Differential effects of neuropathic analgesics on wind-up-like pain and somatosensory function in healthy volunteers

OBJECTIVES: To investigate the effects of gabapentin, carbamazepine, and amitriptyline on temporal summation, simple nociceptive pain, and innocuous touch sensation in healthy volunteers. METHODS: A placebo controlled four-way crossover double-blind randomized protocol was followed. Seventeen healthy subjects, male and female, aged 18 to 24, took part. Punctate pain, temporal summation pain to repeat punctate stimulation, and vibration detection threshold were assessed in triplicate. Study drugs were given as bedtime and early morning doses with assessments carried out midmorning. RESULTS: Gabapentin and carbamazepine significantly reduced the intensity of temporal summation pain (P < 0.001 and P < 0.01 respectively), whereas amitriptyline significantly increased temporal summation pain (P < 0.001). None of the drugs affected pain produced by a single punctate stimulus (P > 0.05). Carbamazepine increased vibration detection thresholds (P < 0.05), but neither gabapentin nor amitriptyline had any detectable effect on vibration. DISCUSSION: We have shown that gabapentin, carbamazepine, and amitriptyline, three pharmacologically different drugs, have distinct and quantifiable effects on somatosensory pathways in healthy volunteers. These findings provide a link between pharmacology of the study drugs and clinical effectiveness. The effects of gabapentin and carbamazepine on temporal summation pain show that these drugs can block centrally amplified wind-up pain in the absence of a neuropathic disorder.     

The analgesic effects of acupuncture on experimental pain threshold and somatosensory evoked potentials in healthy volunteers

Recently, the analgesic effects of acupuncture have been brought into question, mainly because of the methodological inadequacies of previous studies. This single-blind placebo-controlled study examined the effects of manual acupuncture administered at a point related to the site of electrically induced pain at the finger (i.e. Pericardium 6) and a point unrelated to the site of electrically induced pain (i.e. Gallbladder 20) in normal subjects. The effects of acupuncture on the amplitudes of the late waveform components of the somatosensory evoked potentials elicited by painful electrical stimulation of the index finger were also examined. The main findings of this study were that, when compared to sham acupuncture or control groups, acupuncture administered at either Pericardium 6 or Gallbladder 20 did not significantly change: (i) sensory detection threshold, pain threshold or pain tolerance to electrically induced pain administered to the index finger, and (ii) P₁N₁ or N₁P₂ amplitudes of late latency waveform components of the somatosensory evoked potentials elicited by a painful electrical stimulus delivered to the index finger. Although acupuncture appears to be successful in relieving the pain of many chronic pain sufferers, these findings substantiate recent meta-analyses which conclude that the analgesic effects of acupuncture under placebo-controlled conditions remain in doubt. Our results should serve as an incentive for further research into the analgesic effects of acupuncture under placebo-controlled conditions.     

Immune response to autologous transfusion in healthy volunteers: WB versus packed RBCs and FFP

BACKGROUND: Storage of blood as packed RBCs and FFP is standard practice in allogeneic transfusion. Separation into components has been proposed for autologous transfusion, as well, but beneficial effects have not yet been shown. STUDY DESIGN AND METHODS: Twenty-four healthy male volunteers were randomly assigned to receive 1 unit of either autologous RBCs and FFP (RCP group) or WB (WB group) after 49 or 35 days of storage, respectively. The immune response was analyzed by ELISA for IL-6, C3a, terminal complement complex SC5b-9, TNF-alpha, and neopterin. Differential WBC counts and the phagocytosis of neutrophils and monocytes were measured by flow cytometry. RESULTS: Cell counts of monocytes (0.85 x 10(3) ng/microL) [corrected] and neutrophils (6.9 x 10(3) ng/microL) [corrected] increased 30 minutes after WB transfusion and then returned to close to the baseline values seen in the RCP group (0.47 and 2.9 x 10(3) ng/microL [corrected], respectively) throughout the monitored period (p<0.05). C3a (169 vs. 116 ng/microL) [corrected] and IL-6 (29 vs. 6 pg/mL) reached higher plasma concentrations in the WB group (n = 11) than in the RCP group (n = 10). Phagocytosis of opsonized Escherichia coli was increased in neutrophils and monocytes and lasted up to 7 days after the transfusion of whole blood. CONCLUSION: Autologous WB induces a modest immunomodulation, but this effect is not observed upon transfusion of autologous blood components.     

健康志愿者肩关节肱二头肌长头肌腱位置、方向及形态学的MRI测量

背景：以往的研究中仅对肱二头肌长头肌腱在肱二头肌腱沟入口偏离度进行定性描述,未进行定量测量.目的：通过分析健康志愿者肩关节中立位、外旋位和内旋位MRI之轴位图像上肱二头肌长头肌腱位置、方向及形态学改变,探讨肱二头肌长头肌腱MRI形态学特征以利临床评价肱二头肌长头肌腱.方法：纳入35名无症状志愿者,在肩关节中立位、外旋位、内旋位进行MR扫描.2名评价者对MR图像进行评价,排除标准为具有肩袖、喙肱韧带、上盂肱韧带、滑车韧带病灶或退行性改变者.一名测量者在轴位3D WATSc序列的上、中、下3个测量层面上对肱二头肌长头肌腱位置、方向及形态进行测量.结果与结论：健康志愿者肩关节中立位、外旋位和内旋位MR轴位图像上肱二头肌长头肌腱改变结果：①肱二头肌长头肌腱位置：中立位肱二头肌长头肌腱在内外方向的偏离度最大.②肱二头肌长头肌腱方向：肱二头肌长头肌腱的方向角度均为锐角,在中、下测量层面上,肩关节3个体位的肱二头肌长头肌腱角度之间的差异具有显著性意义.③形态：在下测量层面上,肩关节3个体位肱二头肌长头肌腱形态的改变具有显著性意义.结果显示健康志愿者肱二头肌长头肌腱位置、方向、形态与肩关节旋转体位具有潜在关联.     

Measurement of left ventricular velocities: phase contrast MRI velocity mapping versus tissue-doppler-ultrasound in healthy volunteers.

The aim of this study was the comparison of phase contrast magnetic resonance imaging (PCMRI) measurements of left ventricular velocities in a physiological in vivo setting with tissue-Doppler-ultrasound (tissue Doppler imaging: TDI) data in healthy volunteers. Images were acquired in short axis view using a flow compensated black blood k-space segmented gradient echo sequence. Velocity encoding was performed by adding a bipolar gradient after each rf-pulse to the otherwise identical pulse sequences. Full in-plane velocity information of the moving heart was obtained in 16 heartbeats within one breath-hold measurement. Twenty-nine healthy volunteers (mean age=25 years) were examined with both imaging modalities. Both PCMRI and TDI demonstrate a biphasic profile of radial velocities over the cardiac cycle. Intraindividual comparison of left ventricular velocity data acquired using PCMRI and TDI show a very good correspondence with r-values of 0.97. The in vivo study in 29 healthy volunteers demonstrates a high validity of time-resolved phase contrast measurements for the analysis of left ventricular myocardial velocities.     

Reproducible activation in BA2, 1 and 3b associated with texture discrimination in healthy volunteers over time

We aimed to quantify specific location and reproducibility of brain activation associated with discrimination of a moving textured surface in adult healthy volunteers over a 6-month interval. A sensory stimulation device was developed to provide a texture stimulus to the fingertips at a controlled speed and pressure. Repeat measurements of regional cerebral blood flow, using positron emission tomography (PET), were obtained in 10 healthy individuals, aged 33 to 80 years (mean=55.8 years), at scanning sessions separated by 6 months. Stimulation and rest conditions were presented to either the right, dominant (n=5) or left non-dominant (n=5) hand. Activation location was objectively quantified with reference to probabilistic cytoarchitectonic maps. Differences in activation over time and regions of common activation were also quantified. Participants consistently activated Brodmann areas (BA) 2, 3b and 1, somatosensory areas of postcentral gyrus, at initial and 6-month studies: 93.1% of common activation for the right-hand (RH) and 60.6% for left-hand (LH) stimulation group were in these areas. Reproducible activation in BA6, 4a and 4p was also observed for the RH group (6.8% of common activation) and LH group (39.4%). There were no sites of significant difference over time for either hand. Highly consistent location of activation over time suggests that changes in loci of activation may be confidently monitored in adults using this paradigm. Use of probabilistic cytoarchitectonic maps permitted objective quantification of the anatomical location of the core of reproducible activation.     

Cross-over assessment of serum bactericidal activity of moxifloxacin and levofloxacin versus penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae in healthy volunteers

We compared the serum bactericidal activity (SBA) of moxifloxacin and levofloxacin against penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae in 12 healthy volunteers. Each subject received 3 days of oral moxifloxacin 400 mg daily and levofloxacin 750 mg daily, respectively, with a 2- to 4-week washout period between regimens. Blood was drawn at 6 time points after the third dose of each antibiotic. Mean serum bactericidal titers (MSBTRs) for moxifloxacin were 4-fold higher than the mean titers for levofloxacin at each time point. For each drug, MSBTRs at each time point were the same or within one 2-fold dilution when analyzed according to the penicillin susceptibility of the strains or the sex of the subjects. The difference in SBA of the 2 drugs may have implications for the emergence of resistance and clinical outcome.     

Pulse-wave morphology and pulse-wave velocity in healthy human volunteers: examination conditions

OBJECTIVE: Applanation tonometry for pulse-wave analysis (PWA) and determination of pulse-wave velocity (PWV) is a non-invasive method for assessment of the central aortic pressure waveform and indices of arterial stiffness. The objective of this study was to examine the influence of eating and smoking on PWA and PWV measurements in order to establish standard examination conditions. Furthermore, intra- and interobserver reproducibility and the effects of varying the site of measurements were observed. MATERIAL AND METHODS: Duplicate measurements of the radial pressure waveform and of the brachial and aortic PWV on the right and left side of the body were recorded in 23 healthy subjects by two trained observers. Measurements were performed in the fasting state and 3 h after a high-calorie meal, and before and 1 h after smoking a cigarette. RESULTS: Intake of a high-calorie meal as well as smoking caused significant changes in both PWA and PWV parameters and an inter-arm difference was observed. Intra- and interobserver reproducibility was good. CONCLUSIONS: Pulse-wave measurements by applanation tonometry should be undertaken in the same arm during fasting and smoking abstinence.     

Intranasal midazolam: pharmacokinetics and pharmacodynamics assessed by quantitative EEG in healthy volunteers

The pharmacokinetics and pharmacodynamics of a highly concentrated cyclodextrin-based intranasal (i.n.) midazolam formulation containing the absorption-enhancer chitosan were studied in 12 healthy volunteers and compared with intravenous (i.v.) midazolam. The pharmacodynamic (PD) effects were assessed using quantitative electroencephalography (EEG). Maximal plasma concentrations of 63 and 110 ng/ml were reached at 8.4 and 7.6 min after 3 and 6 mg i.n. midazolam, respectively. After 5 mg i.v. and 6 and 3 mg i.n. midazolam, the times to onset of significant EEG effects in the β2 band (18-25 Hz) were 1.2, 5.5, and 6.9 min, respectively, and the times to loss of response to auditory stimuli were 3.0, 8.0, and 15.0 min, respectively. A sigmoid maximum-effect (E(max)) model indicated disequilibrium between plasma and effect-site concentrations, with equilibration half-lives of 2.1-4.8 min. The observed pharmacokinetic-PD (PK-PD) properties suggest that i.n. midazolam deserves to be evaluated as an easy and noninvasive method of administering a first benzodiazepine dose, e.g., in out-of-hospital emergency settings with no immediate i.v. access.     

Indomethacin: effects on cold-induced pain and the nervous system in healthy volunteers

The sensitivity of the cold-induced pain (CP) model to the non-steroidal anti-inflammatory drug (NSAID) indomethacin was studied in healthy volunteers. Effects on the central nervous system were also sought.

Subjects received single oral doses of indomethacin 50 and 100 mg, dipipanone 8 mg and placebo, according to a double-blind, randomised, balanced, cross-over design with an interval of 7 days between occasions. A test battery was performed before each treatment and then at 45, 105 and 165 min post treatment.

Pain scores were unaltered by indomethacin at either dose, but the drug certainly affected the CNS, increasing respiratory drive and changing self-assessed mood.

It is concluded that the CP model is insensitive to indomethacin, even in doses which have clear-cut CNS effects. The respiratory stimulant action of indomethacin may deserve further study.     

A new esomeprazole packet (sachet) formulation for suspension: in vitro characteristics and comparative pharmacokinetics versus intact capsules/tablets in healthy volunteers

BACKGROUND: A packet (sachet) formulation of esomeprazole for suspension has been developed for use in patients who have difficulty swallowing. OBJECTIVES: This article reports the in vitro characteristics of the new esomeprazole formulation, including stability in suspension and suitability for administration orally or via enteral tubes. It also describes the pharmacokinetic profile of the esomeprazole 40-mg packet compared with that of existing solid dosage forms (capsules and tablets) in a clinical bioequivalence study. METHODS: The stability in suspension of the packet formulation was assessed after reconstitution at various strengths (2.5, 10, and 40 mg) and a different pH (3.4-5.0) in strength-appropriate volumes of water held at temperatures ranging from 5 degrees C to 37 degrees C for up to 60 minutes. Suitability for oral administration was examined in terms of reconstitution time and the actual dose delivered after simulated oral administration, as well as in terms of the actual dose delivered by enteral tubes ranging in diameter from 6 to 20 Fr. Chemical stability and suspension characteristics were also analyzed using alternative reconstitution vehicles (applesauce, apple juice, and orange juice). The comparative pharmacokinetics of the packet, capsule, and tablet formulations of esomeprazole were evaluated in a randomized, open-label, 3-way crossover study in healthy volunteers, who received single 40-mg doses of each formulation. Bioequivalence was assumed if the 90% CIs for the ratios of the geometric mean AUC and CmaX were between 0.80 and 1.25. Reversephase liquid chromatography with ultraviolet detection was used to assess the esomeprazole content and/or degradation products of esomeprazole in the tests for in-suspension stability, dose delivery, and acid resistance. Normal-phase liquid chromatography was used to assess the esomeprazole content of the plasma samples in the bioequivalence study. RESULTS: At the pH and temperature ranges investigated, the packet formulation was stable for up to 60 minutes after reconstitution. Chemical degradation was low (<0.1%) for all reconstitution vehicles investigated. Reconstitution time was 2 minutes with water and 9 to 10 minutes with apple or orange juice. Dose delivery was >/=98% after simulated oral administration and was generally >/=96% after administration via enteral tubes. Ninety-six healthy volunteers (56 women, 40 men; mean age, 24.9 years; mean weight, 68.9 kg) participated in the randomized, crossover, comparative pharmacokinetic study of the packet and capsule/tablet formulations. The estimated ratios of the geometric mean AUC and C(max) for the packet:capsule and packet: tablet formulations were 0.98 (90% CI, 0.93-1.03) and 0.99 (90% CI, 0.94-1.04), respectively. CONCLUSIONS: In these analyses, the packet (sachet) formulation of esomeprazole was chemically stable in suspension and when administered orally and via enteral tubes. The formulation had a short reconstitution time, remaining fully dispersed in water for at least 30 minutes, and was dispersed in applesauce, apple juice, or orange juice without compromising its stability or dispersion characteristics. The packet formulation met the regulatory definition for bioequivalence to the tablet and capsule formulations.     

Haemodynamic effects of hyperbaric hyperoxia in healthy volunteers: an echocardiographic and Doppler study

In the present study, we observed the haemodynamic changes, using echocardiography and Doppler, in ten healthy volunteers during 6 h of compression in a hyperbaric chamber with a protocol designed to reproduce the conditions as near as possible to a real dive. Ambient pressure varied from 1.6 to 3 atm (1 atm=101.325 kPa) and partial pressure of inspired O2 from 1.2 to 2.8 atm. Subjects performed periods of exercise with breathing through a closed-circuit self-contained underwater breathing apparatus (SCUBA). Subjects did not eat or drink during the study. Examinations were performed after 15 min and 5 h. After 15 min, stroke volume (SV), left atrial (LA) diameter and left ventricular (LV) end-diastolic diameter (LVEDD) decreased. Heart rate (HR) and cardiac output (CO) did not vary, but indices of the LV systolic performance decreased by 10% and the LV meridional wall stress increased by 17%. After 5 h, although weight decreased, the serum protein concentration increased. Compared with values obtained after 15 min, SV and CO decreased, but LV systolic performance, LA diameter, LVEDD and LV meridional wall stress remained unchanged. Compared with the reference values obtained at sea level, total arterial compliance decreased, HR remained unchanged and CO decreased. In conclusion, hyperbaric hyperoxia results in significant haemodynamic changes. Initially, hyperoxia and the SCUBA system are responsible for reducing LV preload, increasing LV afterload and decreasing LV systolic performance, although CO did not change. Prolonged exposure resulted in a further decrease in LV preload, because of dehydration, and in a further increase in LV afterload, due to systemic vasoconstriction, with the consequence of decreasing CO.     

Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo

OBJECTIVE: This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects. RESEARCH DESIGN AND METHODS: Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose. RESULTS: Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 microU x ml(-1) x min(-1), respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose. CONCLUSIONS: In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia.     

The pharmacokinetics of fluconazole in healthy Chinese adult volunteers: influence of ethnicity and gender

Objective: The purpose of the present study was to investigate and compare the influence of ethnicity (including Han, Mongolian, Korean, Hui and Uygur) and gender on the pharmacokinetics of fluconazole in healthy adult volunteers after administration of 200‐mg fluconazole tablet. Methods: Ten healthy subjects (five males and five females) of each ethnicity were recruited and given a single 200‐mg dose of fluconazole in tablet form. Blood samples were obtained before dosing and at various predetermined time points after administration up to 96 h. Drug levels were measured by high‐performance liquid chromatography. The blood concentration–time profiles were analyzed using a non‐compartmental approach to estimate the absorption parameters (AUC_(0–96), C_max and t_max), the distribution parameter (V_d) and the disposition parameters (t_1/2 and CL). Results: Ethnicity did not affect the parameter estimates, but gender did. However, the gender differences in pharmacokinetic parameter could be accounted for by differences in weight. There was a high linear correlation between weight and ln C_max, ln AUC (ln means natural logarithmic transformation), V_d and CL. Conclusions: Ethnicity (Chinese Han, Mongolian, Korean, Hui and Uygur) influences the pharmacokinetics of fluconazole tablet. However, there were statistically significant gender differences in AUC, C_max, V_d and CL. But these could be accounted for by weight differences. If fluconazole dose‐adjustment is deemed necessary, this can be done on a weight basis rather than gender basis.     

Pharmacokinetic interaction between fluoxetine and omeprazole in healthy male volunteers: a prospective pilot study

Background: Fluoxetine is an inhibitor of the main metabolizing enzymes (cytochrome P450 [CYP] 2C19 and CYP3A4) of omeprazole and thus might influence that drug''s pharmacokinetics. The changes in omeprazole''s pharmacokinetics may have clinical significance concerning efficacy and tolerability of the treatment.Objective: The aim of this study was to assess the pharmacokinetic interaction of fluoxetine with omeprazole in healthy volunteers.Methods: The study enrolled healthy adult men and consisted of 2 periods. In the first period, all subjects received a single 40-mg dose of omeprazole. This was followed by an 8-day period during which fluoxetine monotherapy (60 mg/d) was administered as a single oral daily dose. At the end of those 8 days, the subjects were administered a 40-mg dose of omeprazole with a 60-mg dose of fluoxetine. Plasma concentrations of omeprazole were determined at 0.5, 1, 1.33, 1.66, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 12 hour(s) after study drug administration. Omeprazole plasma concentrations were determined by a validated HPLC method. Pharmacokinetic parameters of omep-razole were calculated using noncompartmental analysis. Adverse events were assessed throughout the study duration.Results: Eighteen healthy male volunteers (mean [SD] age, 22.11 [2.52] years [range, 18–26 years]; body mass index, 23.34 [2.31] kg/m² [range, 19.1–27.1 kg/m²]) were enrolled and completed the study. In the 2 periods of treatment, the mean Cmax of omeprazole was 730.8 ng/mL (omeprazole monotherapy) and 1725.5 ng/mL (combination treatment with fluoxetine). The observed AUC0−∞ was 1453.3 and 5072.5 ng/mL/h and AUC_0−t was 1465.0 and 5185.3 ng/mL/h, respectively. The T_max was 1.30 and 1.63 hours and the elimination rate constant was 0.753 and 0.482 hr⁻¹. The t½ was 0.96 and 1.47 hours, whereas the mean residence time was 2.33 and 3.35 hours, respectively. Statistically significant differences were observed for all parameters between periods 1 and 2 (all, P < 0.001).Conclusion: The data found in this prospective pilot study suggest a pharmacokinetic interaction between fluoxetine and omeprazole in these healthy volunteers, but its relevance has to be confirmed.Key words: omeprazole, fluoxetine, pharmacokinetics, drug interaction     

Tolerability and safety profile of posaconazole: evaluation of 18 controlled studies in healthy volunteers

Background and objectives: Antifungal agent utility can be limited by safety and tolerability concerns. Posaconazole is an extended‐spectrum triazole antifungal agent for the treatment and prophylaxis of invasive fungal infection. The aim was to analyse the overall safety profile of posaconazole in healthy volunteers. Methods: Safety data from all 18 clinical pharmacology single‐ and multiple‐dose trials of posaconazole conducted in healthy volunteers plus 2 additional healthy subsets from other pharmacology trials were pooled and analysed. Four hundred and forty‐nine healthy volunteers (354 men; 95 women) were enrolled. Three hundred and twenty‐seven were white, and the mean age and weight of subjects were similar across all dosing groups. The population evaluated had no confounding factors of underlying disease or concomitant medications. Safety evaluations included spontaneously reported adverse events, clinical laboratory test results, electrocardiograms and vital sign measurements. Results: A total of 448 subjects received posaconazole, 50–1200 mg/day administered as single or multiple doses for up to 14 days. Two hundred and seventeen subjects received ≥800 mg/day posaconazole, and 188 subjects received multiple doses of posaconazole at 800 mg/day. Two hundred and thirty‐one subjects received <800 mg/day. Forty‐eight subjects from three studies received placebo. The incidence of treatment‐emergent adverse events reported with posaconazole was similar to that seen with placebo (57% vs. 63% respectively) and unrelated to dose. The most common treatment‐related adverse events (posaconazole vs. placebo) were headache (17% vs. 13%), dry mouth (9% vs. 0%) and dizziness (6% vs. 2%). No clinically significant changes in vital signs or laboratory test parameters were observed, except for transient, mild to moderate elevations in liver function test results. Posaconazole also demonstrated minimal potential to prolong corrected QT interval. Conclusions: The safety profile analysis found posaconazole to be well tolerated, and results were similar across sex, age and race.     

Source localization of sensory gating: a combined EEG and fMRI study in healthy volunteers

Reduced sensory gating appears to be among the core features in schizophrenia. The sources of sensory gating however are largely unknown. The aim of the current study was to identify these sources, with concurrent EEG and fMRI methodology. Twenty healthy male volunteers were tested with identical P50 suppression paradigms in two separate sessions: an EEG setting, and an EEG concurrent with fMRI setting. The stimuli in the P50 paradigm consisted of weak electrical stimulation of the left median nerve. The stimuli were presented in pairs with either 500 ms or 1000 ms interstimulus intervals (ISI). No difference was found between the EEG setting and the concurrent EEG and fMRI setting. P50 suppression was, in both settings, found only in the 500 ms trials, not in the 1000 ms trials. EEG-dipole modeling resulted in 4 sources located in the medial frontal gyrus, the insula, the hippocampus, and primary somatosensory cortex. These sources corresponded to significant fMRI clusters located in the medial frontal gyrus, the insula, the claustrum, and the hippocampus. Activity in the hippocampus and the claustrum was higher in the trials with suppression, suggesting that these brain areas are involved in the inhibitory processes of P50 suppression. The opposite was found for activity in the medial frontal gyrus and the insula, suggesting that these brain areas are involved in the generation of the P50 amplitude. To our knowledge, this is the first study demonstrating that P50 suppression can be reliably assessed inside an MRI scanner.     

Selecting healthy volunteers in specific populations: a retrospective analysis of clinical and laboratory screening

Healthy volunteers must undergo a medical examination before enrolment in a clinical trial. An increasing number of trials include specific populations designed to match the target populations of the drugs tested. Our study aimed at evaluating which investigations are the most appropriate in different sub-populations of healthy volunteers. Data from 350 healthy volunteers who attended our Research Center from 1997 to 2004 were retrospectively analysed. Volunteers were distributed into five sub-populations: young men, senior men, overweight men, young women, postmenopausal women. The screening procedure comprised a review of medical history, physical examination, electrocardiogram and laboratory tests. Ineligibility criteria were classified as non-medical causes, protocol specific medical causes and non-specific medical causes. A total of 148 subjects (42%) were not-eligible, mainly because of non-specific medical causes (111 subjects), including abnormal medical history (34.5% of all ineligibilities). Blood pressure abnormalities were frequent in all sub-populations except young women. Electrocardiographic abnormalities led to ineligibility of only five overweight men and one menopausal woman. Abnormal laboratory tests accounted for 19.6% of ineligibilities. In senior subjects and overweight men, serologies, liver function tests and lipid profile contributed importantly to the selection process. Low red cells count was the most frequent laboratory abnormality in young women. Erythrocyte sedimentation rate, phosphocalcic metabolism and standard clotting tests led to frequent insignificant and non-contributive abnormalities. Our study confirms that a complete review of medical history is essential and determines the major part of ineligibilities. Complementary laboratory tests are always needed and may be adjusted to the population considered.