) min, and averaged across all end-points was 6.1 min. Conclusions This first observation that norketamine produces effects in the opposite direction of ketamine requires further proof. It can explain the observation of ketamine-related excitatory phenomena (such as hyperalgesia and allodynia) upon the termination of ketamine infusions. PMID:22692377

  19. Is generic rifaximin still a poorly absorbed antibiotic? A comparison of branded and generic formulations in healthy volunteers.

    PubMed

    Blandizzi, Corrado; Viscomi, Giuseppe Claudio; Marzo, Antonio; Scarpignato, Carmelo

    2014-07-01

    Rifaximin is an antibiotic, locally acting in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The branded rifaximin formulation contains the polymorph rifaximin-α, whose systemic bioavailability is very limited. This study was performed to compare the pharmacokinetics of this formulation with that of a generic product, whose composition in terms of solid state forms of the active pharmaceutical ingredient was found to be different. Two tablets (2×200mg) of branded and generic formulations were given to 24 healthy volunteers of either sex, according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urinary samples were collected at preset times (for 24h or 48h, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry. Rifaximin plasma and urine concentration-time profiles showed relevant differences when generic and branded rifaximin were compared. Most pharmacokinetic parameters were significantly higher after administration of generic rifaximin than after rifaximin-α. In particular, the differences for Cmax, AUC and cumulative urinary excretion between the generic formulation and the branded product ranged from 165% to 345%. The few adverse events recorded were not serious and not related to study medications. The results of the present investigation demonstrate different systemic bioavailability of generic and branded formulations of rifaximin. As a consequence, the therapeutic results obtained with rifaximin-α should not be translated sic et simpliciter to the generic formulations of rifaximin, which do not claim containing only rifaximin-α and will display significantly higher systemic absorption in both health and disease.

  20. Comparable lumefantrine oral bioavailability when co-administered with oil-fortified maize porridge or milk in healthy volunteers.

    PubMed

    Mwebaza, Norah; Jerling, Markus; Gustafsson, Lars L; Obua, Celestino; Waako, Paul; Mahindi, Margarita; Ntale, Muhammad; Beck, Olof; Hellgren, Urban

    2013-07-01

    Co-administration of artemether-lumefantrine with milk is recommended to improve lumefantrine (L) absorption but milk may not be available in resource-limited settings. This study explored the effects of cheap local food in Uganda on oral bioavailability of lumefantrine relative to milk. In an open-label, four-period crossover study, 13 healthy adult volunteers were randomized to receive a single oral dose of artemether-lumefantrine (80 mg artemether/480 mg lumefantrine) with water, milk, maize porridge or maize porridge with oil on separate occasions. Plasma lumefantrine was assayed using high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic exposure parameters were determined by non-compartmental methods using WinNonlin. Peak concentrations (Cmax ) and area under concentration-time curve restricted to 48 hr after single dosing (AUC(0-48) ) were selected for relative bioavailability evaluations using confidence interval approach for average bioequivalence. Lumefantrine exposure was comparable in milk and maize porridge plus oil study groups. When artemether-lumefantrine was administered with maize porridge plus oil, average bioequivalence ranges (means ratios 90% CI, 0.84-1.88 and 0.85-1.69 for Cmax and AUC(0-48) , respectively) were within and exceeded acceptance ranges relative to milk (90% CI, 0.80-1.25). Both fasted and maize porridge groups demonstrated similarly much lower ranges of lumefantrine exposures (bioinequivalence) relative to milk. If milk is not available, it is thus possible to recommend fortification of carbohydrate-rich food with little fat (maize porridge plus vegetable oil) to achieve similarly optimal absorption of lumefantrine after artemether-lumefantrine administration.

  1. Localization of MDMA-induced brain activity in healthy volunteers using low resolution brain electromagnetic tomography (LORETA).

    PubMed

    Frei, E; Gamma, A; Pascual-Marqui, R; Lehmann, D; Hell, D; Vollenweider, F X

    2001-11-01

    3,4-Methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a psychostimulant drug producing heightened mood and facilitated social communication. In animal studies, MDMA effects are primarily mediated by serotonin (5-HT), but also by dopamine (DA) and possibly noradrenaline (NA). In humans, however, the neurochemical and neurophysiological basis of acute MDMA effects remains unknown. The distribution of active neuronal populations after administration of a single dose of MDMA (1.7 mg/kg) or placebo was studied in 16 healthy, MDMA-naïve volunteers. Thirty-one-channel scalp EEGs during resting with open and closed eyes was analyzed in the different EEG frequency bands. Scalp maps of power showed significant, global differences between MDMA and placebo in both eye conditions and all frequency bands. Low resolution brain electromagnetic tomography (LORETA) was used to compute 3D, functional images of electric neuronal activity from the scalp EEG data. MDMA produced a widespread decrease of slow and medium frequency activity and an increase of fast frequency activity in the anterior temporal and posterior orbital cortex, concomitant with a marked enhancement of mood, emotional arousal and increased extraversion. This activation of frontotemporal areas indicates that the observed enhancement of mood and possibly the increased extroversion rely on modulation of limbic orbitofrontal and anterotemporal structures known to be involved in emotional processes. Comparison of the MDMA-specific EEG pattern with that of various 5-HT, DA, and NA agonists indicates that serotonin, noradrenaline, and, to a lesser degree, dopamine, contribute to the effects of MDMA on EEG, and possibly also on mood and behavior.

  2. The tridimensional personality theory and pain: harm avoidance and reward dependence traits correlate with pain perception in healthy volunteers.

    PubMed

    Pud, Dorit; Eisenberg, Elon; Sprecher, Elliot; Rogowski, Zeev; Yarnitsky, David

    2004-02-01

    The aim of the present study was to examine the possible role of personality traits in determining the variability of pain perception among individuals. More specifically, it was intended to test whether or not the three personality dimensions suggested by Cloninger in 1987 - mainly harm avoidance (HA), but also reward dependence (RD), and novelty seeking (NS), can predict interpersonal differences in responsiveness to experimental pain. Seventy healthy volunteers participated in the study. Their personality traits were evaluated through Cloninger's tridimensional personality questionnaire (TPQ). Pain threshold (latency to pain onset), pain magnitude (VAS), and pain tolerance (time to withdrawal) were measured by using the cold pressor test. Bonferroni-adjusted correlations were found between HA and the pain parameters as follows: a negative correlation between HA and threshold (rho=-0.297, P(adj)=0.039); no significant correlation between HA and tolerance (rho=-0.219, P(adj)=0.207); and a trend for a positive correlation between HA and VAS (rho=0.266, P(adj)=0.081). Possible correlations between pain perception and the various possible combinations of high and low scoring for each of the three traits were also investigated. Correlations were found only for the combinations of high/low HA and high/low RD. The low HA/low RD combination demonstrated the lowest responsiveness to pain (VAS 65.2+/-21.4; tolerance 107.6+/-71.8 s), whereas the high HA/low RD combination was correlated with the highest responsiveness (VAS 83.3+/-10.8; tolerance 30.8+/-28.4 s). The results indicate that HA personality trait correlates best with pain responsiveness. As such, a high HA are likely to predict a heightened pain response. RD may modify this pattern. The possible relevant behavioral and neuro-chemical mechanisms are discussed.

  3. Platelet full length TFPI-α in healthy volunteers is not affected by sex or hormonal use

    PubMed Central

    Winckers, Kristien; Thomassen, Stella; ten Cate, Hugo; Hackeng, Tilman M.

    2017-01-01

    Background Only 10% of plasma TFPIα (TFPI) exists in the full length form, the rest circulates as a C-terminally truncated form. However, blood platelets exclusively contain full length TFPI, which is released at the site of injury upon platelet activation, and which could play an important local regulatory role in thrombin generation and prevention of thrombosis. Methods The anticoagulant activities of full length and truncated TFPI were investigated using thrombin generation assays. Blood samples were obtained from 30 healthy volunteers (10 male subjects, 10 female subjects, and 10 females using oral contraceptives). Platelet TFPI was released in platelet rich plasma and in platelet isolates using convulxin or thrombin, and measured by free TFPI ELISA and thrombin generation assays. Results Full length TFPI and platelet TFPI were much more potent inhibitors of thrombin generation than truncated TFPI, which was virtually inactive. Although mean plasma TFPI antigen levels decreased from men (0.30 nM) to women (0.20 nM) to women using oral contraceptives (0.11 nM), no relevant differences were found in platelet TFPI among those subgroups. Conclusions Platelets release similar amounts of TFPI regardless of plasma TFPI concentrations and is unaffected by sex or oral contraceptive use. We speculate that platelet TFPI is important to prevent systemic coagulation and thrombosis and restrict thrombus formation to the site of the growing platelet plug. The stable contribution of platelet TFPI to the anticoagulant potential in plasma is likely to become particularly relevant under conditions of low plasma TFPI levels in combination of oral contraceptives use. PMID:28158181

  4. Comparison of finasteride (Proscar) and Serenoa repens (Permixon) in the inhibition of 5-alpha reductase in healthy male volunteers.

    PubMed

    Strauch, G; Perles, P; Vergult, G; Gabriel, M; Gibelin, B; Cummings, S; Malbecq, W; Malice, M P

    1994-01-01

    A total of 32 healthy male volunteers (age range 20-30 years) were enrolled in a 1-week open, randomized, placebo-controlled study comparing finasteride (Proscar), a 5 alpha-reductase inhibitor, with Permixon, the plant extract of Serenoa repens. The objective of the study was to evaluate the effect of single and multiple doses of the drugs on the inhibition of 5 alpha-reductase as assessed by serum dihydrotestosterone level determination. Following baseline measurements on day 1, the subjects were randomized to finasteride 5 mg once a day (n = 10), Permixon 80 mg x 2 twice a day (n = 11), or to placebo once a day (n = 11) for 7 days. Serum testosterone and dihydrotestosterone levels, were determined on day 1 (baseline and 12 h) and on days 2 (24 h), 3 (48 h), 4 (72 h), 6 (120 h), and 8 (168 h). After 12 h, a single dose of finasteride 5 mg reduced the serum dihydrotestosterone level by 65% (p < or = 0.01). The decreases ranged from -52 to -60% with multiple doses of finasteride 5 mg once a day (p < or = 0.01). As in the placebo group, there was no effect of Permixon on the serum dihydrotestosterone level. No significant difference was detected between finasteride and Permixon or between finasteride and placebo with respect to serum testosterone, except on days 3 and 6, respectively (p < or = 0.05). However, the corresponding serum testosterone levels remained within the normal ranges. These data confirm the efficacy of finasteride as inhibitor of 5 alpha-reductase.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Effect of 3 weeks treatment with yohimbine on salivary secretion in healthy volunteers and in depressed patients treated with tricyclic antidepressants.

    PubMed Central

    Bagheri, H; Schmitt, L; Berlan, M; Montastruc, J L

    1992-01-01

    The effect of yohimbine treatment (4 mg three times daily) for 3 weeks on salivary secretion was investigated. In healthy volunteers, acute administration of yohimbine increased salivary volume within 1 h to a similar extent before and at the end of the treatment period. In depressed patients treated with tricyclic antidepressants (and exhibiting a reduced salivary flow), yohimbine also acutely increased salivary volume. In contrast, the alpha 2-adrenoceptor antagonist failed to modify resting values measured in the morning (i.e. 10 and 14 h after the last administration in healthy volunteers and depressed patients respectively). This result indicates that alpha 2-adrenoceptor antagonists may have a potential therapeutic use in the treatment of dry mouth caused by tricyclic antidepressant drugs. PMID:1362888

  6. Clinical toxicology study of an herbal medicinal extract of Paullinia cupana, Trichilia catigua, Ptychopetalum olacoides and Zingiber officinale (Catuama) in healthy volunteers.

    PubMed

    Oliveira, Celso H; Moraes, Maria Elizabete A; Moraes, Manoel O; Bezerra, Fernando A F; Abib, Eduardo; De Nucci,