Characteristics Of Healthy Volunteers Research Articles

Pharmacometabolomics Approach to Explore Pharmacokinetic Variation and Clinical Characteristics of a Single Dose of Desvenlafaxine in Healthy Volunteers

This study investigated the effects of a single dose of desvenlafaxine via oral administration on the pharmacokinetic parameters and clinical and laboratory characteristics in healthy volunteers using a pharmacometabolomics approach. In order to optimize desvenlafaxine’s therapeutic use and minimize potential adverse effects, this knowledge is essential. Methods: Thirty-five healthy volunteers were enrolled after a health trial and received a single dose of desvenlafaxine (Pristiq®, 100 mg). First, liquid chromatography coupled to tandem mass spectrometry was used to determine the main pharmacokinetic parameters. Next, ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry was used to identify plasma metabolites with different relative abundances in the metabolome at pre-dose and when the desvenlafaxine peak plasma concentration was reached (pre-dose vs. post-dose). Results: Correlations were observed between metabolomic profiles, such as tyrosine, sphingosine 1-phosphate, and pharmacokinetic parameters, as well as acetoacetic acid and uridine diphosphate glucose associated with clinical characteristics. Our findings suggest that desvenlafaxine may have a broader effect than previously thought by acting on the proteins responsible for the transport of various molecules at the cellular level, such as the solute carrier SLC and adenosine triphosphate synthase binding cassette ABC transporters. Both of these molecules have been associated with PK parameters and adverse events in our study. Conclusions: This altered transporter activity may be related to the reported side effects of desvenlafaxine, such as changes in blood pressure and liver function. This finding may be part of the explanation as to why people respond differently to the drug.

A Study on the Characteristics of Healthy Volunteers who Participate in Phase I Clinical Trials in Korea.

The phase I trial is the first step in administering a drug to humans, but it has no therapeutic purpose. Under the absence of therapeutic purpose, healthy volunteers demonstrated different motivations, unlike the actual patients participating in trials. There were many reported motivations, such as financial motivation, contributing to the health science, accessing ancillary health care benefits, scientific interest or interest in the goals of the study, meeting people, and general curiosity. The aim of this study was to identify the motivation and characteristics of healthy volunteers participating in phase I trials in the Republic of Korea. We gave surveys to 121 healthy volunteers to study their demographic characteristics and the reasons of participation. We identified whether the decision to participate in the research was influenced by demographic factors and whether the perception and attitudes toward the research were influenced by the characteristics of the healthy volunteers. After completion of the first survey, 12 healthy volunteers who had participated in a phase I clinical trial were selected to answer the second interview. According to our survey, most healthy volunteers were unmarried men and economically dependent. Most of them participated in the study because of financial reward. The most important factor to measure financial reward was the research period. Also, 43% of the volunteers were university students, 42% answered "university graduation" and 55% were residing in family-owned houses. Many healthy volunteers were found to be living in family homes and to have a student status or lack of economic independence. Results of the survey showed that 64% of respondents indicated having more than one clinical trial participation. In-depth interviews showed that healthy volunteers had diverse motivation to participate in research and that healthy volunteer perceive the clinical trial positively. The main motivation for healthy volunteers' participation in research was "financial reward." Healthy volunteers also considered research schedules, processes, and safety, and had a positive perception of clinical trials, but they thought that the public has a negative perception.

Effect of administration of synbiotics mixture containing Bifidobacterium longum and xylooligosaccharide on fecal microbiota and defecation characteristics in healthy volunteers

Effect of administration of synbiotics mixture containing <i>Bifidobacterium longum</i> and xylooligosaccharide on fecal microbiota and defecation characteristics in healthy volunteers

A sonographic technique to evaluate the anterior bundle of the ulnar collateral ligament of the elbow: imaging features and anatomic correlation.

The aim of this study was to test a sonographic technique used to view the anterior bundle of the ulnar collateral ligament (UCL), describe its sonographic characteristics in healthy volunteers, and verify these characteristics by determining interobserver variability and their correlations in cadavers. Sonographic studies of the anterior bundle of the UCL were performed on 48 elbows of asymptomatic healthy volunteers. The participants were examined by 3 experts, who identified the insertion sites of the anterior bundle and subjectively evaluated its echogenicity and echo texture. A sonographic examination of the anterior bundle of the UCL in a cadaveric elbow was performed, and the same aspects were evaluated. In all cases, the anterior bundle of the UCL appeared as a triangular structure in the coronal plane and had a hyperechoic homogeneous echo texture in most of these cases. The cadaveric elbow had the same sonographic characteristics as the volunteers. As shown by examining the interobserver variability and determining the correlation with cadaveric tissue, sonography proved to be a reliable tool for evaluating the normal aspects of the anterior bundle of the UCL.

Effect of fresh orange juice intake on physiological characteristics in healthy volunteers.

Background. Impaired endothelial function is a predictor of cardiovascular events. Orange juice (OJ) is rich in dietary flavonoids and could inhibit oxidative stress and inflammatory responses. We examined the effects of commercial (COJ) and fresh orange juice (FOJ) on endothelial function and physiological characteristics in healthy humans. Materials and Methods. Twenty-two healthy volunteers years were enrolled in a single blind randomized crossover controlled trial. The two groups consumed either COJ for the first 4 weeks and then FOJ (CFOJ, 4 weeks), or FOJ for the first 4 weeks and then COJ (FCOJ, 4 weeks). We assessed endothelial function by measuring flow-mediated dilation, serum concentrations of lipids, apolipoproteins A and B (apo A-1 and apo B), and inflammatory markers such as vascular endothelial adhesion molecule 1 (VCAM-1), E-selectin, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6. Results. Consumption of both juices decreased VCAM, hs-CRP, and E-selectin but increased apo A-1. A decline in LDL occurred in the FOJ group. There were no differences between the characteristics of two groups, with the exception of apo A-1 levels that were increased with both forms of OJ. The largest variations occurred with hs-CRP, VCAM in both groups. Conclusion. Consumption of COJ and FOJ produced beneficial effects on the physiological characteristics of healthy volunteers. Although these results could encourage the consumption of OJ, intervention studies are needed to determine the long-term effects of these types of OJ on metabolic and cardiovascular endpoints.

Sa2032 Anal Evoked Potentials At ‘Twitch’ Threshold: A New Method for Exploration of Anal Sensory Function

Introduction Faecal incontinence can be associated with impaired anal sensitivity. Anal evoked potentials (EPs) have previously been used to quantify anal sensory function; however the traditional technique of stimulating at a percentage of pain threshold may result in poorly reproducible results with significant inter-individual variability. The aim of this study was to develop a reliable and reproducible method of recording anal EPs, and to define waveform characteristics in healthy volunteers. Methods Twenty eight healthy volunteers (21 F, median age 34 [range 21–74]) without bowel dysfunction were recruited for the study. Anal EPs were recorded in response to stimulation (using a bipolar electrode) 1cm from the anal verge. In contrast to previous studies, stimulation intensity was delivered at motor threshold (determined by visualisation of an anal ‘twitch’). Four sets of 50 stimuli (0.2 Hz frequency, 0.2 ms pulse duration) were given with 5-minute intervals between sets to reduce habituation. A repeat study was performed in 7 volunteers after a minimum interval of 2 weeks. Recordings were taken between channels Cz-A1 and Cz’-Fz (International 10–20 system) in accordance with previously published literature. Runs were averaged and latencies for EP responses were defined, analysed and compared. Results Motor threshold stimulation (median 20, range 10–36 mA) was well tolerated in all volunteers and resulted in reproducible polyphasic waveforms. The first negative peak (N1) was clearly identifiable on all traces. In the Cz’-Fz channel, the latency to N1 was 130 ± 20 ms (coefficient of variation [COV] = 15%). This was less variable than N1 in Cz-A1 (153 ± 34 ms; COV = 22%) and much less than published previously (COV of N1 = 39%; Remes-Troche et al. Neurogastroenterol Motil 2011). Analysis of repeat studies demonstrated that latencies in channel Cz’-Fz were the most reproducible (ICC of N1 latency = 0.95 [very strong agreement]). Conclusion Electrical stimulation at motor threshold and recording of evoked potentials from channel Cz’-Fz is a reliable and reproducible method for examination of anal sensory function. Latency to N1 is the most consistent waveform component and is highly reproducible. The technique of stimulation at ‘twitch’ threshold appears to reduce inter-subject variability and may allow application to further explore both the pathophysiology of anal dysfunction and the effect of treatments aimed at modulating anal neuronal function. Disclosure of Interest None Declared Reference Remes-Troche JM, Tantiphlachiva K, Attaluri A, et al . A bi-directional assessment of the human brain-anorectal axis. Neurogastroenterol Motil 2011; 23 : 240–248, e117–248

* The affect of bolus consistency on the oesophageal transition zone in dysphagia patients

IntroductionOesophageal manometry reveals a well-defined trough in peristaltic pressure amplitude in the upper oesophagus of healthy subjects. This manometric ‘transition zone’ (TZ) is associated with the striated-to-smooth oesophageal muscle fibre...

Assessment of levetiracetam bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy: Open-label, single-dose, randomized, four-way crossover study in healthy male volunteers

Background: Levetiracetam is a broad-spectrum antiepileptic drug that binds to synaptic vesicle protein SV2A. Levetiracetam is indicated in the adjunctive treatment of partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures. It is also approved in Europe as monotherapy for newly diagnosed partial-onset seizures. A Phase I clinical pharmacology trial was conducted during preregistration clinical development to better understand the regional gastrointestinal (GI) absorption of levetiracetam. Objective: This study evaluated the relative bioavailability of levetiracetam in various regions of the GI tract using a noninvasive, remote-controlled capsule device providing targeted drug delivery, relative to that after oral administration, and explored the drug's absorption characteristics in healthy volunteers. Methods: Pharmacokinetic data were obtained from healthy men aged 18 to 65 years in an open-label, single-dose, randomized, 4-way crossover study. Treatments included levetiracetam 250 mg administered as an immediate-release tablet and capsule delivery of 250 mg drug substance (levetiracetam powder without excipients) to the proximal small bowel, distal small bowel, and ascending colon. The location of the capsule in the GI tract was monitored using γ-scintigraphic imaging. Blood samples for plasma levetiracetam concentration were collected before dosing; at 10, 20, 30, and 45 minutes; and at 1, 1.5, 2, 3, 6, 9, 12, 16, 20, and 24 hours after tablet intake or after capsule activation. Pharmacokinetic parameters C max, T max, AUC 0−last, AUC 0−∞ and t ½ were calculated using noncompartmental methods. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and interviews with the volunteers regarding adverse events. Results: Nine healthy men, 7 whites and 2 Asians, were enrolled (mean [SD] age, 31 [14] years; weight, 77 [5] kg; height, 176 [6] cm). Six volunteers completed all 4 treatments. Seven adverse events (headache [3], lethargy [2], tachycardia [1], and contusion [1]) were reported in 5 volunteers, but only 2 (headache and lethargy) were judged by the investigator to be possibly drug related. The geometric mean (%CV) AUC 0−last values of levetiracetam delivered in the proximal small bowel, distal small bowel, ascending colon, and stomach (oral tablet) were 58.2 (9.3%), 59.6 (8.9%), 51.5 (12.0%), and 59.0 (7.4%) μg · h/mL, respectively. Values for bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the tablet were 98.5% (95% CI, 89.7%–108.2%), 100.8% (95% CI, 91.4%–111.1%), and 87.1% (95% CI, 77.9%–97.5%). Conclusion: After delivery in the proximal small bowel, distal small bowel, or ascending colon, the systemic bioavailability of levetiracetam (AUC), but not C max and T max, appeared comparable to that after oral administration and thus appeared site independent in this small group of healthy fasting men.

Time-resolved three-dimensional magnetic resonance velocity mapping of cardiovascular flow paths in volunteers and patients with Fontan circulation

To apply flow-sensitive magnetic resonance imaging for the evaluation of whole-heart flow characteristics in healthy volunteers and patients with Fontan circulation. Time-resolved three-dimensional magnetic resonance velocity mapping (spatial resolution = 2.5 × 2.8 × 2.8mm(3), temporal resolution = 38.4 ms) was acquired in normal controls and in four Fontan patients with extracardiac total cavopulmonary connection. Data analysis included flow connectivity mapping and flow quantification of arterial and venous blood flow. Haemodynamics in four patients with Fontan circulation were individually evaluated in the aorta, caval veins and left and right pulmonary arteries. In four controls, nine distinct flow features were consistently identified with good feature clarity (median = 2 in 80.6% of readings) and image quality (median = 2 in 75.0% of readings). In patients, a marked variability of flow from the caval veins towards the left and right pulmonary arteries (flow ratio = 1.7 ± 0.6, range 1.2-2.6 vs 1.1 ± 0.1 in controls) was found. Increased offset of the caval venous connection resulted in enhanced pulmonary flow asymmetry. Compared with controls, reduced pulsatility in pulmonary arteries (1.4 ± 0.6 vs 4.1 ± 0.6 in controls) and caval veins (1.2 ± 0.4 vs 2.8 ± 1.1 in controls) were observed. Peak flow was reduced in both superior (22 ± 14 mls(-1) vs 76 ± 7 mls(-1) in controls) and inferior vena cava (61 ± 28 mls(-1) vs 187 ± 42 mls(-1) in controls). This feasibility study demonstrated the potential of whole-heart three-dimensional magnetic resonance velocity mapping to reveal overt haemodynamic differences in surgically palliated congenital heart with similar extracardiac cavopulmonary connection geometry. Future studies are warranted to evaluate its diagnostic impact for improved evaluation of the pre- and postoperative status in the individual patient.

The effects of reboxetine on emotional processing in healthy volunteers: an fMRI study

Recent neuropsychological studies in healthy volunteers suggest that antidepressants enhance the processing of positive emotional information. However, the neural substrates underpinning these changes have not been fully elucidated. The current study, therefore, used functional magnetic resonance imaging (fMRI) to map brain systems activated during successful categorization and subsequent recognition of self-referent positive and negative personality characteristics in healthy volunteers following short-term (7 days) repeated administration of the selective noradrenergic reuptake inhibitor reboxetine. Twenty-four healthy volunteers were randomly assigned to 7-day double-blind intervention with reboxetine or placebo. On day 7, neural responses during the categorization and subsequent recognition of positive and negative characteristics were assessed using fMRI. Questionnaires monitoring mood, hostility and anxiety were given before and during this intervention. During categorization, reboxetine was associated with greater activation to positive words, relative to negative words, in left precuneus and right inferior frontal gyrus. By contrast, at subsequent recognition reboxetine was associated with reduced response to positive words, relative to negative words, in left precuneus, anterior cingulate and medial frontal gyrus. These changes in the neural processing of positive and negative words occurred in the absence of significant differences in ratings of mood and anxiety. Such adaptations in the neural processing of emotional information support the hypothesis that antidepressants have early effects on emotional processing in a manner which would be expected to reverse negative biases in depression.

Pharmacokinetic and pharmacodynamic characteristics in healthy volunteers of razaxaban, an orally-active, potent, selective inhibitor of factor XA

In this study, the PK characteristics and PD effects of razaxaban were evaluated after administration of single- (10–200 mg) and multiple-doses (25–100 mg either Q12h or Q24h during 5 days) in healthy subjects. Subjects were confined to a study unit where samples were obtained for determination of the razaxaban PK/PD profile. Study evaluations included adverse experiences monitoring, bleeding time (BT), Factor X deficiency (FXD), Factor Xa inhibition (FXI), and standard tests of antithrombotic activity. Razaxaban was well absorbed reaching maximal plasma concentrations between 1 and 6 h after oral administration. There were dose-related proportional increases in Cmax, AUC and AUCt. Steady state plasma concentrations were achieved within 3–4 days. Razaxaban administration was well tolerated with concentration and dose-related changes in markers of antithrombotic activity but without clinical significant changes in BT. The maximal percent changes in FXD and FXI were observed at the 200 mg Q24h dose (median of 96 and 93%, respectively), followed by the 100 mg Q12h dose (median 90 and 83%, respectively). At the highest levels of percent change in FXD and FXI no major bleeding was observed. These results indicate that once- or twice-daily oral administration of razaxaban are well tolerated producing predictable dose-related changes in antithrombotic markers and support further clinical studies to assess efficacy in patients at risk of venous and arterial thromboembolism. Clinical Pharmacology & Therapeutics (2004) 75, P6–P6; doi: 10.1016/j.clpt.2003.11.022

Specific Characteristics of Healthy Volunteers with Different Reactions to Psychological Stress

The authors studied the psychological, psychophysiological, and biochemical characteristics of healthy volunteers divided into stress-activated and stress-disorganized subjects on the basis of the quantification of operator activity results under conditions of modeled psychological stress. The initial values and dynamics of changes was specific to these groups, which proves the advisability of a comprehensive evaluation of an individual on the basis of the selected signs to predict productivity of operator activity under extreme conditions.

Pharmacokinetic Characteristics of Roxatidine

This article reviews the published and unpublished results of pharmacokinetic studies with roxatidine acetate in healthy volunteers of different ethnic origins, patients with various degrees of renal impairment, patients on maintenance hemodialysis, lactating women, and elderly patients. In addition, it reports on the findings of interaction studies with food and other drugs. The pharmacokinetic characteristics of roxatidine were found to be nearly identical for different doses, formulations, and ethnic groups. The decrease in relative total clearance (oral clearance) in patients with renal impairment and in the elderly can be explained almost completely by their level of renal function. As expected from the pharmacokinetic characteristics in healthy volunteers, only a small amount of roxatidine is removed by hemodialysis. Dose reduction is recommended in patients with renal impairment, but dose supplementation after hemodialysis is not necessary. Only a negligible fraction of the dose administered is excreted with breast milk. No pharmacokinetic interactions were found with theophylline, warfarin, propranolol, diazepam, and desmethyldiazepam, antipyrine or antacids. Food did not interfere with the absorption or disposition of roxatidine.